Graphical Abstract
Keywords: ART, dopamine, neuroinflammation, substance use disorder, NeuroHIV
Introduction
While the development of antiretroviral therapy (ART) has significantly changed the nature of HIV disease, it remains a major public health issue, affecting more than 37 million people worldwide (Lucas and Nelson 2015, Sanchez and Kaul 2017). The effectiveness of ART has transformed HIV from a terminal to a chronic illness. In the current era, people living with HIV (PLWH) have longer lifespans and often healthier outcomes than in previous decades (Cihlar and Fordyce 2016, Saylor, Dickens et al. 2016, Eggers, Arendt et al. 2017, Boender, Smit et al. 2018). However, ART can only inhibit viral replication but does not eliminate the virus. While ART ameliorates many of the sequelae that result from HIV, it does not cure the disease (Cihlar and Fordyce 2016, Ulfhammer, Eden et al. 2018). The resulting chronic infection, as well as long term ART treatment, has engendered a variety of new health issues, including many associated with HIV infection of the central nervous system (CNS) (Grabar, Weiss et al. 2006, Heaton, Clifford et al. 2010, Treisman and Soudry 2016).
Infection of the CNS occurs within days after peripheral infection (Davis, Hjelle et al. 1992, Valcour, Chalermchai et al. 2012), and can result in the development of several distinct neuropathologies, as well as HIV-associated neurocognitive disorders (HAND). Globally, the prevalence of HAND ranges from 15 – 70% of PLWH despite ART, with a higher prevalence more common in resource poor areas (Heaton, Clifford et al. 2010, Heaton, Franklin et al. 2015, Saylor, Dickens et al. 2016, Saloner and Cysique 2017, Yusuf, Hassan et al. 2017, Gascon, Vidal et al. 2018, Debalkie Animut, Sorrie et al. 2019). Many studies have shown that these neurologic sequelae, collectively known as neuroHIV, are altered by substance abuse (Arnsten, Demas et al. 2002, Martin, Pitrak et al. 2003, Lucas, Griswold et al. 2006, Baum, Rafie et al. 2009, Byrd, Fellows et al. 2011, Devlin, Gongvatana et al. 2012, Meyer, Rubin et al. 2013, Chang, Connaghan et al. 2014, Small, Milloy et al. 2016). However, the impact of distinct substances of abuse on the development of neuroHIV remains unclear, or in some cases controversial (Ferris, Mactutus et al. 2008, Byrd, Fellows et al. 2011, Chang, Connaghan et al. 2014).
While different classes of drugs have distinct mechanisms of action, all addictive substances acutely increase CNS dopamine concentrations in the mesocorticolimbic pathway (Di Chiara and Imperato 1988, Carboni, Imperato et al. 1989, Pierce and Kumaresan 2006, Kleijn, Folgering et al. 2011, Clarke, Adermark et al. 2014). This suggests that elevated CNS dopamine may be a common mechanism by which different types of drugs impact the development of neuroHIV. These effects may be most pronounced during early acute and/or intermittent use of substances of abuse, as chronic drug abuse downregulates dopamine release (Volkow, Wang et al. 1996, Volkow, Wise et al. 2017). Changes in dopamine-rich brain regions have long been associated with HIV infection within the CNS, and although these effects are often subtler in the ART era, they still persist (Larsson, Hagberg et al. 1991, Aylward, Henderer et al. 1993, Hestad, McArthur et al. 1993, Wiley, Soontornniyomkij et al. 1998, Berger and Arendt 2000, Bell, Anthony et al. 2006, Gelman, Spencer et al. 2006, Scheller, Arendt et al. 2010, Becker, Sanders et al. 2011, Kumar, Ownby et al. 2011, Wright, Pyakurel et al. 2016, Deren, Cortes et al. 2019). Defining more precisely the dopamine-associated impact of both legal and illicit drugs on the development of HIV associated comorbidities is a critical need, as the number of HIV-infected individuals with substance use disorder (SUD) continues to increase, particularly among older individuals, the fastest growing segment of the infected population (Grabar, Weiss et al. 2006, Han, Gfroerer et al. 2009, Kirk and Goetz 2009, Skalski, Sikkema et al. 2013, Deren, Cortes et al. 2019). Additionally, the specific interactions between SUD and ART, and the pathological consequences of those interactions, must also be addressed and understanding the interplay between ART and substances of abuse will be essential to improving HIV treatment in vulnerable populations. However, the study of HIV infection in the presence of a disrupted dopaminergic system is complex and technically challenging, and examining this interplay effectively will require refinements or even shifts in hypotheses, approaches, and technique. In this review, we will address these issues by briefly describing what is known about the impact of dopamine on the development of CNS infection and neuropathogenesis, examining experimental approaches, and then discussing treatment strategies that may decrease the incidence and/or severity of neuroHIV in PLWH with SUD.
Neuropathogenesis of HIV in the era of ART
Infection of the CNS occurs within 1 – 2 weeks of peripheral infection (Davis, Hjelle et al. 1992, Valcour, Chalermchai et al. 2012), primarily through the transmigration of infected mature CD14+CD16+ monocytes across the blood brain barrier (BBB) (Crowe, Zhu et al. 2003, Williams, Calderon et al. 2013, Williams, Veenstra et al. 2014). Within the brain, both infected monocytes and the monocyte-derived macrophages into which they can mature produce HIV and inflammatory mediators, infecting and activating CNS myeloid cells, including microglia and perivascular macrophages (Koenig, Gendelman et al. 1986, Minagar, Shapshak et al. 2002, Rappaport and Volsky 2015). These cells are the primary targets of HIV in the CNS, and their infection is significant to the development of neuroHIV, as well as to the establishment and maintenance of viral reservoirs in the brain (Yadav and Collman 2009, Churchill and Nath 2013, Honeycutt, Wahl et al. 2016, Castellano, Prevedel et al. 2017, Honeycutt, Thayer et al. 2017, Abreu, Veenhuis et al. 2019).
Both infected and activated myeloid cells produce inflammatory cytokines and chemokines, such as TNF-α, IL-6, IL-1β, CCL2, CXCL10 and CXCL12 (Laskin and Pendino 1995, Brabers and Nottet 2006, Arango Duque and Descoteaux 2014). This leads to recruitment and activation of additional myeloid populations, as well as other immune cells, and to BBB damage, resulting in chronic neuroinflammation (Minagar, Shapshak et al. 2002, Eugenin, Osiecki et al. 2006, Kraft-Terry, Buch et al. 2009, Saylor, Dickens et al. 2016). These cells may also release neurotoxic viral proteins, such as Tat or gp120, that exacerbate the neurotoxic environment (Sanchez and Kaul 2017). In addition, a number of studies suggest that HIV also infects astrocytes at low levels (Eugenin and Berman 2007, Churchill, Wesselingh et al. 2009, Eugenin, Clements et al. 2011), suggesting these cells may also act as a viral reservoir and contribute to neuroinflammation and CNS damage. Astrocytes are the most numerous glial cells in the CNS and modulate immune function and maintain neuronal health (Bylicky, Mueller et al. 2018). Therefore, any HIV-associated changes in astrocyte function would be important to HIV neuropathogenesis, although characterization of their specific impact is not clear and requires further study.
Prior to the introduction of ART in 1996, infection of the CNS led to a variety of neuropathologies including meningitis, microglial nodules, white matter lesions, multinucleated giant cells, myelin loss, HIV encephalitis, reactive astrogliosis, regional atrophy and significant neuronal injury and death (Navia, Cho et al. 1986, Kure, Llena et al. 1991, Hestad, McArthur et al. 1993, Everall, Hansen et al. 2005, Anthony and Bell 2008). These effects, which were found in approximately 50% of infected individuals, resulted in many symptoms of subcortical dementia, including cognitive decline, decreased mental processing and executive function, apathy, and sometimes Parkinsonian-like symptoms (Dube, Benton et al. 2005, Everall, Hansen et al. 2005, Heaton, Franklin et al. 2011). Although the percentage of PLWH who present with neurocognitive symptoms is similar with or without ART, the severity of the neurocognitive impairment is most often diminished with treatment (Bell 2004, Cysique and Brew 2009, Saylor, Dickens et al. 2016, Walker and Brown 2018). Prior to ART, extensive neurocognitive impairment was relatively common, with HIV-associated dementia (HAD) found in 15 – 20% of infected individuals. In the current era, HAD is found in fewer than 2% of PLWH (Heaton, Clifford et al. 2010, Heaton, Franklin et al. 2011, Saylor, Dickens et al. 2016).
The use of ART has also significantly increased lifespans and quality of life of PLWH (Cihlar and Fordyce 2016, Boender, Smit et al. 2018). Unfortunately, PLWH who use ART often still experience a variety of behavioral and cognitive symptoms, as well as substantial neuropathology, and the prevalence of mild and asymptomatic forms of neurocognitive impairment have increased (Valcour, Shikuma et al. 2004, Heaton, Clifford et al. 2010, Becker, Sanders et al. 2011, Heaton, Franklin et al. 2011, Saylor, Dickens et al. 2016). While ART-treated individuals have decreased neuronal death as compared to PLWH in the pre-ART era, neuronal dysfunction is still common in these individuals (Bell 2004, Everall, Hansen et al. 2005, Cysique and Brew 2009, Heaton, Franklin et al. 2011, Clifford, Samboju et al. 2017, Walker and Brown 2018). A number of recent studies also suggest that neuroHIV involves the disruption of neurocircuitry, with significant alterations in the strength and efficacy of connections, particularly in resting state functional connectivity. These effects are present irrespective of ART, and many are seen in the frontostriatal pathway, which also mediates the effects of dopamine (Itoh, Mehraein et al. 2000, Koutsilieri, ter Meulen et al. 2001, Gelman, Spencer et al. 2006, Becker, Sanders et al. 2011, Gongvatana, Harezlak et al. 2013, Ann, Jun et al. 2016, Bak, Jun et al. 2018, Walker and Brown 2018).
All of these symptoms often overlap with or exacerbate the age-related neurological co-morbidities that are increasingly prevalent in the aging, HIV-infected population in the ART era (Manfredi 2002, Grabar, Weiss et al. 2006, Valcour, Paul et al. 2011, Watkins and Treisman 2012, Clifford, Samboju et al. 2017). In the US, approximately 18% of individuals newly diagnosed with HIV are over 50 (Deren, Cortes et al. 2019), with these people exhibiting more advanced disease (Grabar, Weiss et al. 2006, Kirk and Goetz 2009). Older PLWH are also more frequently diagnosed with SUD than non-infected individuals of the same age, potentially exacerbating the development of neuroHIV through changes in the dopaminergic system (Byrd, Fellows et al. 2011, Lyons, Pitts et al. 2013, Skalski, Sikkema et al. 2013, Deren, Cortes et al. 2019, Matt and Gaskill 2019). Substance abuse may have a more extensive impact on older PLWH, as several studies show older individuals who use methamphetamine have greater impairment in more cognitive domains than non-users (Iudicello, Morgan et al. 2014, Montoya, Cattie et al. 2016, Minassian, Henry et al. 2017). Substance use disorders can also interfere with effective treatment, disrupting scheduled care and adherence to ART, and may interfere with the action of some antiretroviral medications (Becker, Thames et al. 2011, Anderson, Higgins et al. 2015, Azar, Wood et al. 2015, De Boni, Shepherd et al. 2016). These issues are further compounded by pill burden and polypharmacy, which are common in older adults, increasing medication errors, drug-drug interactions, or toxicity (Edelman, Gordon et al. 2013, Deren, Cortes et al. 2019). Thus, characterizing the specific impact of dopamine on the etiology of neuroHIV is essential to identifying and developing adjunctive therapies for PLWH with SUD, especially considering the number of older individuals in this group.
How the dopaminergic system is disrupted during HIV infection
Dopaminergic dysfunction has been associated with the development of CNS infection since early in the epidemic, and dopamine-rich brain regions appear to be particularly vulnerable to the effects of HIV (Navia, Cho et al. 1986, Kure, Llena et al. 1991, Larsson, Hagberg et al. 1991, Reyes, Faraldi et al. 1991, Aylward, Henderer et al. 1993, Hestad, McArthur et al. 1993, Fujimura, Goodkin et al. 1997, Wiley, Soontornniyomkij et al. 1998, Itoh, Mehraein et al. 2000, Valcour, Sithinamsuwan et al. 2011). Prior to ART, neuropathology was prominent in these regions, including the striatum, the substantia nigra and the prefrontal cortex (Reyes, Faraldi et al. 1991, Aylward, Henderer et al. 1993, Hestad, McArthur et al. 1993, Wiley, Soontornniyomkij et al. 1998, Itoh, Mehraein et al. 2000). These areas contained higher numbers of both infected cells and HIV RNA (Fujimura, Goodkin et al. 1997, Wiley, Soontornniyomkij et al. 1998), and exhibited the greatest amount of neuroinflammation (Navia, Cho et al. 1986, Kure, Llena et al. 1991). Individuals infected with HIV also showed aberrant dopamine metabolism in the cerebral spinal fluid (CSF) (Larsson, Hagberg et al. 1991, Kumar, Ownby et al. 2011), and HIV infection was shown to increase CSF dopamine in ART-naïve individuals (Scheller, Arendt et al. 2010). These data suggest that dopamine is involved in HIV neuropathogenesis, a hypothesis corroborated in studies of SIV infected macaques with pharmacologically elevated dopamine levels, as these animals showed both increased CNS viral load and neuropathology (Czub, Koutsilieri et al. 2001, Czub, Czub et al. 2004).
While ART has diminished HIV neuropathology in dopaminergic regions, PLWH on ART still show substantial damage in these areas (Valcour, Sithinamsuwan et al. 2011). These effects include striatal dysfunction (du Plessis, Vink et al. 2015, Ipser, Brown et al. 2015), increased microglial activation and inflammation (Tavazzi, Morrison et al. 2014, Vera, Guo et al. 2016), and neuronal damage (Gongvatana, Harezlak et al. 2013) associated with neuroinflammation. This suggests that even in individuals on ART, these CNS areas are still vulnerable (Becker, Sanders et al. 2011, Alakkas, Ellis et al. 2019, Popov, Molsberry et al. 2019). Substance abuse, which increases CNS dopamine, is associated with increased neurocognitive decline in PLWH in the ART era (Poundstone, Chaisson et al. 2001, Martin, Pitrak et al. 2003, Rippeth, Heaton et al. 2004, Ferris, Mactutus et al. 2008, Baum, Rafie et al. 2009, Meade, Conn et al. 2011, Meade, Lowen et al. 2011, Devlin, Gongvatana et al. 2012, Blackstone, Iudicello et al. 2013, Meyer, Rubin et al. 2013, Chang, Connaghan et al. 2014, Meyer, Little et al. 2014, Meade, Towe et al. 2015), suggesting that dopamine plays an important role in the development of CNS disease when viremia is significantly reduced by ART for extended time periods.
All substances of abuse, despite distinct mechanisms of action, can either directly or indirectly increase CNS dopamine (Di Chiara and Imperato 1988, Carboni, Imperato et al. 1989, Pierce and Kumaresan 2006, Kleijn, Folgering et al. 2011, Clarke, Adermark et al. 2014). The largest effects on CNS dopamine are induced by the use of stimulants, such as cocaine or methamphetamine, that act directly on the dopamine transporter to either block dopamine reuptake, as with cocaine (Jones, Garris et al. 1995), or reverse the direction of the transporter to release more dopamine, as for amphetamines (Cruickshank and Dyer 2009). Both of these drugs have deleterious effects on the CNS (Ferris, Mactutus et al. 2008, Krasnova and Cadet 2009, Kousik, Napier et al. 2012), compromising the BBB (Mahajan, Aalinkeel et al. 2008, Buch, Yao et al. 2012, Kousik, Napier et al. 2012), increasing oxidative stress (Dietrich, Mangeol et al. 2005, Ferris, Mactutus et al. 2008, Krasnova and Cadet 2009, Melo, Zanon-Moreno et al. 2010), and altering dopaminergic neurotransmission (Seiden, Fischman et al. 1976, Wu, Reith et al. 2001, Ferris, Mactutus et al. 2008). Many of these effects are similar to those associated with HIV infection in the CNS, suggesting that drug abuse and HIV infection may amplify the effects of the other, leading to increased cognitive decline in HIV infected people with SUD compared to infected non-drug users or uninfected individuals with SUD.
A large number of studies demonstrate the additive or synergistic impact of stimulants and HIV in both in vitro and in rodent systems (Turchan, Anderson et al. 2001, Nath, Hauser et al. 2002, Aksenov, Aksenova et al. 2006, Griffin, Middaugh et al. 2007, Cotto, Natarajaseenivasan et al. 2018). However, there are also studies showing that stimulants and HIV do not interact (Durvasula, Myers et al. 2000, Byrd, Fellows et al. 2011, Weed, Adams et al. 2012, Levine, Reynolds et al. 2014, Meade, Towe et al. 2015, Minassian, Henry et al. 2017), making it difficult to determine the precise impact stimulants have on HIV neuropathogenesis. This controversy is compounded by an inability to separate the effects of direct stimulant exposure from those of dopamine release induced by stimulant use. Human studies, particularly those designed to characterize molecular mechanisms by which drug-HIV interactions may occur, are needed to address these questions, but these are technically and logistically limited (Ferris, Mactutus et al. 2008, Nightingale, Winston et al. 2014, Norman and Basso 2015). Improving the integration of in vitro experiments with animal models and human studies in a clinically relevant manner is one of the primary challenges facing this field in the future.
In addition to an increased risk of SUD, individuals infected with HIV, particularly those over 50, also show an increased risk for depression, anxiety, and Parkinsonian disorders (Bing, Burnam et al. 2001, Watkins and Treisman 2012, Munjal, Ferrando et al. 2017, Matt and Gaskill 2019). This is important because these and many other age-related disorders are often treated with therapies that affect the dopaminergic system (D’Aquila, Collu et al. 2000, Manfredi 2002, Matt and Gaskill 2019). Reuptake inhibitors such as Fluoxetine (Prozac), Bupropion (Wellbutrin) or Venlafaxine (Effexor) increase extracellular dopamine (Stahl 1998, D’Aquila, Collu et al. 2000), while other medications such as Selegiline (Emsam), Aripiprazole (Abilify) or Pramipexole (Mirapex) either reduce dopamine breakdown (Stahl 1998) or directly activate dopamine receptors (Stahl 1998, D’Aquila, Collu et al. 2000). The impact of these medications on extracellular dopamine is very similar to that produced by stimulants (Matt and Gaskill 2019), so the effects of these types of drugs should also be considered and studied when examining how changes in dopamine can impact neuroHIV.
Another consideration is the impact of ART on dopamine neurotransmission. While there is currently very little information on this topic, the research that has been performed does indicate that some ART drugs impact the dopaminergic system (Matt and Gaskill 2019). Efavirenz, a non-nucleoside reverse transcriptase inhibitor that can induce neuropsychiatric complications (Silveira, Guttier et al. 2012, Mollan, Smurzynski et al. 2014), can interfere with the dopamine transporter (Gatch, Kozlenkov et al. 2013) or monoamine oxidase (Dalwadi, Kim et al. 2016, Akang 2019), and has been shown to both increase and decrease striatal dopamine in rodents, depending on the dose (Cavalcante, Chaves Filho et al. 2017). Zidovudine, a nucleoside analogue reverse transcriptase inhibitor, can interfere with the activity of D1-like receptors (Venerosi, Valanzano et al. 2005), and the antiretroviral protease inhibitor Lopinavir interferes with dopamine uptake by inhibiting plasma membrane monoamine transporters (Duan, Hu et al. 2015). These studies suggest that antiretrovirals may impact the dopaminergic system and could amplify or interfere with the effects of dopamine-inducing drugs and therapies, making it critical to expand our understanding of these interactions to treat HIV and its consequences more efficiently.
Effects of disrupted dopaminergic system on CNS immune cells
The primary targets for HIV infection in the CNS are myeloid cells, including microglia, perivascular macrophages and monocytes (Koenig, Gendelman et al. 1986, Minagar, Shapshak et al. 2002, Crowe, Zhu et al. 2003, Rappaport and Volsky 2015), although T-cells may also play a role in some circumstances (Marcondes, Burudi et al. 2001, Anthony, Crawford et al. 2003, Petito, Adkins et al. 2003, Nguyen, Soukup et al. 2010, Gaskill, Calderon et al. 2013). These cell types express all subtypes of dopamine receptors, the D1-like receptors, D1 and D5, and the D2-like receptors, D2, D3 and D4. Both myeloid cells and T-cells also express a number of other dopamine related proteins including the dopamine transporter, tyrosine hydroxylase, and monoamine oxidases (Levite, Chowers et al. 2001, McKenna, McLaughlin et al. 2002, Gaskill, Calderon et al. 2009, Gaskill, Carvallo et al. 2012, Coley, Calderon et al. 2015, Levite 2016, Nolan and Gaskill 2018, Matt and Gaskill 2019). Canonically, dopamine acts through the two subtypes of dopamine receptors by inducing opposing effects on cyclic AMP (Bacic 1991, Beaulieu and Gainetdinov 2011), but the signaling pathways and overall effects of dopamine on immune function are not well understood, particularly in myeloid cells. Recent data suggest that activation of dopamine receptors in human macrophages could act through a non-canonical pathway to regulate cell functions through changes in calcium release (Nickoloff, Mackie et al. 2019), but this area is still relatively undefined.
Dopamine has significant immunomodulatory effects in both myeloid cells and T-cells, regulating their activation, production of cytokines, chemokines and nitric oxide, chemotaxis and transmigration, and phagocytosis (Basu and Dasgupta 2000, Farber, Pannasch et al. 2005, Sarkar, Basu et al. 2010, Gaskill, Carvallo et al. 2012, Coley, Calderon et al. 2015, Yan, Jiang et al. 2015, Levite 2016, Calderon, Williams et al. 2017, Nolan and Gaskill 2018, Nolan, Muir et al. 2019). Many of these effects could specifically impact the development of neuroHIV. Dopamine concentrations induced by SUD increase cell motility and adhesion, as well as transmigration of both infected and uninfected CD14+CD16+ monocytes across the BBB that is mediated by D1-like receptors (Coley, Calderon et al. 2015, Calderon, Williams et al. 2017). Activation of D1-like dopamine receptors also increases the susceptibility of macrophages to HIV entry (Gaskill, Yano et al. 2014), potentially through modulation of calcium flux (Nickoloff, Mackie et al. 2019). Additionally, human macrophages exposed to dopamine produce greater amounts of inflammatory cytokines and chemokines such as IL-1β, IL-6, CCL2 and CXCL10 (Gaskill, Carvallo et al. 2012, Nolan, Muir et al. 2019). These effects could increase the influx of both HIV infected and inflammatory immune cells into the CNS, promote the spread of viral infection and reseeding of reservoirs within the brain, and contribute to the development of neuroinflammation and a neurotoxic environment. These effects would be greater in regions with elevated dopamine, connecting increased HIV-associated neuropathology in these regions with the effects of dopamine on immune cell function.
Although myeloid cells are the primary mediators of neuroHIV (Koenig, Gendelman et al. 1986, Minagar, Shapshak et al. 2002, Crowe, Zhu et al. 2003, Rappaport and Volsky 2015), studies suggest that T-cells can also contribute to CNS infection (Marcondes, Burudi et al. 2001, Anthony, Crawford et al. 2003, Petito, Adkins et al. 2003), especially in PLWH with SUD (Tomlinson, Simmonds et al. 1999, Anthony, Ramage et al. 2005, Gaskill, Calderon et al. 2013). Dopamine has also been shown to increase viral replication in T-cells, and to regulate a number of T-cell functions (Levite 2016), suggesting that dopamine could also impact the development of disease through its effects on this population. While the role of T-cells in HIV neuropathogenesis is not clearly defined (Gaskill, Calderon et al. 2013), they are central to systemic HIV infection (Fox and Cottler-Fox 1992, Okoye and Picker 2013) and changes in peripheral dopamine induced by substances of abuse could alter the contribution of T-cells to disease pathogenesis in non-CNS tissues. While the impact of SUD on peripheral dopamine concentrations is unknown, it needs to be examined as dopamine is important to homeostatic functions in a number of peripheral organs (Matt and Gaskill 2019). Therefore, the impact of dopamine on HIV infection in peripheral immune cells in the context of SUD is an area for future studies.
How any of these effects would be changed with ART is not well characterized. The use of stimulants, and many other types of drugs, is strongly correlated with diminished therapeutic effectiveness of ART (Ellis, Childers et al. 2003, Rippeth, Heaton et al. 2004, Meade, Conn et al. 2011, Blackstone, Iudicello et al. 2013, Levine, Reynolds et al. 2014, Dash, Balasubramaniam et al. 2015, Meade, Towe et al. 2015). This is believed to be driven by SUD associated problems with medication adherence and access to treatment, rather than specific biological interactions between the stimulants and the antiretrovirals themselves (Arnsten, Demas et al. 2002, Lucas, Griswold et al. 2006, Ferris, Mactutus et al. 2008, Byrd, Fellows et al. 2011, Meade, Conn et al. 2011, Schuster and Gonzalez 2012, Levine, Reynolds et al. 2014, Anderson, Higgins et al. 2015), although more studies are necessary to support this.
While successful ART may eliminate, or at least dramatically decrease, viral replication, the effects of antiretrovirals on myeloid cells are much less clear (Matt and Gaskill 2019). A recent study showed that in macrophages derived from a small cohort of PLWH on fully suppressive ART and from uninfected individuals, the effects of dopamine on cytokine production are similar, suggesting that ART does not change dopamine-mediated effects on cytokine production by macrophages (Nolan, Muir et al. 2019). Another recent study showed that cocaine treatment increased the expression of inflammasome associated genes in HIV-infected macrophages (Atluri, Pilakka-Kanthikeel et al. 2016), although it is not known whether cocaine induces the release of dopamine from these cells, and whether dopamine contributes to cocaine-mediated inflammasome activation in macrophages. While not associated with dopamine, experiments in the human macrophage-like THP-1 cell line showed that treatment with Stavudine, Zidovudine, Nelfinavir, and Lopinavir increased their production of IL-1β and TNF-α (Lagathu, Eustace et al. 2007). Cohort studies have also shown that while overall HIV-associated inflammation is decreased with successful ART, biomarkers of inflammation and myeloid activation are still detected in PLWH on ART when compared to uninfected individuals (Gisolf, van Praag et al. 2000, Eden, Price et al. 2007, Wada, Jacobson et al. 2015, Sereti, Krebs et al. 2017). Together, these data suggest that ART does not inhibit the impact of elevated dopamine on the development of inflammation, highlighting the need to understand the role of dopamine in neuroHIV to develop adjuvant therapies that can be included with ART for PLWH with SUD.
Defining the interaction between dopamine and HIV infection
Many studies examining the effects of either specific substances of abuse or dopamine on immune cells and viral infection have been done in vitro (Peterson, Gekker et al. 1991, Steele, Henderson et al. 2003, Mahajan, Aalinkeel et al. 2008, Gaskill, Calderon et al. 2009, Gaskill, Carvallo et al. 2012, Mantri, Pandhare Dash et al. 2012, Addai, Pandhare et al. 2015, Rao, Ande et al. 2016, Calderon, Williams et al. 2017, Cotto, Natarajaseenivasan et al. 2018, Nickoloff, Mackie et al. 2019). While these experiments are critical to define the molecular mechanism(s) underlying the effects of dopamine, some of these studies are inherently limited as they are focused on the pharmacology of the drug being studied, not specifically on dopamine (Jones, Garris et al. 1995, Ferris, Mactutus et al. 2008, Kish 2008, Cruickshank and Dyer 2009). In addition, studies using cell culture systems are not optimal due to the lack of “history” in these types of experiments. Use of cell lines, and even primary cells, makes it difficult to assess the continuous, chronic impact of infection, SUD, and/or ART on individual health, as it is not clear this can be modeled completely in these types of systems. Research demonstrates that the length of time an individual is infected with HIV prior to the use of ART can have significant impacts on long term health outcomes (Yilmaz, Price et al. 2008, Gay, Dibben et al. 2011, Shive, Biancotto et al. 2012, Funderburg and Lederman 2014, Cao, Mehraj et al. 2015, Sereti, Krebs et al. 2017, Hellmuth, Slike et al. 2019). In the brain, extended infection with HIV prior to treatment could result in irreversible damage to dopaminergic and other circuits, a kind of neurological “scar”, leaving infected individuals vulnerable to developing impairments or aberrant behaviors more easily. The use of large numbers of primary human cells from specific populations with strong demographic and epidemiological data can help to eliminate some of these deficiencies, especially if the studies include approximation of the length of time infected prior to ART. Questions about how these data can be translated to patient care will remain and need to be considered.
These studies will characterize the effect of dopamine on cellular proteins and signaling pathways involved in both CNS and peripheral myeloid cells of ART treated PLWH with SUD. This will identify novel targets for development of adjuvant therapies that inhibit the effects of SUD on neurocognitive deficits in PLWH. To optimize these studies, both in vitro and in vivo experimental systems with human cells, and rodent and non-human primate animal models should be used. Although primate models remain the gold standard in HIV research, their cost and size make them difficult to use extensively, resulting in increased use of rodent model systems. Identification of targets by most, if not all, of these model systems will add to both the rigor and translational value of the data.
Rodent systems use expression of viral proteins to simulate HIV infection, as rodents are not naturally susceptible to infection by this virus (Morrow, Wharton et al. 1987, Hatziioannou and Evans 2012). While none of these models appears to recapitulate completely the complex network of immune and neuronal cells observed in humans, these systems have been essential for evaluating the effects of HIV on the dopaminergic system in vivo, and have greatly contributed to the understanding of the impact of substance abuse and dopamine on HIV infection (Roth, Tashkin et al. 2002, Bagetta, Piccirilli et al. 2004, Griffin, Middaugh et al. 2007, Yao and Buch 2012, Kim, Lowe et al. 2015, Liu, Xu et al. 2017, Sanchez and Kaul 2017). They have been particularly valuable in examining the neuroinflammatory and neurotoxic impact of viral proteins in conjunction with methamphetamine or cocaine, and many showed a synergistic impact of these drugs with HIV proteins (Liu, Williams et al. 2000, Bagetta, Piccirilli et al. 2004, Kim, Lowe et al. 2015, Sanchez and Kaul 2017). However, expression of viral proteins in these models is, however, artificial, and can result in the release of varying amounts of viral protein in different brain regions relative to human infection (Gaskill, Miller et al. 2017). Further, as the concentrations of HIV proteins in distinct regions of the CNS are not defined (Gaskill, Miller et al. 2017), it is not clear how accurately the protein concentrations used in these studies mimic those found in the CNS of PLWH (Spudich and González-Scarano 2012).
This is significant, as exposure to non-relevant concentrations of viral protein could result in neurological alterations or damage not seen in human infection. While determining how much HIV protein is present in the CNS would improve the reliability of these model systems, expression of HIV proteins in the absence of viral infection means that the regulatory processes that control the amount of viral proteins produced and released in the human brain are not present (Gorantla, Poluektova et al. 2012, Saylor, Dickens et al. 2016). This suggests that the neuropathology in these systems may be different from what develops in humans in vivo. Future studies should focus on modeling development of neuroHIV more accurately, and on characterizing specifc effects of SUD and aberrant dopaminergic function on this disease process. However, it is important to underscore that the amount of HIV and its associated proteins in the human brain is unlikely to be consistent among individuals as well as among different demographics (Nightingale, Winston et al. 2014). Thus, human studies must clearly state which demographic or other specific group of people is being modelled.
A number of technological advances enabled the development of new rodent models. These include the creation of humanized mice, in which immunodeficient mice are implanted with human tissue or injected with human cells (Lan, Tonomura et al. 2006, Gorantla, Poluektova et al. 2012, Honeycutt, Wahl et al. 2016), and the development of a mouse tropic HIV hybrid virus, EcoHIV (Potash, Chao et al. 2005). More recently, a model has been developed in which CNS myeloid populations have been recapitulated in a mouse brain (Honeycutt, Wahl et al. 2016, Honeycutt, Thayer et al. 2017). These models provide valuable in vivo systems in which to test the effects of SUD on viral replication, disease pathogenesis, and behavior. They also show that macrophages are infected with HIV in the absence of T-cells (Honeycutt, Wahl et al. 2016, Honeycutt, Thayer et al. 2017), demonstrating the importance of these cells in the development of neuroHIV, which is largely driven by myeloid cells in humans (Koenig, Gendelman et al. 1986, Minagar, Shapshak et al. 2002, Crowe, Zhu et al. 2003, Rappaport and Volsky 2015). A caveat for models that inject virus directly into the CNS is that this can cause mechanical trauma and inflammation (Stevenson, Hawke et al. 1997, Hauss-Wegrzyniak, Lukovic et al. 1998, Cartmell, Southgate et al. 1999), potentially inducing neuronal damage independent of viral infection, confounding the results.
Another consideration, particularly when examining the immunomodulatory effects of dopamine, is that rodent cells do not always respond to immunologic stimuli in the same way as do human cells. For example, relative to human cells, rodent myeloid cells show significant species-specific differences in terms of the gene targets, TLR response, IL-1β regulation and NLRP3 inflammasome activation in response to a number of immunomodulatory stimuli (Schroder, Irvine et al. 2012, Ariffin and Sweet 2013, Yan, Jiang et al. 2015, Schaale, Peters et al. 2016, Dawson, Smith et al. 2017, Nolan 2019). Additionally, recent data indicate that dopamine may act through distinct signaling cascades in different cell types (Nickoloff, Mackie et al. 2019), and this may apply to different species as well. It is possible that these species-specific differences account for the lack of translatability of these data to humans, as the data resulting from these studies have not always proven to model the neuropathology accurately in PLWH with SUD.
Taken together, these caveats suggest that use of non-human primates to study the synergistic impact of HIV and SUD is warranted, as these animals show the greatest resemblance to the human system and can be infected with SIV (Hatziioannou and Evans 2012). Studies in primates have been used to demonstrate increases in inflammation and neuropathology in response to dopamine-altering therapeutic drugs (Czub, Koutsilieri et al. 2001, Czub, Czub et al. 2004), and alterations in dopamine-rich brain regions in response to untreated infection (Jenuwein, Scheller et al. 2004, Scheller, Sopper et al. 2005) supporting findings from human studies. SIV models have been used to examine effects of methamphetamine and other drugs of abuse on immune cells in the infected CNS, showing increased viral load, neuroinflammation, and microglial CCR5 expression (Marcondes, Flynn et al. 2010, Najera, Bustamante et al. 2016). These findings are similar to those in non-human primates treated with drugs that elevate CNS dopamine directly (Czub, Koutsilieri et al. 2001, Czub, Czub et al. 2004), suggesting that some of the effects of SUD are mediated by increases in dopamine. More studies in non-human primates, in which animals are given drugs of abuse and treated with ART, will be needed to evaluate whether drugs of abuse and dopaminergic therapies impact neuroHIV in the ART era. However, even these models do not fully replicate the complexity of infection in the human brain, and the expense and logistical challenges involving their use are significant hurdles.
While human studies have the most potential to define the broad effects of drug-induced alterations in dopamine on neuroHIV, these are limited by the inability to control the length of infection and time to ART, and to examine the more mechanistic aspects of neurologic infection. There are several additional factors that complicate these studies, particularly related to SUD in the ART era. One major issue is how studies define drug use, particularly the length of time following use that is considered current and how poly-drug use is considered (Byrd, Fellows et al. 2011, Fernandez-Serrano, Perez-Garcia et al. 2011, Norman and Basso 2015). Many of the differences among studies examining the cognitive impact of SUD in PLWH may be attributable to different definitions of substance abuse (Fernandez-Serrano, Perez-Garcia et al. 2011). Creating standard definitions of active and past drug abuse would be valuable, as they would enable better consolidation and meta-analysis of multiple studies, providing a broader understanding of the cognitive impact of drug-associated changes in dopamine concentrations in PLWH. Additionally, the length of time from initial infection to ART initiation, the type of ART, as well as other cofactors such as age, reading level, and starting CD4+ T-cell count, can all impact cognitive status independent of drug abuse (Heaton, Clifford et al. 2010, Nightingale, Winston et al. 2014, Heaton, Franklin et al. 2015). Therefore, future studies in humans should include access to detailed epidemiologic and immunologic data, with longitudinal changes in immune populations and functions being assessed.
Conclusion
Given the complexity of the problem, no single model system can accommodate all the necessary types of research into CNS infection with the level of detail required for mechanistic examination of the interactions between drugs of abuse and ART on HIV neuropathogenesis. Therefore, future studies should combine results from multiple modalities to develop a more complete picture of the impact of drug-induced changes in dopamine etiology on neuroHIV. Research that focuses on correlating results among in vitro experiments, animal models, and human studies will provide a more complete understanding of the effects of SUD and dopaminergic dysfunction in the HIV infected CNS. They will also provide a detailed understanding of the proteins and pathways involved in this disease process that is required to develop new targets and strategies to reduce both HIV infection and its consequences in the vulnerable population with SUD.
Acknowledgements
We greatly appreciate the thoughtful discussions of the ideas presented in this manuscript with all members of the Berman and Gaskill laboratories. This work was supported by grants from the National Institutes of Drug Abuse, DA039005 (PJG), DA041931 (JWB and TMC), DA044584 (JWB), DA048609 (JWB) and the National Institutes of Mental Health MH112391 (JWB and TMC) and T32MH079785 (Khalili), supporting EAN.
Abbreviations:
- ART
antiretroviral therapy
- BBB
blood brain barrier
- CNS
central nervous system
- CSF
cerebrospinal fluid
- PLWH
people living with HIV
- SUD
substance use disorder
Footnotes
Conflict of Interest Statement
All the authors of this manuscript declare that they have no conflicts of interest either directly or indirectly related to the content of this manuscript.
Bibliography
- Abreu CM, Veenhuis RT, Avalos CR, Graham S, Parrilla DR, Ferreira EA, Queen SE, Shirk EN, Bullock BT, Li M, Metcalf Pate KA, Beck SE, Mangus LM, Mankowski JL, Mac Gabhann F, O’Connor SL, Gama L and Clements JE (2019). “Myeloid and CD4 T Cells Comprise the Latent Reservoir in Antiretroviral Therapy-Suppressed SIVmac251-Infected Macaques.” MBio 10(4). [DOI] [PMC free article] [PubMed] [Google Scholar]
- Addai AB, Pandhare J, Paromov V, Mantri CK, Pratap S and Dash C (2015). “Cocaine modulates HIV-1 integration in primary CD4+ T cells: implications in HIV-1 pathogenesis in drug-abusing patients.” J Leukoc Biol 97(4): 779–790. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Akang EN (2019). “Combination antiretroviral therapy (cART)-induced hippocampal disorders: Highlights on therapeutic potential of Naringenin and Quercetin.” IBRO Rep 6: 137–146. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Aksenov MY, Aksenova MV, Nath A, Ray PD, Mactutus CF and Booze RM (2006). “Cocaine-mediated enhancement of Tat toxicity in rat hippocampal cell cultures: the role of oxidative stress and D1 dopamine receptor.” Neurotoxicology 27(2): 217–228. [DOI] [PubMed] [Google Scholar]
- Alakkas A, Ellis RJ, Watson CW, Umlauf A, Heaton RK, Letendre S, Collier A, Marra C, Clifford DB, Gelman B, Sacktor N, Morgello S, Simpson D, McCutchan JA, Kallianpur A, Gianella S, Marcotte T, Grant I, Fennema-Notestine C and Group C (2019). “White matter damage, neuroinflammation, and neuronal integrity in HAND.” J Neurovirol 25(1): 32–41. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Anderson AM, Higgins MK, Ownby RL and Waldrop-Valverde D (2015). “Changes in neurocognition and adherence over six months in HIV-infected individuals with cocaine or heroin dependence.” AIDS Care 27(3): 333–337. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ann HW, Jun S, Shin NY, Han S, Ahn JY, Ahn MY, Jeon YD, Jung IY, Kim MH, Jeong WY, Ku NS, Kim JM, Smith DM and Choi JY (2016). “Characteristics of Resting-State Functional Connectivity in HIV-Associated Neurocognitive Disorder.” PLoS One 11(4): e0153493. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Anthony IC and Bell JE (2008). “The Neuropathology of HIV/AIDS.” Int Rev Psychiatry 20(1): 15–24. [DOI] [PubMed] [Google Scholar]
- Anthony IC, Crawford DH and Bell JE (2003). “B lymphocytes in the normal brain: contrasts with HIV-associated lymphoid infiltrates and lymphomas.” Brain 126(Pt 5): 1058–1067. [DOI] [PubMed] [Google Scholar]
- Anthony IC, Ramage SN, Carnie FW, Simmonds P and Bell JE (2005). “Influence of HAART on HIV-related CNS disease and neuroinflammation.” J Neuropathol Exp Neurol 64(6): 529–536. [DOI] [PubMed] [Google Scholar]
- Arango Duque G and Descoteaux A (2014). “Macrophage cytokines: involvement in immunity and infectious diseases.” Front Immunol 5: 491. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ariffin JK and Sweet MJ (2013). “Differences in the repertoire, regulation and function of Toll-like Receptors and inflammasome-forming Nod-like Receptors between human and mouse.” Curr Opin Microbiol 16(3): 303–310. [DOI] [PubMed] [Google Scholar]
- Arnsten JH, Demas PA, Grant RW, Gourevitch MN, Farzadegan H, Howard AA and Schoenbaum EE (2002). “Impact of active drug use on antiretroviral therapy adherence and viral suppression in HIV-infected drug users.” J Gen Intern Med 17(5): 377–381. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Atluri VSR, Pilakka-Kanthikeel S, Garcia G, Jayant RD, Sagar V, Samikkannu T, Yndart A and Nair M (2016). “Effect of Cocaine on HIV Infection and Inflammasome Gene Expression Profile in HIV Infected Macrophages.” Scientific reports 6: 27864–27864. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Aylward EH, Henderer JD, McArthur JC, Brettschneider PD, Harris GJ, Barta PE and Pearlson GD (1993). “Reduced basal ganglia volume in HIV-1-associated dementia: results from quantitative neuroimaging.” Neurology 43(10): 2099–2104. [DOI] [PubMed] [Google Scholar]
- Azar P, Wood E, Nguyen P, Luma M, Montaner J, Kerr T and Milloy MJ (2015). “Drug use patterns associated with risk of non-adherence to antiretroviral therapy among HIV-positive illicit drug users in a Canadian setting: a longitudinal analysis.” BMC Infect Dis 15: 193. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bacic F, Uematsu S, McCarron RM, Spatz M (1991). “Dopaminergic Receptors Linked to Adenylate Cyclase in Human Cerebromicrovascular Endothelium.” [DOI] [PubMed]
- Bagetta G, Piccirilli S, Del Duca C, Morrone LA, Rombola L, Nappi G, De Alba J, Knowles RG and Corasaniti MT (2004). “Inducible nitric oxide synthase is involved in the mechanisms of cocaine enhanced neuronal apoptosis induced by HIV-1 gp120 in the neocortex of rat.” Neurosci Lett 356(3): 183–186. [DOI] [PubMed] [Google Scholar]
- Bak Y, Jun S, Choi JY, Lee Y, Lee SK, Han S and Shin NY (2018). “Altered intrinsic local activity and cognitive dysfunction in HIV patients: A resting-state fMRI study.” PLoS One 13(11): e0207146. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Basu S and Dasgupta PS (2000). “Dopamine, a neurotransmitter, influences the immune system.” Journal of Neuroimmunology 102(2): 113–124. [DOI] [PubMed] [Google Scholar]
- Baum MK, Rafie C, Lai S, Sales S, Page B and Campa A (2009). “Crack-Cocaine Use Accelerates HIV Disease Progression in a Cohort of HIV-Positive Drug Users.” JAIDS Journal of Acquired Immune Deficiency Syndromes 50(1): 93–99. [DOI] [PubMed] [Google Scholar]
- Beaulieu JM and Gainetdinov RR (2011). “The physiology, signaling, and pharmacology of dopamine receptors.” Pharmacol Rev 63(1): 182–217. [DOI] [PubMed] [Google Scholar]
- Becker BW, Thames AD, Woo E, Castellon SA and Hinkin CH (2011). “Longitudinal change in cognitive function and medication adherence in HIV-infected adults.” AIDS Behav 15(8): 1888–1894. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Becker JT, Sanders J, Madsen SK, Ragin A, Kingsley L, Maruca V, Cohen B, Goodkin K, Martin E, Miller EN, Sacktor N, Alger JR, Barker PB, Saharan P, Carmichael OT, Thompson PM and Multicenter ACS (2011). “Subcortical brain atrophy persists even in HAART-regulated HIV disease.” Brain Imaging Behav 5(2): 77–85. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bell JE (2004). “An update on the neuropathology of HIV in the HAART era.” Histopathology 45(6): 549–559. [DOI] [PubMed] [Google Scholar]
- Bell JE, Anthony IC and Simmonds P (2006). “Impact of HIV on regional & cellular organisation of the brain.” Curr HIV Res 4(3): 249–257. [DOI] [PubMed] [Google Scholar]
- Berger JR and Arendt G (2000). “HIV dementia: the role of the basal ganglia and dopaminergic systems.” J Psychopharmacol 14(3): 214–221. [DOI] [PubMed] [Google Scholar]
- Bing EG, Burnam MA, Longshore D, Fleishman JA, Sherbourne CD, London AS, Turner BJ, Eggan F, Beckman R, Vitiello B, Morton SC, Orlando M, Bozzette SA, Ortiz-Barron L and Shapiro M (2001). “Psychiatric disorders and drug use among human immunodeficiency virus-infected adults in the United States.” Arch Gen Psychiatry 58(8): 721–728. [DOI] [PubMed] [Google Scholar]
- Blackstone K, Iudicello JE, Morgan EE, Weber E, Moore DJ, Franklin DR, Ellis RJ, Grant I, Woods SP and Translational Methamphetamine ARCG (2013). “Human immunodeficiency virus infection heightens concurrent risk of functional dependence in persons with long-term methamphetamine use.” J Addict Med 7(4): 255–263. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Boender TS, Smit C, Sighem AV, Bezemer D, Ester CJ, Zaheri S, Wit F, Reiss P and A. n. o. H. cohort (2018). “AIDS Therapy Evaluation in the Netherlands (ATHENA) national observational HIV cohort: cohort profile.” BMJ Open 8(9): e022516. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brabers NA and Nottet HS (2006). “Role of the pro-inflammatory cytokines TNF-alpha and IL-1beta in HIV-associated dementia.” Eur J Clin Invest 36(7): 447–458. [DOI] [PubMed] [Google Scholar]
- Buch S, Yao H, Guo M, Mori T, Mathias-Costa B, Singh V, Seth P, Wang J and Su TP (2012). “Cocaine and HIV-1 interplay in CNS: cellular and molecular mechanisms.” Curr HIV Res 10(5): 425–428. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bylicky MA, Mueller GP and Day RM (2018). “Mechanisms of Endogenous Neuroprotective Effects of Astrocytes in Brain Injury.” Oxidative medicine and cellular longevity 2018: 6501031–6501031. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Byrd DA, Fellows RP, Morgello S, Franklin D, Heaton RK, Deutsch R, Atkinson JH, Clifford DB, Collier AC, Marra CM, Gelman B, McCutchan JA, Duarte NA, Simpson DM, McArthur J, Grant I and Group C (2011). “Neurocognitive impact of substance use in HIV infection.” J Acquir Immune Defic Syndr 58(2): 154–162. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Calderon TM, Williams DW, Lopez L, Eugenin EA, Cheney L, Gaskill PJ, Veenstra M, Anastos K, Morgello S and Berman JW (2017). “Dopamine Increases CD14(+)CD16(+) Monocyte Transmigration across the Blood Brain Barrier: Implications for Substance Abuse and HIV Neuropathogenesis.” J Neuroimmune Pharmacol 12(2): 353–370. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cao W, Mehraj V, Vyboh K, Li T and Routy JP (2015). “Antiretroviral Therapy in Primary HIV-1 Infection: Influences on Immune Activation and Gut Mucosal Barrier Dysfunction.” AIDS Rev 17(3): 135–146. [PubMed] [Google Scholar]
- Carboni E, Imperato A, Perezzani L and Di Chiara G (1989). “Amphetamine, cocaine, phencyclidine and nomifensine increase extracellular dopamine concentrations preferentially in the nucleus accumbens of freely moving rats.” Neuroscience 28(3): 653–661. [DOI] [PubMed] [Google Scholar]
- Cartmell T, Southgate T, Rees GS, Castro MG, Lowenstein PR and Luheshi GN (1999). “Interleukin-1 mediates a rapid inflammatory response after injection of adenoviral vectors into the brain.” J Neurosci 19(4): 1517–1523. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Castellano P, Prevedel L and Eugenin EA (2017). “HIV-infected macrophages and microglia that survive acute infection become viral reservoirs by a mechanism involving Bim.” Sci Rep 7(1): 12866. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cavalcante GI, Chaves Filho AJ, Linhares MI, de Carvalho Lima CN, Venancio ET, Rios ER, de Souza FC, Vasconcelos SM, Macedo D and de Franca Fonteles MM (2017). “HIV antiretroviral drug Efavirenz induces anxiety-like and depression-like behavior in rats: evaluation of neurotransmitter alterations in the striatum.” Eur J Pharmacol 799: 7–15. [DOI] [PubMed] [Google Scholar]
- Chang SL, Connaghan KP, Wei Y and Li MD (2014). “NeuroHIV and use of addictive substances.” Int Rev Neurobiol 118: 403–440. [DOI] [PubMed] [Google Scholar]
- Churchill M and Nath A (2013). “Where does HIV hide? A focus on the central nervous system.” Curr Opin HIV AIDS 8(3): 165–169. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Churchill MJ, Wesselingh SL, Cowley D, Pardo CA, McArthur JC, Brew BJ and Gorry PR (2009). “Extensive astrocyte infection is prominent in human immunodeficiency virus-associated dementia.” Ann Neurol 66(2): 253–258. [DOI] [PubMed] [Google Scholar]
- Cihlar T and Fordyce M (2016). “Current status and prospects of HIV treatment.” Curr Opin Virol 18: 50–56. [DOI] [PubMed] [Google Scholar]
- Clarke RB, Adermark L, Chau P, Soderpalm B and Ericson M (2014). “Increase in nucleus accumbens dopamine levels following local ethanol administration is not mediated by acetaldehyde.” Alcohol Alcohol 49(5): 498–504. [DOI] [PubMed] [Google Scholar]
- Clifford KM, Samboju V, Cobigo Y, Milanini B, Marx GA, Hellmuth JM, Rosen HJ, Kramer JH, Allen IE and Valcour VG (2017). “Progressive Brain Atrophy Despite Persistent Viral Suppression in HIV Patients Older Than 60 Years.” J Acquir Immune Defic Syndr 76(3): 289–297. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Coley JS, Calderon TM, Gaskill PJ, Eugenin EA and Berman JW (2015). “Dopamine increases CD14+CD16+ monocyte migration and adhesion in the context of substance abuse and HIV neuropathogenesis.” PLoS One 10(2): e0117450. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cotto B, Natarajaseenivasan K, Ferrero K, Wesley L, Sayre M and Langford D (2018). “Cocaine and HIV-1 Tat disrupt cholesterol homeostasis in astrocytes: Implications for HIV-associated neurocognitive disorders in cocaine user patients.” Glia 66(4): 889–902. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Crowe S, Zhu T and Muller WA (2003). “The contribution of monocyte infection and trafficking to viral persistence, and maintenance of the viral reservoir in HIV infection.” J Leukoc Biol 74(5): 635–641. [DOI] [PubMed] [Google Scholar]
- Cruickshank CC and Dyer KR (2009). “A review of the clinical pharmacology of methamphetamine.” Addiction 104(7): 1085–1099. [DOI] [PubMed] [Google Scholar]
- Cysique LA and Brew BJ (2009). “Neuropsychological functioning and antiretroviral treatment in HIV/AIDS: a review.” Neuropsychol Rev 19(2): 169–185. [DOI] [PubMed] [Google Scholar]
- Cysique LA and Brew BJ (2009). “Neuropsychological Functioning and Antiretroviral Treatment in HIV/AIDS: A Review.” Neuropsychology Review 19(2): 169–185. [DOI] [PubMed] [Google Scholar]
- Czub S, Czub M, Koutsilieri E, Sopper S, Villinger F, Muller JG, Stahl-Hennig C, Riederer P, Ter Meulen V and Gosztonyi G (2004). “Modulation of simian immunodeficiency virus neuropathology by dopaminergic drugs.” Acta Neuropathol 107(3): 216–226. [DOI] [PubMed] [Google Scholar]
- Czub S, Koutsilieri E, Sopper S, Czub M, Stahl-Hennig C, Muller JG, Pedersen V, Gsell W, Heeney JL, Gerlach M, Gosztonyi G, Riederer P and ter Meulen V (2001). “Enhancement of central nervous system pathology in early simian immunodeficiency virus infection by dopaminergic drugs.” Acta Neuropathol 101(2): 85–91. [DOI] [PubMed] [Google Scholar]
- D’Aquila PS, Collu M, Gessa GL and Serra G (2000). “The role of dopamine in the mechanism of action of antidepressant drugs.” Eur J Pharmacol 405(1–3): 365–373. [DOI] [PubMed] [Google Scholar]
- Dalwadi DA, Kim S, Amdani SM, Chen Z, Huang RQ and Schetz JA (2016). “Molecular mechanisms of serotonergic action of the HIV-1 antiretroviral efavirenz.” Pharmacol Res 110: 10–24. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dash S, Balasubramaniam M, Villalta F, Dash C and Pandhare J (2015). “Impact of cocaine abuse on HIV pathogenesis.” Front Microbiol 6: 1111. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Davis LE, Hjelle BL, Miller VE, Palmer DL, Llewellyn AL, Merlin TL, Young SA, Mills RG, Wachsman W and Wiley CA (1992). “Early viral brain invasion in iatrogenic human immunodeficiency virus infection.” Neurology 42(9): 1736–1739. [DOI] [PubMed] [Google Scholar]
- Dawson HD, Smith AD, Chen C and Urban JF Jr. (2017). “An in-depth comparison of the porcine, murine and human inflammasomes; lessons from the porcine genome and transcriptome.” Vet Microbiol 202: 2–15. [DOI] [PubMed] [Google Scholar]
- De Boni RB, Shepherd BE, Grinsztejn B, Cesar C, Cortes C, Padgett D, Gotuzzo E, Belaunzaran-Zamudio PF, Rebeiro PF, Duda SN and McGowan CC (2016). “Substance Use and Adherence Among People Living with HIV/AIDS Receiving cART in Latin America.” AIDS Behav 20(11): 2692–2699. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Debalkie Animut M, Sorrie MB, Birhanu YW and Teshale MY (2019). “High prevalence of neurocognitive disorders observed among adult people living with HIV/AIDS in Southern Ethiopia: A cross-sectional study.” PLoS One 14(3): e0204636. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Deren S, Cortes T, Dickson VV, Guilamo-Ramos V, Han BH, Karpiak S, Naegle M, Ompad DC and Wu B (2019). “Substance Use Among Older People Living With HIV: Challenges for Health Care Providers.” Front Public Health 7: 94. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Devlin KN, Gongvatana A, Clark US, Chasman JD, Westbrook ML, Tashima KT, Navia B and Cohen RA (2012). “Neurocognitive effects of HIV, hepatitis C, and substance use history.” J Int Neuropsychol Soc 18(1): 68–78. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Di Chiara G and Imperato A (1988). “Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.” Proc Natl Acad Sci U S A 85(14): 5274–5278. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dietrich JB, Mangeol A, Revel MO, Burgun C, Aunis D and Zwiller J (2005). “Acute or repeated cocaine administration generates reactive oxygen species and induces antioxidant enzyme activity in dopaminergic rat brain structures.” Neuropharmacology 48(7): 965–974. [DOI] [PubMed] [Google Scholar]
- du Plessis S, Vink M, Joska JA, Koutsilieri E, Bagadia A, Stein DJ and Emsley R (2015). “HIV Infection Is Associated with Impaired Striatal Function during Inhibition with Normal Cortical Functioning on Functional MRI.” J Int Neuropsychol Soc 21(9): 722–731. [DOI] [PubMed] [Google Scholar]
- Duan H, Hu T, Foti RS, Pan Y, Swaan PW and Wang J (2015). “Potent and Selective Inhibition of Plasma Membrane Monoamine Transporter by HIV Protease Inhibitors.” Drug Metab Dispos 43(11): 1773–1780. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dube B, Benton T, Cruess DG and Evans DL (2005). “Neuropsychiatric manifestations of HIV infection and AIDS.” J Psychiatry Neurosci 30(4): 237–246. [PMC free article] [PubMed] [Google Scholar]
- Durvasula RS, Myers HF, Satz P, Miller EN, Morgenstern H, Richardson MA, Evans G and Forney D (2000). “HIV-1, cocaine, and neuropsychological performance in African American men.” J Int Neuropsychol Soc 6(3): 322–335. [DOI] [PubMed] [Google Scholar]
- Edelman EJ, Gordon KS, Glover J, McNicholl IR, Fiellin DA and Justice AC (2013). “The next therapeutic challenge in HIV: polypharmacy.” Drugs Aging 30(8): 613–628. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Eden A, Price RW, Spudich S, Fuchs D, Hagberg L and Gisslen M (2007). “Immune activation of the central nervous system is still present after >4 years of effective highly active antiretroviral therapy.” J Infect Dis 196(12): 1779–1783. [DOI] [PubMed] [Google Scholar]
- Eggers C, Arendt G, Hahn K, Husstedt IW, Maschke M, Neuen-Jacob E, Obermann M, Rosenkranz T, Schielke E, Straube E and A. u. N.-I. German Association of Neuro (2017). “HIV-1-associated neurocognitive disorder: epidemiology, pathogenesis, diagnosis, and treatment.” J Neurol 264(8): 1715–1727. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ellis RJ, Childers ME, Cherner M, Lazzaretto D, Letendre S and Grant I (2003). “Increased human immunodeficiency virus loads in active methamphetamine users are explained by reduced effectiveness of antiretroviral therapy.” J Infect Dis 188(12): 1820–1826. [DOI] [PubMed] [Google Scholar]
- Eugenin EA and Berman JW (2007). “Gap junctions mediate human immunodeficiency virus-bystander killing in astrocytes.” J Neurosci 27(47): 12844–12850. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Eugenin EA, Clements JE, Zink MC and Berman JW (2011). “Human immunodeficiency virus infection of human astrocytes disrupts blood-brain barrier integrity by a gap junction-dependent mechanism.” J Neurosci 31(26): 9456–9465. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Eugenin EA, Osiecki K, Lopez L, Goldstein H, Calderon TM and Berman JW (2006). “CCL2/monocyte chemoattractant protein-1 mediates enhanced transmigration of human immunodeficiency virus (HIV)-infected leukocytes across the blood-brain barrier: a potential mechanism of HIV-CNS invasion and NeuroAIDS.” J Neurosci 26(4): 1098–1106. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Everall IP, Hansen LA and Masliah E (2005). “The shifting patterns of HIV encephalitis neuropathology.” Neurotoxicity Research 8(1): 51–61. [DOI] [PubMed] [Google Scholar]
- Farber K, Pannasch U and Kettenmann H (2005). “Dopamine and noradrenaline control distinct functions in rodent microglial cells.” Mol Cell Neurosci 29(1): 128–138. [DOI] [PubMed] [Google Scholar]
- Fernandez-Serrano MJ, Perez-Garcia M and Verdejo-Garcia A (2011). “What are the specific vs. generalized effects of drugs of abuse on neuropsychological performance?” Neurosci Biobehav Rev 35(3): 377–406. [DOI] [PubMed] [Google Scholar]
- Ferris MJ, Mactutus CF and Booze RM (2008). “Neurotoxic profiles of HIV, psychostimulant drugs of abuse, and their concerted effect on the brain: current status of dopamine system vulnerability in NeuroAIDS.” Neurosci Biobehav Rev 32(5): 883–909. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fox CH and Cottler-Fox M (1992). “The pathobiology of HIV infection.” Immunol Today 13(9): 353–356. [DOI] [PubMed] [Google Scholar]
- Fujimura RK, Goodkin K, Petito CK, Douyon R, Feaster DJ, Concha M and Shapshak P (1997). “HIV-1 proviral DNA load across neuroanatomic regions of individuals with evidence for HIV-1-associated dementia.” J Acquir Immune Defic Syndr Hum Retrovirol 16(3): 146–152. [DOI] [PubMed] [Google Scholar]
- Funderburg NT and Lederman MM (2014). “Coagulation and morbidity in treated HIV infection.” Thromb Res 133 Suppl 1: S21–24. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gascon MRP, Vidal JE, Mazzaro YM, Smid J, Marcusso RMN, Capitao CG, Coutinho EM, Benute GRG, De Lucia MCS and de Oliveira ACP (2018). “Neuropsychological Assessment of 412 HIV-Infected Individuals in Sao Paulo, Brazil.” AIDS Patient Care STDS 32(1): 1–8. [DOI] [PubMed] [Google Scholar]
- Gaskill PJ, Calderon TM, Coley JS and Berman JW (2013). “Drug induced increases in CNS dopamine alter monocyte, macrophage and T cell functions: implications for HAND.” J Neuroimmune Pharmacol 8(3): 621–642. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gaskill PJ, Calderon TM, Luers AJ, Eugenin EA, Javitch JA and Berman JW (2009). “Human immunodeficiency virus (HIV) infection of human macrophages is increased by dopamine: a bridge between HIV-associated neurologic disorders and drug abuse.” Am J Pathol 175(3): 1148–1159. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gaskill PJ, Carvallo L, Eugenin EA and Berman JW (2012). “Characterization and function of the human macrophage dopaminergic system: implications for CNS disease and drug abuse.” J Neuroinflammation 9: 203. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gaskill PJ, Miller DR, Gamble-George J, Yano H and Khoshbouei H (2017). “HIV, Tat and dopamine transmission.” Neurobiol Dis 105: 51–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gaskill PJ, Yano HH, Kalpana GV, Javitch JA and Berman JW (2014). “Dopamine receptor activation increases HIV entry into primary human macrophages.” PLoS One 9(9): e108232. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gatch MB, Kozlenkov A, Huang RQ, Yang W, Nguyen JD, Gonzalez-Maeso J, Rice KC, France CP, Dillon GH, Forster MJ and Schetz JA (2013). “The HIV antiretroviral drug efavirenz has LSD-like properties.” Neuropsychopharmacology 38(12): 2373–2384. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gay C, Dibben O, Anderson JA, Stacey A, Mayo AJ, Norris PJ, Kuruc JD, Salazar-Gonzalez JF, Li H, Keele BF, Hicks C, Margolis D, Ferrari G, Haynes B, Swanstrom R, Shaw GM, Hahn BH, Eron JJ, Borrow P and Cohen MS (2011). “Cross-sectional detection of acute HIV infection: timing of transmission, inflammation and antiretroviral therapy.” PLoS One 6(5): e19617. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gelman BB, Spencer JA, Holzer CE 3rd and Soukup VM (2006). “Abnormal striatal dopaminergic synapses in National NeuroAIDS Tissue Consortium subjects with HIV encephalitis.” J Neuroimmune Pharmacol 1(4): 410–420. [DOI] [PubMed] [Google Scholar]
- Gisolf EH, van Praag RM, Jurriaans S, Portegies P, Goudsmit J, Danner SA, Lange JM and Prins JM (2000). “Increasing cerebrospinal fluid chemokine concentrations despite undetectable cerebrospinal fluid HIV RNA in HIV-1-infected patients receiving antiretroviral therapy.” J Acquir Immune Defic Syndr 25(5): 426–433. [DOI] [PubMed] [Google Scholar]
- Gongvatana A, Harezlak J, Buchthal S, Daar E, Schifitto G, Campbell T, Taylor M, Singer E, Algers J, Zhong J, Brown M, McMahon D, So YT, Mi D, Heaton R, Robertson K, Yiannoutsos C, Cohen RA, Navia B and Consortium HIVN (2013). “Progressive cerebral injury in the setting of chronic HIV infection and antiretroviral therapy.” J Neurovirol 19(3): 209–218. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gorantla S, Poluektova L and Gendelman HE (2012). “Rodent models for HIV-associated neurocognitive disorders.” Trends in neurosciences 35(3): 197–208. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Grabar S, Weiss L and Costagliola D (2006). “HIV infection in older patients in the HAART era.” J Antimicrob Chemother 57(1): 4–7. [DOI] [PubMed] [Google Scholar]
- Griffin WC, Middaugh LD and Tyor WR (2007). “Chronic Cocaine Exposure in the SCID mouse model of HIV Encephalitis.” Brain research 1134(1): 214–219. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Han B, Gfroerer JC, Colliver JD and Penne MA (2009). “Substance use disorder among older adults in the United States in 2020.” Addiction 104(1): 88–96. [DOI] [PubMed] [Google Scholar]
- Hatziioannou T and Evans DT (2012). “Animal models for HIV/AIDS research.” Nature reviews. Microbiology 10(12): 852–867. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hauss-Wegrzyniak B, Lukovic L, Bigaud M and Stoeckel ME (1998). “Brain inflammatory response induced by intracerebroventricular infusion of lipopolysaccharide: an immunohistochemical study.” Brain Res 794(2): 211–224. [DOI] [PubMed] [Google Scholar]
- Heaton RK, Clifford DB, Franklin DR Jr., Woods SP, Ake C, Vaida F, Ellis RJ, Letendre SL, Marcotte TD, Atkinson JH, Rivera-Mindt M, Vigil OR, Taylor MJ, Collier AC, Marra CM, Gelman BB, McArthur JC, Morgello S, Simpson DM, McCutchan JA, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I and Group C (2010). “HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study.” Neurology 75(23): 2087–2096. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Heaton RK, Franklin DR, Ellis RJ, McCutchan JA, Letendre SL, Leblanc S, Corkran SH, Duarte NA, Clifford DB, Woods SP, Collier AC, Marra CM, Morgello S, Mindt MR, Taylor MJ, Marcotte TD, Atkinson JH, Wolfson T, Gelman BB, McArthur JC, Simpson DM, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I, Group C and Group H (2011). “HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors.” J Neurovirol 17(1): 3–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Heaton RK, Franklin DR Jr., Deutsch R, Letendre S, Ellis RJ, Casaletto K, Marquine MJ, Woods SP, Vaida F, Atkinson JH, Marcotte TD, McCutchan JA, Collier AC, Marra CM, Clifford DB, Gelman BB, Sacktor N, Morgello S, Simpson DM, Abramson I, Gamst AC, Fennema-Notestine C, Smith DM, Grant I and Group C (2015). “Neurocognitive change in the era of HIV combination antiretroviral therapy: the longitudinal CHARTER study.” Clin Infect Dis 60(3): 473–480. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hellmuth J, Slike BM, Sacdalan C, Best J, Kroon E, Phanuphak N, Fletcher JLK, Prueksakaew P, Jagodzinski LL, Valcour V, Robb M, Ananworanich J, Allen IE, Krebs SJ, Spudich S, Search RV and Groups SRS (2019). “Very early ART initiation during acute HIV infection is associated with normalization of cerebrospinal fluid but not plasma markers of immune activation.” J Infect Dis. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hestad K, McArthur JH, Dal Pan GJ, Selnes OA, Nance-Sproson TE, Aylward E, Mathews VP and McArthur JC (1993). “Regional brain atrophy in HIV-1 infection: association with specific neuropsychological test performance.” Acta Neurol Scand 88(2): 112–118. [DOI] [PubMed] [Google Scholar]
- Honeycutt JB, Thayer WO, Baker CE, Ribeiro RM, Lada SM, Cao Y, Cleary RA, Hudgens MG, Richman DD and Garcia JV (2017). “HIV persistence in tissue macrophages of humanized myeloid-only mice during antiretroviral therapy.” Nat Med 23(5): 638–643. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Honeycutt JB, Wahl A, Baker C, Spagnuolo RA, Foster J, Zakharova O, Wietgrefe S, Caro-Vegas C, Madden V, Sharpe G, Haase AT, Eron JJ and Garcia JV (2016). “Macrophages sustain HIV replication in vivo independently of T cells.” J Clin Invest 126(4): 1353–1366. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ipser JC, Brown GG, Bischoff-Grethe A, Connolly CG, Ellis RJ, Heaton RK, Grant I and Translational Methamphetamine ARCG (2015). “HIV infection is associated with attenuated frontostriatal intrinsic connectivity: a preliminary study.” J Int Neuropsychol Soc 21(3): 203–213. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Itoh K, Mehraein P and Weis S (2000). “Neuronal damage of the substantia nigra in HIV-1 infected brains.” Acta Neuropathol 99(4): 376–384. [DOI] [PubMed] [Google Scholar]
- Iudicello JE, Morgan EE, Gongvatana A, Letendre SL, Grant I, Woods SP and Translational Methamphetamine ARCG (2014). “Detrimental impact of remote methamphetamine dependence on neurocognitive and everyday functioning in older but not younger HIV+ adults: evidence for a legacy effect?” J Neurovirol 20(1): 85–98. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jenuwein M, Scheller C, Neuen-Jacob E, Sopper S, Tatschner T, ter Meulen V, Riederer P and Koutsilieri E (2004). “Dopamine deficits and regulation of the cAMP second messenger system in brains of simian immunodeficiency virus-infected rhesus monkeys.” J Neurovirol 10(3): 163–170. [DOI] [PubMed] [Google Scholar]
- Jones SR, Garris PA and Wightman RM (1995). “Different effects of cocaine and nomifensine on dopamine uptake in the caudate-putamen and nucleus accumbens.” J Pharmacol Exp Ther 274(1): 396–403. [PubMed] [Google Scholar]
- Kim SG, Lowe EL, Dixit D, Youn CS, Kim IJ, Jung JB, Rovner R, Zack JA and Vatakis DN (2015). “Cocaine-mediated impact on HIV infection in humanized BLT mice.” Sci Rep 5: 10010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kirk JB and Goetz MB (2009). “Human immunodeficiency virus in an aging population, a complication of success.” J Am Geriatr Soc 57(11): 2129–2138. [DOI] [PubMed] [Google Scholar]
- Kish SJ (2008). “Pharmacologic mechanisms of crystal meth.” CMAJ : Canadian Medical Association Journal 178(13): 1679–1682. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kleijn J, Folgering JH, van der Hart MC, Rollema H, Cremers TI and Westerink BH (2011). “Direct effect of nicotine on mesolimbic dopamine release in rat nucleus accumbens shell.” Neurosci Lett 493(1–2): 55–58. [DOI] [PubMed] [Google Scholar]
- Koenig S, Gendelman HE, Orenstein JM, Dal Canto MC, Pezeshkpour GH, Yungbluth M, Janotta F, Aksamit A, Martin MA and Fauci AS (1986). “Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy.” Science 233(4768): 1089–1093. [DOI] [PubMed] [Google Scholar]
- Kousik SM, Napier TC and Carvey PM (2012). “The effects of psychostimulant drugs on blood brain barrier function and neuroinflammation.” Front Pharmacol 3: 121. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Koutsilieri E, ter Meulen V and Riederer P (2001). “Neurotransmission in HIV associated dementia: a short review.” J Neural Transm (Vienna) 108(6): 767–775. [DOI] [PubMed] [Google Scholar]
- Kraft-Terry SD, Buch SJ, Fox HS and Gendelman HE (2009). “A coat of many colors: neuroimmune crosstalk in human immunodeficiency virus infection.” Neuron 64(1): 133–145. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Krasnova IN and Cadet JL (2009). “METHAMPHETAMINE TOXICITY AND MESSENGERS OF DEATH.” Brain research reviews 60(2): 379–407. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kumar AM, Ownby RL, Waldrop-Valverde D, Fernandez B and Kumar M (2011). “Human immunodeficiency virus infection in the CNS and decreased dopamine availability: relationship with neuropsychological performance.” J Neurovirol 17(1): 26–40. [DOI] [PubMed] [Google Scholar]
- Kure K, Llena JF, Lyman WD, Soeiro R, Weidenheim KM, Hirano A and Dickson DW (1991). “Human immunodeficiency virus-1 infection of the nervous system: an autopsy study of 268 adult, pediatric, and fetal brains.” Hum Pathol 22(7): 700–710. [DOI] [PubMed] [Google Scholar]
- Lagathu C, Eustace B, Prot M, Frantz D, Gu Y, Bastard JP, Maachi M, Azoulay S, Briggs M, Caron M and Capeau J (2007). “Some HIV antiretrovirals increase oxidative stress and alter chemokine, cytokine or adiponectin production in human adipocytes and macrophages.” Antivir Ther 12(4): 489–500. [PubMed] [Google Scholar]
- Lan P, Tonomura N, Shimizu A, Wang S and Yang YG (2006). “Reconstitution of a functional human immune system in immunodeficient mice through combined human fetal thymus/liver and CD34+ cell transplantation.” Blood 108(2): 487–492. [DOI] [PubMed] [Google Scholar]
- Larsson M, Hagberg L, Forsman A and Norkrans G (1991). “Cerebrospinal fluid catecholamine metabolites in HIV-infected patients.” J Neurosci Res 28(3): 406–409. [DOI] [PubMed] [Google Scholar]
- Laskin DL and Pendino KJ (1995). “Macrophages and inflammatory mediators in tissue injury.” Annu Rev Pharmacol Toxicol 35: 655–677. [DOI] [PubMed] [Google Scholar]
- Levine AJ, Reynolds S, Cox C, Miller EN, Sinsheimer JS, Becker JT, Martin E, Sacktor N and Neuropsychology ACS Working Group of the Multicenter (2014). “The longitudinal and interactive effects of HIV status, stimulant use, and host genotype upon neurocognitive functioning.” J Neurovirol 20(3): 243–257. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Levite M (2016). “Dopamine and T cells: dopamine receptors and potent effects on T cells, dopamine production in T cells, and abnormalities in the dopaminergic system in T cells in autoimmune, neurological and psychiatric diseases.” Acta Physiol (Oxf) 216(1): 42–89. [DOI] [PubMed] [Google Scholar]
- Levite M, Chowers Y, Ganor Y, Besser M, Hershkovits R and Cahalon L (2001). “Dopamine interacts directly with its D3 and D2 receptors on normal human T cells, and activates beta1 integrin function.” Eur J Immunol 31(12): 3504–3512. [DOI] [PubMed] [Google Scholar]
- Liu J, Xu E, Tu G, Liu H, Luo J and Xiong H (2017). “Methamphetamine potentiates HIV-1gp120-induced microglial neurotoxic activity by enhancing microglial outward K(+) current.” Molecular and cellular neurosciences 82: 167–175. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Liu QH, Williams DA, McManus C, Baribaud F, Doms RW, Schols D, De Clercq E, Kotlikoff MI, Collman RG and Freedman BD (2000). “HIV-1 gp120 and chemokines activate ion channels in primary macrophages through CCR5 and CXCR4 stimulation.” Proc Natl Acad Sci U S A 97(9): 4832–4837. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lucas GM, Griswold M, Gebo KA, Keruly J, Chaisson RE and Moore RD (2006). “Illicit drug use and HIV-1 disease progression: a longitudinal study in the era of highly active antiretroviral therapy.” Am J Epidemiol 163(5): 412–420. [DOI] [PubMed] [Google Scholar]
- Lucas S and Nelson AM (2015). “HIV and the spectrum of human disease.” J Pathol 235(2): 229–241. [DOI] [PubMed] [Google Scholar]
- Lyons A, Pitts M and Grierson J (2013). “Methamphetamine use in a nationwide online sample of older Australian HIV-positive and HIV-negative gay men.” Drug Alcohol Rev 32(6): 603–610. [DOI] [PubMed] [Google Scholar]
- Mahajan SD, Aalinkeel R, Sykes DE, Reynolds JL, Bindukumar B, Adal A, Qi M, Toh J, Xu G, Prasad PN and Schwartz SA (2008). “Methamphetamine alters blood brain barrier permeability via the modulation of tight junction expression: Implication for HIV-1 neuropathogenesis in the context of drug abuse.” Brain research 1203: 133–148. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Manfredi R (2002). “HIV disease and advanced age: an increasing therapeutic challenge.” Drugs Aging 19(9): 647–669. [DOI] [PubMed] [Google Scholar]
- Mantri CK, Pandhare Dash J, Mantri JV and Dash CC (2012). “Cocaine enhances HIV-1 replication in CD4+ T cells by down-regulating MiR-125b.” PLoS One 7(12): e51387. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Marcondes MC, Burudi EM, Huitron-Resendiz S, Sanchez-Alavez M, Watry D, Zandonatti M, Henriksen SJ and Fox HS (2001). “Highly activated CD8(+) T cells in the brain correlate with early central nervous system dysfunction in simian immunodeficiency virus infection.” J Immunol 167(9): 5429–5438. [DOI] [PubMed] [Google Scholar]
- Marcondes MCG, Flynn C, Watry DD, Zandonatti M and Fox HS (2010). “Methamphetamine Increases Brain Viral Load and Activates Natural Killer Cells in Simian Immunodeficiency Virus-Infected Monkeys.” The American Journal of Pathology 177(1): 355–361. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Martin EM, Pitrak DL, Rains N, Grbesic S, Pursell K, Nunnally G and Bechara A (2003). “Delayed nonmatch-to-sample performance in HIV-seropositive and HIV-seronegative polydrug abusers.” Neuropsychology 17(2): 283–288. [DOI] [PubMed] [Google Scholar]
- Matt SM and Gaskill PJ (2019). “Dopaminergic impact of cART and anti-depressants on HIV neuropathogenesis in older adults.” Brain Res 1723: 146398. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Matt SM and Gaskill PJ (2019). “Where Is Dopamine and how do Immune Cells See it?: Dopamine-Mediated Immune Cell Function in Health and Disease.” J Neuroimmune Pharmacol. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McKenna F, McLaughlin PJ, Lewis BJ, Sibbring GC, Cummerson JA, Bowen-Jones D and Moots RJ (2002). “Dopamine receptor expression on human T- and B-lymphocytes, monocytes, neutrophils, eosinophils and NK cells: a flow cytometric study.” Journal of Neuroimmunology 132(1): 34–40. [DOI] [PubMed] [Google Scholar]
- Meade CS, Conn NA, Skalski LM and Safren SA (2011). “Neurocognitive impairment and medication adherence in HIV patients with and without cocaine dependence.” J Behav Med 34(2): 128–138. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Meade CS, Lowen SB, MacLean RR, Key MD and Lukas SE (2011). “fMRI brain activation during a delay discounting task in HIV-positive adults with and without cocaine dependence.” Psychiatry Res 192(3): 167–175. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Meade CS, Towe SL, Skalski LM and Robertson KR (2015). “Independent effects of HIV infection and cocaine dependence on neurocognitive impairment in a community sample living in the southern United States.” Drug Alcohol Depend 149: 128–135. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Melo P, Zanon-Moreno V, Alves CJ, Magalhaes A, Tavares MA, Pinazo-Duran MD and Moradas-Ferreira P (2010). “Oxidative stress response in the adult rat retina and plasma after repeated administration of methamphetamine.” Neurochem Int 56(3): 431–436. [DOI] [PubMed] [Google Scholar]
- Meyer VJ, Little DM, Fitzgerald DA, Sundermann EE, Rubin LH, Martin EM, Weber KM, Cohen MH and Maki PM (2014). “Crack cocaine use impairs anterior cingulate and prefrontal cortex function in women with HIV infection.” J Neurovirol 20(4): 352–361. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Meyer VJ, Rubin LH, Martin E, Weber KM, Cohen MH, Golub ET, Valcour V, Young MA, Crystal H, Anastos K, Aouizerat BE, Milam J and Maki PM (2013). “HIV and recent illicit drug use interact to affect verbal memory in women.” J Acquir Immune Defic Syndr 63(1): 67–76. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Minagar A, Shapshak P, Fujimura R, Ownby R, Heyes M and Eisdorfer C (2002). “The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis.” Journal of the Neurological Sciences 202(1): 13–23. [DOI] [PubMed] [Google Scholar]
- Minassian A, Henry BL, Iudicello JE, Morgan EE, Letendre SL, Heaton RK, Perry W and Translational Methamphetamine ARC (2017). “Everyday functional ability in HIV and methamphetamine dependence.” Drug Alcohol Depend 175: 60–66. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mollan KR, Smurzynski M, Eron JJ, Daar ES, Campbell TB, Sax PE, Gulick RM, Na L, O’Keefe L, Robertson KR and Tierney C (2014). “Association between efavirenz as initial therapy for HIV-1 infection and increased risk for suicidal ideation or attempted or completed suicide: an analysis of trial data.” Ann Intern Med 161(1): 1–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Montoya JL, Cattie J, Morgan E, Woods SP, Cherner M, Moore DJ, Atkinson JH, Grant I and Translational G Methamphetamine Aids Research Center (2016). “The impact of age, HIV serostatus and seroconversion on methamphetamine use.” Am J Drug Alcohol Abuse 42(2): 168–177. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Morrow WJ, Wharton M, Lau D and Levy JA (1987). “Small animals are not susceptible to human immunodeficiency virus infection.” J Gen Virol 68 (Pt 8): 2253–2257. [DOI] [PubMed] [Google Scholar]
- Munjal S, Ferrando SJ and Freyberg Z (2017). “Neuropsychiatric Aspects of Infectious Diseases: An Update.” Crit Care Clin 33(3): 681–712. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Najera JA, Bustamante EA, Bortell N, Morsey B, Fox HS, Ravasi T and Marcondes MC (2016). “Methamphetamine abuse affects gene expression in brain-derived microglia of SIV-infected macaques to enhance inflammation and promote virus targets.” BMC Immunol 17(1): 7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nath A, Hauser KF, Wojna V, Booze RM, Maragos W, Prendergast M, Cass W and Turchan JT (2002). “Molecular basis for interactions of HIV and drugs of abuse.” J Acquir Immune Defic Syndr 31 Suppl 2: S62–69. [DOI] [PubMed] [Google Scholar]
- Navia BA, Cho ES, Petito CK and Price RW (1986). “The AIDS dementia complex: II. Neuropathology.” Ann Neurol 19(6): 525–535. [DOI] [PubMed] [Google Scholar]
- Nguyen TP, Soukup VM and Gelman BB (2010). “Persistent hijacking of brain proteasomes in HIV-associated dementia.” Am J Pathol 176(2): 893–902. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nickoloff EA, Mackie P, Runner K, Matt SM, Khoshbouei H and Gaskill PJ (2019). “Dopamine increases HIV entry into macrophages by increasing calcium release via an alternative signaling pathway.” Brain Behav Immun. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nightingale S, Winston A, Letendre S, Michael BD, McArthur JC, Khoo S and Solomon T (2014). “Controversies in HIV-associated neurocognitive disorders.” The Lancet Neurology 13(11): 1139–1151. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nolan R and Gaskill PJ (2018). “The role of catecholamines in HIV neuropathogenesis.” Brain Res. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nolan RA, Muir R, Runner K, Haddad EK and Gaskill PJ (2019). “Role of Macrophage Dopamine Receptors in Mediating Cytokine Production: Implications for Neuroinflammation in the Context of HIV-Associated Neurocognitive Disorders.” J Neuroimmune Pharmacol 14(1): 134–156. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nolan RA, Reeb KL, Rong Y, Matt SM, Johnson HS, Runner K, and Gaskill PJ (2019). “Dopamine activates NF-κB and primes the NLRP3 inflammasome in primary human macrophages.” Brain, Behavior and Immunity - Health. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Norman LR and Basso M (2015). “An Update of the Review of Neuropsychological Consequences of HIV and Substance Abuse: A Literature Review and Implications for Treatment and Future Research.” Current drug abuse reviews 8(1): 50–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Okoye AA and Picker LJ (2013). “CD4(+) T-cell depletion in HIV infection: mechanisms of immunological failure.” Immunological reviews 254(1): 54–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Peterson PK, Gekker G, Chao CC, Schut R, Molitor TW and Balfour HH Jr. (1991). “Cocaine potentiates HIV-1 replication in human peripheral blood mononuclear cell cocultures. Involvement of transforming growth factor-beta.” J Immunol 146(1): 81–84. [PubMed] [Google Scholar]
- Petito CK, Adkins B, McCarthy M, Roberts B and Khamis I (2003). “CD4+ and CD8+ cells accumulate in the brains of acquired immunodeficiency syndrome patients with human immunodeficiency virus encephalitis.” J Neurovirol 9(1): 36–44. [DOI] [PubMed] [Google Scholar]
- Pierce RC and Kumaresan V (2006). “The mesolimbic dopamine system: the final common pathway for the reinforcing effect of drugs of abuse?” Neurosci Biobehav Rev 30(2): 215–238. [DOI] [PubMed] [Google Scholar]
- Popov M, Molsberry SA, Lecci F, Junker B, Kingsley LA, Levine A, Martin E, Miller E, Munro CA, Ragin A, Seaberg E, Sacktor N and Becker JT (2019). “Brain structural correlates of trajectories to cognitive impairment in men with and without HIV disease.” Brain Imaging Behav. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Potash MJ, Chao W, Bentsman G, Paris N, Saini M, Nitkiewicz J, Belem P, Sharer L, Brooks AI and Volsky DJ (2005). “A mouse model for study of systemic HIV-1 infection, antiviral immune responses, and neuroinvasiveness.” Proceedings of the National Academy of Sciences of the United States of America 102(10): 3760–3765. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Poundstone KE, Chaisson RE and Moore RD (2001). “Differences in HIV disease progression by injection drug use and by sex in the era of highly active antiretroviral therapy.” AIDS 15(9): 1115–1123. [DOI] [PubMed] [Google Scholar]
- Rao P, Ande A, Sinha N, Kumar A and Kumar S (2016). “Effects of Cigarette Smoke Condensate on Oxidative Stress, Apoptotic Cell Death, and HIV Replication in Human Monocytic Cells.” PLoS One 11(5): e0155791. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rappaport J and Volsky DJ (2015). “Role of the macrophage in HIV-associated neurocognitive disorders and other comorbidities in patients on effective antiretroviral treatment.” J Neurovirol 21(3): 235–241. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Reyes MG, Faraldi F, Senseng CS, Flowers C and Fariello R (1991). “Nigral degeneration in acquired immune deficiency syndrome (AIDS).” Acta Neuropathol 82(1): 39–44. [DOI] [PubMed] [Google Scholar]
- Rippeth JD, Heaton RK, Carey CL, Marcotte TD, Moore DJ, Gonzalez R, Wolfson T, Grant I and Group H (2004). “Methamphetamine dependence increases risk of neuropsychological impairment in HIV infected persons.” J Int Neuropsychol Soc 10(1): 1–14. [DOI] [PubMed] [Google Scholar]
- Roth MD, Tashkin DP, Choi R, Jamieson BD, Zack JA and Baldwin GC (2002). “Cocaine enhances human immunodeficiency virus replication in a model of severe combined immunodeficient mice implanted with human peripheral blood leukocytes.” J Infect Dis 185(5): 701–705. [DOI] [PubMed] [Google Scholar]
- Saloner R and Cysique LA (2017). “HIV-Associated Neurocognitive Disorders: A Global Perspective.” J Int Neuropsychol Soc 23(9–10): 860–869. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sanchez AB and Kaul M (2017). “Neuronal Stress and Injury Caused by HIV-1, cART and Drug Abuse: Converging Contributions to HAND.” Brain Sci 7(3). [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sarkar C, Basu B, Chakroborty D, Dasgupta PS and Basu S (2010). “The immunoregulatory role of dopamine: an update.” Brain Behav Immun 24(4): 525–528. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Saylor D, Dickens AM, Sacktor N, Haughey N, Slusher B, Pletnikov M, Mankowski JL, Brown A, Volsky DJ and McArthur JC (2016). “HIV-associated neurocognitive disorder--pathogenesis and prospects for treatment.” Nat Rev Neurol 12(4): 234–248. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schaale K, Peters KM, Murthy AM, Fritzsche AK, Phan MD, Totsika M, Robertson AA, Nichols KB, Cooper MA, Stacey KJ, Ulett GC, Schroder K, Schembri MA and Sweet MJ (2016). “Strain- and host species-specific inflammasome activation, IL-1beta release, and cell death in macrophages infected with uropathogenic Escherichia coli.” Mucosal Immunol 9(1): 124–136. [DOI] [PubMed] [Google Scholar]
- Scheller C, Arendt G, Nolting T, Antke C, Sopper S, Maschke M, Obermann M, Angerer A, Husstedt IW, Meisner F, Neuen-Jacob E, Muller HW, Carey P, Ter Meulen V, Riederer P and Koutsilieri E (2010). “Increased dopaminergic neurotransmission in therapy-naive asymptomatic HIV patients is not associated with adaptive changes at the dopaminergic synapses.” J Neural Transm (Vienna) 117(6): 699–705. [DOI] [PubMed] [Google Scholar]
- Scheller C, Sopper S, Jenuwein M, Neuen-Jacob E, Tatschner T, Grunblatt E, ter Meulen V, Riederer P and Koutsilieri E (2005). “Early impairment in dopaminergic neurotransmission in brains of SIV-infected rhesus monkeys due to microglia activation.” J Neurochem 95(2): 377–387. [DOI] [PubMed] [Google Scholar]
- Schroder K, Irvine KM, Taylor MS, Bokil NJ, Le Cao KA, Masterman KA, Labzin LI, Semple CA, Kapetanovic R, Fairbairn L, Akalin A, Faulkner GJ, Baillie JK, Gongora M, Daub CO, Kawaji H, McLachlan GJ, Goldman N, Grimmond SM, Carninci P, Suzuki H, Hayashizaki Y, Lenhard B, Hume DA and Sweet MJ (2012). “Conservation and divergence in Toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages.” Proc Natl Acad Sci U S A 109(16): E944–953. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schuster RM and Gonzalez R (2012). “Substance Abuse, Hepatitis C, and Aging in HIV: Common Cofactors that Contribute to Neurobehavioral Disturbances.” Neurobehavioral HIV medicine 2012(4): 15–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Seiden LS, Fischman MW and Schuster CR (1976). “Long-term methamphetamine induced changes in brain catecholamines in tolerant rhesus monkeys.” Drug Alcohol Depend 1(3): 215–219. [DOI] [PubMed] [Google Scholar]
- Sereti I, Krebs SJ, Phanuphak N, Fletcher JL, Slike B, Pinyakorn S, O’Connell RJ, Rupert A, Chomont N, Valcour V, Kim JH, Robb ML, Michael NL, Douek DC, Ananworanich J, Utay NS, R. S. Rv254/Search and S. p. teams (2017). “Persistent, Albeit Reduced, Chronic Inflammation in Persons Starting Antiretroviral Therapy in Acute HIV Infection.” Clin Infect Dis 64(2): 124–131. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shive CL, Biancotto A, Funderburg NT, Pilch-Cooper HA, Valdez H, Margolis L, Sieg SF, McComsey GA, Rodriguez B and Lederman MM (2012). “HIV-1 is not a major driver of increased plasma IL-6 levels in chronic HIV-1 disease.” J Acquir Immune Defic Syndr 61(2): 145–152. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Silveira MP, Guttier MC, Pinheiro CA, Pereira TV, Cruzeiro AL and Moreira LB (2012). “Depressive symptoms in HIV-infected patients treated with highly active antiretroviral therapy.” Braz J Psychiatry 34(2): 162–167. [DOI] [PubMed] [Google Scholar]
- Skalski LM, Sikkema KJ, Heckman TG and Meade CS (2013). “Coping styles and illicit drug use in older adults with HIV/AIDS.” Psychol Addict Behav 27(4): 1050–1058. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Small W, Milloy MJ, McNeil R, Maher L and Kerr T (2016). “Plasma HIV-1 RNA viral load rebound among people who inject drugs receiving antiretroviral therapy (ART) in a Canadian setting: an ethno-epidemiological study.” AIDS Res Ther 13: 26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Spudich S and González-Scarano F (2012). “HIV-1-related central nervous system disease: current issues in pathogenesis, diagnosis, and treatment.” Cold Spring Harbor perspectives in medicine 2(6): a007120–a007120. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stahl SM (1998). “Basic psychopharmacology of antidepressants, part 1: Antidepressants have seven distinct mechanisms of action.” J Clin Psychiatry 59 Suppl 4: 5–14. [PubMed] [Google Scholar]
- Steele AD, Henderson EE and Rogers TJ (2003). “Mu-opioid modulation of HIV-1 coreceptor expression and HIV-1 replication.” Virology 309(1): 99–107. [DOI] [PubMed] [Google Scholar]
- Stevenson PG, Hawke S, Sloan DJ and Bangham CR (1997). “The immunogenicity of intracerebral virus infection depends on anatomical site.” J Virol 71(1): 145–151. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tavazzi E, Morrison D, Sullivan P, Morgello S and Fischer T (2014). “Brain inflammation is a common feature of HIV-infected patients without HIV encephalitis or productive brain infection.” Curr HIV Res 12(2): 97–110. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tomlinson GS, Simmonds P, Busuttil A, Chiswick A and Bell JE (1999). “Upregulation of microglia in drug users with and without pre-symptomatic HIV infection.” Neuropathol Appl Neurobiol 25(5): 369–379. [DOI] [PubMed] [Google Scholar]
- Treisman GJ and Soudry O (2016). “Neuropsychiatric Effects of HIV Antiviral Medications.” Drug Saf 39(10): 945–957. [DOI] [PubMed] [Google Scholar]
- Turchan J, Anderson C, Hauser KF, Sun Q, Zhang J, Liu Y, Wise PM, Kruman I, Maragos W, Mattson MP, Booze R and Nath A (2001). “Estrogen protects against the synergistic toxicity by HIV proteins, methamphetamine and cocaine.” BMC Neuroscience 2: 3–3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ulfhammer G, Eden A, Mellgren A, Fuchs D, Zetterberg H, Hagberg L, Nilsson S, Yilmaz A and Gisslen M (2018). “Persistent central nervous system immune activation following more than 10 years of effective HIV antiretroviral treatment.” AIDS 32(15): 2171–2178. [DOI] [PubMed] [Google Scholar]
- Valcour V, Chalermchai T, Sailasuta N, Marovich M, Lerdlum S, Suttichom D, Suwanwela NC, Jagodzinski L, Michael N, Spudich S, van Griensven F, de Souza M, Kim J and Ananworanich J (2012). “Central nervous system viral invasion and inflammation during acute HIV infection.” J Infect Dis 206(2): 275–282. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Valcour V, Paul R, Neuhaus J and Shikuma C (2011). “The Effects of Age and HIV on Neuropsychological Performance.” J Int Neuropsychol Soc 17(1): 190–195. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Valcour V, Sithinamsuwan P, Letendre S and Ances B (2011). “Pathogenesis of HIV in the central nervous system.” Curr HIV/AIDS Rep 8(1): 54–61. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Valcour VG, Shikuma CM, Watters MR and Sacktor NC (2004). “Cognitive impairment in older HIV-1-seropositive individuals: prevalence and potential mechanisms.” Aids 18 Suppl 1: S79–86. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Venerosi A, Valanzano A, Puopolo M and Calamandrei G (2005). “Neurobehavioral effects of prenatal exposure to AZT: a preliminary investigation with the D1 receptor agonist SKF 38393 in mice.” Neurotoxicol Teratol 27(1): 169–173. [DOI] [PubMed] [Google Scholar]
- Vera JH, Guo Q, Cole JH, Boasso A, Greathead L, Kelleher P, Rabiner EA, Kalk N, Bishop C, Gunn RN, Matthews PM and Winston A (2016). “Neuroinflammation in treated HIV-positive individuals: A TSPO PET study.” Neurology 86(15): 1425–1432. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Volkow ND, Wang GJ, Fowler JS, Logan J, Hitzemannn R, Gatley SJ, MacGregor RR and Wolf AP (1996). “Cocaine uptake is decreased in the brain of detoxified cocaine abusers.” Neuropsychopharmacology 14(3): 159–168. [DOI] [PubMed] [Google Scholar]
- Volkow ND, Wise RA and Baler R (2017). “The dopamine motive system: implications for drug and food addiction.” Nat Rev Neurosci 18(12): 741–752. [DOI] [PubMed] [Google Scholar]
- Wada NI, Jacobson LP, Margolick JB, Breen EC, Macatangay B, Penugonda S, Martinez-Maza O and Bream JH (2015). “The effect of HAART-induced HIV suppression on circulating markers of inflammation and immune activation.” AIDS 29(4): 463–471. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Walker KA and Brown GG (2018). “HIV-associated executive dysfunction in the era of modern antiretroviral therapy: A systematic review and meta-analysis.” J Clin Exp Neuropsychol 40(4): 357–376. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Watkins CC and Treisman GJ (2012). “Neuropsychiatric complications of aging with HIV.” J Neurovirol 18(4): 277–290. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Weed M, Adams RJ, Hienz RD, Meulendyke KA, Linde ME, Clements JE, Mankowski JL and Zink MC (2012). “SIV/Macaque Model of HIV Infection in Cocaine Users: Minimal Effects of Cocaine on Behavior, Virus Replication, and CNS Inflammation.” Journal of Neuroimmune Pharmacology 7(2): 401–411. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wiley CA, Soontornniyomkij V, Radhakrishnan L, Masliah E, Mellors J, Hermann SA, Dailey P and Achim CL (1998). “Distribution of brain HIV load in AIDS.” Brain Pathol 8(2): 277–284. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Williams DW, Calderon TM, Lopez L, Carvallo-Torres L, Gaskill PJ, Eugenin EA, Morgello S and Berman JW (2013). “Mechanisms of HIV Entry into the CNS: Increased Sensitivity of HIV Infected CD14(+)CD16(+) Monocytes to CCL2 and Key Roles of CCR2, JAM-A, and ALCAM in Diapedesis.” PLoS ONE 8(7): e69270. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Williams DW, Veenstra M, Gaskill PJ, Morgello S, Calderon TM and Berman JW (2014). “Monocytes mediate HIV neuropathogenesis: mechanisms that contribute to HIV associated neurocognitive disorders.” Curr HIV Res 12(2): 85–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wright PW, Pyakurel A, Vaida FF, Price RW, Lee E, Peterson J, Fuchs D, Zetterberg H, Robertson KR, Walter R, Meyerhoff DJ, Spudich SS and Ances BM (2016). “Putamen volume and its clinical and neurological correlates in primary HIV infection.” AIDS 30(11): 1789–1794. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wu Q, Reith ME, Kuhar MJ, Carroll FI and Garris PA (2001). “Preferential increases in nucleus accumbens dopamine after systemic cocaine administration are caused by unique characteristics of dopamine neurotransmission.” J Neurosci 21(16): 6338–6347. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yadav A and Collman RG (2009). “CNS inflammation and macrophage/microglial biology associated with HIV-1 infection.” J Neuroimmune Pharmacol 4(4): 430–447. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yan Y, Jiang W, Liu L, Wang X, Ding C, Tian Z and Zhou R (2015). “Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome.” Cell 160(1–2): 62–73. [DOI] [PubMed] [Google Scholar]
- Yao H and Buch S (2012). “Rodent models of HAND and drug abuse: exogenous administration of viral protein(s) and cocaine.” J Neuroimmune Pharmacol 7(2): 341–351. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yilmaz A, Price RW, Spudich S, Fuchs D, Hagberg L and Gisslen M (2008). “Persistent intrathecal immune activation in HIV-1-infected individuals on antiretroviral therapy.” J Acquir Immune Defic Syndr 47(2): 168–173. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yusuf AJ, Hassan A, Mamman AI, Muktar HM, Suleiman AM and Baiyewu O (2017). “Prevalence of HIV-Associated Neurocognitive Disorder (HAND) among Patients Attending a Tertiary Health Facility in Northern Nigeria.” J Int Assoc Provid AIDS Care 16(1): 48–55. [DOI] [PMC free article] [PubMed] [Google Scholar]