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. 2024 Feb 5;36:100737. doi: 10.1016/j.bbih.2024.100737

Accelerated aging in people living with HIV: The neuroimmune feedback model

Joshua M Schrock 1
PMCID: PMC10864877  PMID: 38356933

Abstract

People living with HIV (PLWH) experience earlier onset of aging-related comorbidities compared to their counterparts without HIV. This paper lays out a theoretical model to explain why PLWH experience accelerated aging. Briefly, the model is structured as follows. PLWH experience disproportionately heavy burdens of psychosocial stress across the life course. This psychosocial stress increases risks for depressive symptoms and problematic substance use. Depressive symptoms and problematic substance use interfere with long-term adherence to antiretroviral therapy (ART). Lower ART adherence, in turn, exacerbates the elevated systemic inflammation stemming from HIV infection. This inflammation increases risks for aging-related comorbidities. Systemic inflammation also reduces connectivity in the brain's central executive network (CEN), a large-scale brain network that is critical for coping with stressful circumstances. This reduced capacity for coping with stress leads to further increases in depressive symptoms and problematic substance use. Together, these changes form a neuroimmune feedback loop that amplifies the impact of psychosocial stress on aging-related comorbidities. In this paper, I review the existing evidence relevant to this model and highlight directions for future research.

1. Introduction

People living with HIV (PLWH) experience earlier onset of aging-related comorbidities such as cardiovascular disease (Hanna et al., 2016; Yang et al., 2019), type 2 diabetes (Guaraldi et al., 2018; Hernandez-Romieu et al., 2017), frailty (Desquilbet et al., 2007), and cognitive impairment (Yang et al., 2019) compared to people without HIV. PLWH also exhibit older biological age as indicated by epigenetic clocks and telomere length (Breen et al., 2022). Combination antiretroviral therapy (ART) has dramatically extended life expectancy in PLWH, but comorbidity-free life expectancies remain substantially shorter in PLWH compared to the general population (Marcus et al., 2020). Despite this overall pattern of accelerated aging, healthy aging is possible for PLWH. A pilot study found that 39% of PLWH exhibited healthy aging as indicated by the multidimensional Rotterdam Healthy Aging Score (Walmsley et al., 2020).

This paper lays out a theoretical model to explain why PLWH experience accelerated aging. This model also helps explain why healthy aging is possible for PLWH, despite a clear population-level pattern of accelerated aging among PLWH.

Briefly, the model is structured as follows. PLWH experience disproportionately heavy burdens of psychosocial stress across the life course. This psychosocial stress increases risks for depressive symptoms and problematic substance use. Depressive symptoms and problematic substance use interfere with long-term adherence to ART. Lower ART adherence, in turn, exacerbates the elevated systemic inflammation stemming from HIV infection. This inflammation increases risks for aging-related comorbidities. Systemic inflammation also reduces connectivity in the brain's central executive network (CEN), a large-scale brain network that is critical for coping with stressful circumstances. This reduced capacity for coping with stress leads to further increases in depressive symptoms and problematic substance use. Together, these changes form a neuroimmune feedback loop that amplifies the impact of psychosocial stress on aging-related comorbidities (Fig. 1).

Fig. 1.

Fig. 1

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The neuroimmune feedback model. Repeated cycling of this feedback loop drives increasing risks for aging-related comorbidities in people living with HIV. ART = antiretroviral therapy; CEN = central executive network.

Repeated cycling of this feedback loop leads to increases in systemic inflammation over time. These increases in systemic inflammation accelerate the pathogenesis of aging-related comorbidities such as cardiovascular disease, type 2 diabetes, frailty, and neurocognitive impairment.

PLWH who experience lower burdens of psychosocial stress may be less vulnerable to accelerated aging driven by this neuroimmune feedback loop. Resilience factors that disrupt the feedback loop (e.g., strong social support, retention in medical care, robust mental health) may protect against accelerated aging.

The components of this theoretical model can be divided into six causal hypotheses: 1) Greater psychosocial stress increases the severity of depressive symptoms and problematic substance use, 2) Depressive symptoms and problematic substance use reduce ART adherence, and 3) Lower ART adherence increases systemic inflammation, 4) Greater systemic inflammation reduces connectivity in the CEN, 5) Lower connectivity in the CEN increases depressive symptoms and problematic substance use, and 6) Greater systemic inflammation increases risks for aging-related comorbidities. In the sections below, I briefly review and evaluate the current empirical evidence that bears on each hypothesis.

Hypothesis 1

Greater psychosocial stress increases the severity of depressive symptoms and problematic substance use.

PLWH experience unique stressors, including HIV stigma and the stress of managing a chronic condition (Dale et al., 2022; Orban et al., 2010). PLWH are also more likely to belong to marginalized groups in terms of sexual orientation (Bosh et al., 2021), gender modality (Baral et al., 2013), race/ethnicity (Bosh et al., 2021), socioeconomic status (Centers for Disease Control Prevention, 2011). PLWH experience higher rates of lifetime traumatic events and intimate partner violence compared to the general population (LeGrand et al., 2015). Together, these factors expose PLWH to a disproportionately heavy burden of psychosocial stress across the life course.

Existing evidence shows that psychosocial stressors and structural marginalization in multiple domains is associated with depressive symptoms and problematic substance use among PLWH (Earnshaw et al., 2020; Glynn et al., 2019; Liu et al., 2023; Burke et al., 2005). For example, one study found that lower education was associated with trajectories of worsening or persistently severe depressive symptoms among PLWH (Gunzler et al., 2020). A study of sexual minority men living with HIV and at high risk for HIV found that experiences of victimization were associated with higher levels of alcohol use, marijuana use, and illicit drug use (Swann et al., 2018). A study of Black women living with HIV found that gendered racial microaggressions were associated with increased depressive symptoms and greater odds of depression diagnosis (Dale and Safren, 2020). There is a small but growing body of longitudinal studies that provide evidence of directionality. For example, a study of women living with HIV found that internalized HIV stigma at baseline predicted depressive symptoms 18 months later (Turan et al., 2019). A longitudinal study of women living with or at risk for HIV found that those who reported being food insecure were more likely to report illicit substance use at the following visit (Whittle et al., 2019). Another study reported that unemployment was a longitudinal predictor of depression among men living with HIV (Ware et al., 2020). This paper is focused on depression and problematic substance use, but psychosocial stress may also contribute to other mental health conditions in PLWH, including anxiety and posttraumatic stress disorder (Olagunju et al., 2012; Andu et al., 2018). Further longitudinal work is needed to clarify the combined effects of psychosocial stress in multiple domains on depressive symptoms, problematic substance, and other mental health outcomes in PLWH.

Hypothesis 2

Depressive symptoms and problematic substance use reduce antiretroviral therapy (ART) adherence.

Depressive symptoms and problematic substance use can interfere with everyday life activities, such as attending medical appointments or remembering to take a prescribed medication (Grenard et al., 2011; Socias and Milloy, 2018).

Among PLWH, depressive symptoms and problematic substance use are associated with lower ART adherence. For example, one study found that PLWH who exhibited harmful alcohol use had nearly 7-fold higher odds of non-adherence and PLWH with depression had nearly 6-fold higher odds of non-adherence compared to PLWH who did not have these conditions (Parro-Torres et al., 2022). A study among women living with HIV found that greater internalized HIV stigma predicted lower ART adherence and this effect was longitudinally mediated by depressive symptoms (Turan et al., 2019). A meta-analysis found that receiving treatment for depression led to improvements in ART adherence (Sin and DiMatteo, 2014).

A multisite study examining a range of substances found that alcohol use, cocaine use, other stimulant use, and heroin use were associated with lower ART adherence, but marijuana use was not (Rosen et al., 2013). Another study found that PLWH who exhibit dependence on marijuana use exhibit reduced ART adherence, but those who exhibit non-dependent marijuana use do not (Bonn-Miller et al., 2014). A third study found that problematic cannabis use predicted consistently detectable HIV viral load (Xavier Hall et al., 2021). A meta-analysis found that among PLWH with opioid use disorder, those who were receiving medications to treat opioid use disorder exhibited higher ART adherence and were more likely to exhibit HIV viral suppression (McNamara et al., 2021).

Neurocognitive impairment, which is frequently comorbid with depression and problematic substance use, may also play a role in ART non-adherence (Nyundo, 2022; Rubin and Maki, 2019; Thaler et al., 2015). Along these lines, one study reported that PLWH with HIV-associated neurocognitive disorder had lower resting state functional connectivity in the CEN compared to healthy control participants (Chaganti et al., 2017).

Depressive symptoms and problematic substance use frequently co-occur (Bryant et al., 2015), and both have been linked to ART adherence. The temporal sequence linking depressive symptoms, substance use, and ART adherence is unclear. One possibility is that depressive symptoms lead to problematic substance use, and problematic substance use interferes with ART adherence. Alternatively, problematic substance use could interfere with ART adherence, which in turn could exacerbate depressive symptoms via neuroinflammatory pathways. Longitudinal studies are needed to clarify the timescales and temporal sequences linking depressive symptoms, substance use, and ART adherence (Hammond et al., 2016).

Hypothesis 3

Lower antiretroviral therapy (ART) adherence increases systemic inflammation.

PLWH exhibit elevated markers of immune activation and systemic inflammation compared to their counterparts without HIV (Subramanya et al., 2019; Kiefer et al., 2018; Temu et al., 2021). Successful viral suppression of HIV through ART partially reverses the systemic inflammation associated with HIV, but residual excess systemic inflammation is detectable even in PLWH who achieve sustained viral suppression (Wada et al., 2015; Masyuko et al., 2021; Castillo-Mancilla et al., 2020). Multiple inflammatory markers remain elevated even when ART adherence is good and the virus is suppressed (Castillo-Mancilla et al., 2020).

A growing body of evidence suggests that a patient's level of adherence to ART (e.g., proportion of doses missed) is an important determinant of systemic inflammation among PLWH. For example, one study used electronic monitoring of pill caps to assess ART adherence among PLWH who were virally suppressed. That study reported that longer interruptions of ART adherence were associated with higher plasma levels of multiple inflammatory markers (Musinguzi et al., 2019). Another study found that every 10% increase in ART adherence was associated with a 15% decrease in circulating concentrations of the pro-inflammatory cytokine interleukin-6 (Castillo-Mancilla et al., 2018). A third study found that the effect of ART adherence on circulating interleukin-6 was stronger among PLWH who initiated ART during early infection (Castillo-Mancilla et al., 2022), which suggests that early detection and treatment does not negate the need for high levels of ART adherence to limit systemic inflammation. Intermittent nonadherence to ART can lead to blips of increased viral replication – these blips are a likely cause of peripheral inflammation and neuroinflammation in PLWH (Yukl et al., 2010; Calvo-Cidoncha et al., 2015; Fleming et al., 2019). It is also worth noting that psychosocial stress may also exert direct pro-inflammatory effects, even in the absence of depressive symptoms, problematic substance use, and ART non-adherence (Chow et al., 2023; Stadtler et al., 2021).

It is important to note that reverse causality is a potential alternative explanation for the observed associations between ART adherence and systemic inflammation. For example, increased systemic inflammation could increase depressive symptoms, and depressive symptoms could interfere with ART adherence. Alternatively, a third variable could cause both low ART adherence and high systemic inflammation, resulting in spurious correlations. Rigorous modeling approaches (e.g., random intercept cross-lagged panel models) could be used to establish the directionality of the relationship between ART adherence and systemic inflammation.

Hypothesis 4

Greater inflammation reduces connectivity in the Central Executive Network (CEN).

The CEN is a large-scale brain network that subserves several key functions in the pursuit of goal-directed behavior, including problem-solving, decision-making, and manipulation of information in working memory (Borders, 2020). The CEN plays a key role in exerting self-control, reappraising stressful stimuli, and inhibiting impulses initiated by other brain systems (Turner et al., 2019; Gagnepain et al., 2017). These functions are important for successfully coping with stressful life circumstances (Menon, 2011).

Brain activity exhibits a reliable network architecture that can be observed at rest via functional magnetic resonance imaging (fMRI) (Raichle, 2015). Certain networks (e.g., the CEN) are consistently observed across subjects, but the degree of resting-state functional connectivity (rsFC) in these networks varies between individuals (Bressler and Menon, 2010).

Existing evidence suggests that PLWH exhibit lower resting-state functional connectivity (rsFC) in multiple large-scale networks, including the CEN, compared to healthy controls (Thomas et al., 2013). Recent research suggests that aging and HIV are associated with similar organizational patterns in the brain's network architecture (Lew et al., 2023). Given the role of systemic inflammation in the pathophysiology of both aging- and HIV-related comorbidities (Ferrucci and Fabbri, 2018), it is plausible that systemic inflammation is one of the mechanisms driving lower CEN rsFC in PLWH.

Experiments with animal models suggest that inflammation contributes to deficits in executive function (Culley et al., 2014). A study of PLWH found that peripheral inflammatory markers were associated with executive function (Swanta et al., 2020). Another study found that greater variability in C-reactive protein, perhaps reflecting intermittent waves of inflammation, is associated with lower executive function in PLWH (Rubin et al., 2018). These observations inspire the hypothesis for this section – that greater systemic inflammation reduces CEN rsFC. A growing body of observational and experimental evidence shows that peripheral inflammation leads to alterations in rsFC (Lekander et al., 2016; Labrenz et al., 2016; Walker et al., 2020), but existing studies vary widely in which networks and regions of interest they investigate.

To date, few studies have directly assessed associations between systemic inflammation and CEN rsFC. Inflammatory markers are associated with executive function in PLWH (Swanta et al., 2020; Rubin et al., 2018), but I am unaware of any studies directly assessing the association between CEN rsFC and inflammation in PLWH. A study of people with heart disease reported that cardiac surgery led to alterations in resting-state functional connectivity (rsFC) of the dorsolateral prefrontal cortex, a key anchoring region of the CEN (Zhu et al., 2023). These changes in connectivity were proportional to measures of executive function and plasma levels of tumor necrosis factor-a. These findings suggest that peripheral inflammation may play a role in altering brain networks underlying executive function.

Another study investigated peripheral inflammation and CEN rsFC in two separate age groups (Nusslock et al., 2019). In a sample of African American youth, ages 13–14, higher scores on a composite index of multiple inflammatory markers were associated with lower CEN rsFC. in a sample of African American young adults (age 25), the association between the inflammatory composite score and CEN rsFC was in the same direction as it was in the younger sample but not statistically significant. In this young adult sample, higher classical monocyte counts exhibited a statistically significant association with lower CEN rsFC, highlighting a potential role for monocyte trafficking in driving CEN rsFC.

Notably, monocyte chemoattractant protein-1 (MCP-1 or CCL2), a marker of increased monocyte trafficking, is associated with structural markers of brain tissue damage in PLWH (Ragin et al., 2006). Experimental work has shown that MCP-1 mediates enhanced transmigration of HIV-infected leukocytes across the blood-brain barrier (Eugenin et al., 2006). Reduced integrity of the blood-brain barrier has also been linked to brain tissue damage in HIV (Ellis et al., 2021a). Taken together, these findings suggest that monocyte trafficking from the periphery to the brain may play a key mechanistic role in connecting peripheral inflammatory immune activation to brain alterations in HIV.

A study using fluorodeoxyglucose positron emission tomography found that interferon alpha therapy reduced metabolic activity in the prefrontal cortex (Juengling et al., 2000). Notably these reductions in metabolism covaried with depressive symptoms. This suggests that inflammation-related decreases in CEN rsFC may be mediated by altered patterns of brain metabolism.

A considerable body of evidence demonstrates that systemic inflammation contributes to dopamine depletion (Miller et al., 2009, 2013; Felger et al., 2013; Capuron et al., 2012; Kamata et al., 2000; Mauriño et al., 2010; Harrison et al., 2015; Saloner et al., 2020; Labandeira-Garcia et al., 2012; Goodkin et al., 2023). Dopamine plays a key role in modulating functions of the prefrontal cortex (Ott and Nieder, 2019; Sotoyama et al., 2022). Thus, dopamine depletion is a potential mechanism linking HIV-related inflammation to alterations in CEN rsFC.

It is important to note that inflammation and affective symptoms may be associated with lower rcFC in some parts of the brain but higher rsFC in other parts of the brain. As an example of the latter, one study found that greater rsFC between the subgenual anterior cingulate cortex and the bilateral amygdala was associated with greater intensity of depressive symptoms, and greater amplitude of low-frequency fluctuations in the orbitomedial frontal cortex was associated with higher plasma levels of inflammatory proteins among PLWH (McIntosh et al., 2018).

Longitudinal research among PLWH is needed to test whether peripheral inflammation predicts subsequent reductions in CEN rsFC and to identify the specific mechanistic pathways linking peripheral inflammation to CEN rsFC.

Hypothesis 5

Lower connectivity in the Central Executive Network (CEN) increases depressive symptoms and problematic substance use.

Existing evidence suggests that lower CEN rsFC is associated with an increased risk for depression and problematic substance use (Kaiser et al., 2015; Wilcox et al., 2019). A meta-analysis reported that patients with major depressive disorder exhibit lower rsFC in the CEN compared to healthy controls (Kaiser et al., 2015). Along the same lines, lower rsFC in the CEN is associated with reduced cognitive control in patients with alcohol use disorder (Camchong et al., 2013), nicotine use disorder (Cole et al., 2010), stimulant use disorder (McHugh et al., 2017), and opioid use disorder (Zhai et al., 2015). Further research is needed to investigate whether these patterns persist in PLWH who also have depressive and/or substance use disorders.

Apathy, a general lack of motivation, is an especially common symptom in PLWH (Bryant et al., 2015). Apathy exhibits considerable overlap with the depressive symptom of anhedonia (a loss of interest in activities that are usually rewarding) (Husain and Roiser, 2018). Apathy and anhedonia share a set of underlying neural mechanisms (Husain and Roiser, 2018). Notably, a study of older adults (without HIV) with mild neurocognitive impairment found that lower CEN rsFC was associated with greater severity of affective symptoms, particularly apathy (Munro et al., 2015).

Sickness behavior is a set of behavior changes whose evolved function is to reduce active energy expenditure and prioritize immune function during infection (Shattuck and Muehlenbein, 2015). Depressive symptoms (including apathy and anhedonia) play a prominent role in sickness behavior (Schrock et al., 2019), and some cases of depression may be a chronic form of sickness behavior (Maes et al., 2012). Experimental studies have demonstrated that inflammatory immune activation plays a key mechanistic role in triggering sickness behavior (Lasselin et al., 2020). While depressive symptoms during acute infection are thought to be adaptive, chronic depressive symptoms in the context of chronic inflammation may become maladaptive and increase the risk of acquiring additional chronic comorbidities (Schrock et al., 2022). Clarifying the mechanistic links between sickness behavior and depressive symptoms may advance our understanding of how depressive disorders develop in PLWH.

A growing body of evidence suggests that peripheral inflammation and neuroinflammation may play a mechanistic role in linking HIV to elevated depressive symptoms. For example, a study reported that the association between HIV status and depressive symptoms is mediated by inflammatory markers in plasma and cerebrospinal fluid (Mudra Rakshasa-Loots et al., 2023). Astrocyte activation may play a role in linking inflammation to depressive symptoms – a study of PLWH found that an increased concentration of glial fibrillary acidic protein in cerebrospinal fluid (a marker of astrocyte activation) is associated with elevated depressive symptoms and apathy (Ellis et al., 2022). Social isolation, which can be both a cause and a consequence of depressive symptoms, has been linked to elevated inflammatory markers in plasma and cerebrospinal fluid in PLWH (Ellis et al., 2021b).

Prospective studies are needed to test whether CEN rsFC predicts subsequent severity of depressive symptoms and problematic substance use in PLWH. Studies should also investigate CEN rsFC as a predictor of specific symptoms, particularly apathy and anhedonia. Neuroimaging components could be added to clinical trials to test whether CEN rsFC mediates the effect of treatment on reduced severity of depressive symptoms and problematic substance use.

It is important to note that the causal relations between CEN rsFC, depressive symptoms, and substance use may be multidirectional. For example, lower CEN rsFC may increase susceptibility to problematic cannabis use, and problematic cannabis use may lead to further alterations in CEN rsFC (Ertl et al., 2023). Thus, CEN rsFC, depressive symptoms, and substance use may form their own feedback loop nested within the broader neuroimmune feedback loop. Longitudinal research is needed to clarify how CEN rsFC, depressive symptoms, and substance use interact over time.

CEN function exhibits considerable plasticity and is amenable to improvement through interventions (Tang et al., 2015). For example, a study among older adults (without HIV) found that a multi-domain cognitive training intervention increased CEN rsFC (Cao et al., 2016). Another study of adults with elevated levels of psychological distress (without HIV) found that three days of intensive mindfulness meditation training increased CEN rsFC (Taren et al., 2017). Repetitive transcranial magnetic stimulation over the left dorsolateral prefrontal cortex, a key anchoring region of the CEN, is an effective, non-invasive treatment for depression (Teng et al., 2017). The dorsolateral prefrontal cortex is a highly accessible target for neuromodulation, which makes it an ideal region for interventions aimed at improving CEN rsFC (Tang et al., 2015). These interventions enable experimental enhancement of CEN rsFC, which could be leveraged to strengthen causal inferences about the effects of CEN rsFC on depressive symptoms and problematic substance use.

Hypothesis 6

Greater systemic inflammation increases risks for aging-related comorbidities.

A large body of evidence highlights the role of inflammation in the pathogenesis of aging-related comorbidities (Chung et al., 2009; Liberale et al., 2020). In PLWH, markers of systemic inflammation are longitudinal predictors of coronary artery disease events (Avery et al., 2023) and all-cause mortality (Piggott et al., 2015). Markers of systemic inflammation are cross-sectionally associated with diabetes incidence (Brown et al., 2010) and frailty (Fukui et al., 2018) in PLWH, but longitudinal studies are needed. Other infectious diseases (e.g., Hepatitis B and C) are common comorbidities of HIV, and these coinfections may further exacerbate systemic inflammation (Shmagel et al., 2016; Crane et al., 2014). Associations between inflammation and aging-related outcomes among PLWH are reviewed in detail elsewhere (Deeks, 2011; Leng and Margolick, 2015; Sieg et al., 2021).

A longitudinal study of women living with HIV found that greater variability in the inflammatory marker C-reactive protein over time was associated with greater cognitive impairment (Rubin et al., 2018). This highlights the possibility that repeated waves of systemic inflammation may play a role in driving neurocognitive decline among PLWH. Another longitudinal study of PLWH reported that higher C-reactive protein was associated with poorer neurocognition, but only among those with moderate to severe depressive symptoms (Saloner et al., 2021). This suggests that inflammation and depressive symptoms may interact over time to accelerate neurocognitive aging. This pattern is broadly consistent with the neuroimmune feedback model outlined in this paper.

A growing body of evidence suggests that HIV and consequent systemic inflammation may be associated with biomarkers of accelerated aging among PLWH. One study reported that polymorphisms for genes that express inflammatory proteins were associated with biological age indexed by a methylation clock in among PLWH (Sundermann et al., 2019). Another study reported that PLWH exhibited older sleep-based brain age compared to their counterparts without HIV (Leone et al., 2021). A third study found that HIV, elevated inflammatory markers, methamphetamine use, and comorbid disease risk were each associated with shorter leukocyte telomere length, a marker of older biological age (Mehta et al., 2021). Taken together, these findings suggest that systemic inflammation plays a role in driving accelerated aging and disproportionately high burdens of aging-related comorbidities in PLWH.

2. Conclusion

In this paper, I outline a novel theoretical model to explain why PLWH experience accelerated aging relative to their counterparts without HIV. This model also helps explain the wide range of variability in aging-related health among PLWH.

In this model, depressive symptoms, problematic substance use, low antiretroviral therapy adherence, elevated systemic inflammation, and low connectivity in the brain's central executive network form a self-perpetuating feedback loop. For people facing heavier burdens of psychosocial stress, this feedback loop cycles faster and with greater intensity. Repeated cycling of this feedback loop increases systemic inflammation over time, which accelerates the onset of aging-related comorbidities. Protective factors that interrupt this feedback loop include social support, non-stigmatizing medical care, and interventions that improve mental health and reduce systemic inflammation.

A limitation of this model is that it does not include all causal relations between the variables of interest, nor does it discuss all the potential mechanisms that may link these variables of interest. For example, psychosocial stress may exert a direct effect on ART adherence that is not mediated by depressive symptoms or problematic substance use. I chose to focus this model on a specific set of hypothesized effects that have an important emergent property, the neuroimmune feedback loop, which is the focus of this paper.

This framework could be generalized by replacing ART adherence with other health behaviors, such as diet or physical activity. Adapting the model in this manner could yield useful frameworks for explaining varying health trajectories in PLWH who are highly adherent to ART. It could also provide a useful status-neutral framework for understanding health trajectories in both PLWH and people at elevated risk for HIV seroconversion.

Existing evidence is consistent with the model outlined in this paper, but many of the relevant clinical studies are observational and cross-sectional. Clinical trials and longitudinal studies are needed to identify the specific mechanisms that sustain this feedback loop and the temporal trajectories over which these mechanisms operate. The field of psychoneuroimmunology is uniquely equipped to offer novel insights on mechanisms that drive accelerated aging among PLWH.

Funding

NIH/NIDAK01DA057143.

CRediT authorship contribution statement

Joshua M. Schrock: Conceptualization, Investigation, Writing – original draft, Writing – review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

none

Data availability

No data was used for the research described in the article.

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