Neurologic Complications of Acute HIV Infection

Abstract

Purpose of Review:

This review focuses on the pathophysiology of acute HIV infection (AHI) and related central nervous system (CNS) pathology, the clinical characteristics of neurologic complications of AHI, and the implications of the CNS reservoir and viral escape for HIV treatment and cure strategies.

Recent Findings:

Recent studies in newly seroconverted populations show a high prevalence of peripheral neuropathy and cognitive dysfunction in AHI, even though these findings have been classically associated with chronic HIV infection. HIV cure strategies such as the “shock and kill” strategy are currently being studied in vitro and even in small clinical trials, though the CNS as a reservoir for latent HIV poses unique barriers to these treatment strategies.

Summary:

Limited point of care diagnostic testing for AHI and delayed recognition of infection continue to lead to under-recognition and under-reporting of neurologic manifestations of AHI. AHI should be on the differential for a broad range of neurological conditions, from Bell’s palsy, peripheral neuropathy, and aseptic meningitis, to more rare manifestations such as ADEM, AIDP, meningo-radiculitis, transverse myelitis, and brachial neuritis. Treatment for these conditions involves early initiation of antiretroviral therapy (ART) and then standard presentation-specific treatments. Current HIV cure strategies under investigation include bone marrow transplant, viral reservoir re-activation and eradication, and genome and epigenetic viral targeting. However, CNS penetration by HIV-1 occurs early on in the disease course with the establishment of the CNS viral reservoir and is an important limiting factor for these therapies.

Introduction

HIV-1 infection causes a myriad of both acute and chronic neurologic complications via direct viral damage or, in chronic infection, due to effects of the immunocompromised state. The most common direct effects of chronic HIV infection include HIV associated neurocognitive disorders (HAND) and HIV-associated vacuolar myelopathy, while the immunocompromised state associated with poorly controlled chronic HIV infection may predispose individuals to central nervous system (CNS) opportunistic infections such as toxoplasmosis, cryptococcus, and cytomegalovirus. In this review, however, we focus specifically on the pathophysiology of acute HIV infection, the neurologic complications of the infection itself in the acute period, and its implications for HIV treatment and cure development.

Acute HIV Infection

Acute HIV-1 Infection Overview

Acute HIV-1 infection (AHI) refers to the period immediately after infection with human immunodeficiency virus (HIV) before HIV antibodies develop, during which the HIV-1 viral load rapidly increases to peak levels before leveling off.¹ Patients may present clinically with a non-specific flu-like illness classically characterized by fever, lethargy, pharyngitis, headache, myalgias, arthralgias, lymphadenopathy, and dermatologic manifestations such as maculopapular rash or mucocutaneous ulcerations.² However, many patients are asymptomatic or present with few of these symptoms, making clinical diagnosis during this time challenging. This acute period also plays an important role in HIV transmission and propagation of the infection. Although the precise degree of infectivity during AHI is difficult to ascertain and dependent upon local epidemic patterns,^3,4 it is clear that a substantial number of new infections are transmitted during this early stage before most individuals know they are infected.

Stages of Acute HIV-1 Infection

Stages of AHI, also sometimes referred to as Fiebig stages,⁵ are defined by results of diagnostic testing. The eclipse period lasts approximately 10 days and refers to the period from exposure to the virus until the time when the first diagnostic test, HIV RNA PCR, is able to detect the presence of virus. Fiebig stage I is the next stage where HIV RNA PCR is detectable, while Fiebig stage II is where p24 antigen, a transient core viral protein, becomes detectable. Stages III-VI are defined by HIV-1 IgM enzyme-linked immunosorbent assay (ELISA) reactivity (stage III), HIV antibody Western blot indeterminate result (stage IV), HIV antibody Western blot positivity with negative Western blot for a structural viral protein called p31 (stage V), and finally, antibody reactivity with positive Western blot for p31 (stage V1) [Figure 1].⁵

Figure 1.

Timeline of CNS Invasion in Acute HIV. HIV infection travels from mucosal CD4+ cells and Langerhans cells to the gut-associated lymphoid tissue (GALT), where T lymphocytes become infected and HIV rapidly replicates. Invasion of perivascular macrophages and microglia then leads to local viral replication and establishment of the CNS reservoir. Astrocytes may also be terminally infected, contributing to the CNS reservoir. Fiebig Staging based on Fiebig et al. 2003, “Dynamics of HIV viremia and antibody seroconversion in plasma donors: implications for diagnosis and staging of primary HIV infection.”

Diagnostic testing in acute HIV

Diagnostic testing for HIV spans point-of-care (POC) and laboratory-based assays, as well as several different detection methods that may be used at various stages of infection. The ‘window period’ of a diagnostic test refers to the period from time of infection until the time at which a particular assay or laboratory test would result as positive. The first HIV diagnostic test to be developed (previously termed ‘first or second generation tests’) measures IgG antibody responses to HIV antigens and has a window period of at least a month. IgG/IgM – sensitive tests, formerly referred to as 3^rd generation diagnostic tests, increase rates of early detection but the window period decreases to only a median of 23 days [Figure 1].^6,7

AHI testing occurs in the laboratory setting via p24/IgG/IgM assays, referred to as fourth generation tests, which can detect p24 (associated with Fiebig stage II) as well as anti-HIV IgG or IgM antibodies in tested serum as early as several weeks after infection. Rapid diagnostic tests (RDTs) with a similar strategy have been less successful in the POC setting, with high specificity but unacceptably low sensitivity.⁸ However, fourth generation antigen/antibody POC tests seem to have better sensitivity for AHI, detecting more than a quarter of acute infections in one study and 12 of 13 acute infections in another.^9,10 Testing for HIV RNA via PCR still detects AHI more reliably at earlier time periods, with some results becoming positive as early as the end of the first week of infection. However, its window period is variable, testing is not available in the form of POC testing, and it has limited availability.⁷ As a result, implementing 4^th generation POC tests in diagnostic algorithms may reduce the need for HIV RNA testing, but the sensitivity of these POC tests would still need to be improved further to obviate the need for HIV RNA testing for AHI. Of note, HIV antibody-based diagnostic tests may also produce false negatives in early infection in the setting of pre-exposure prophylaxis (PrEP), post-exposure prophylaxis (PEP), or empiric ART initiation.¹¹

Pathophysiology of Acute HIV

Pathophysiology of HIV infection

According to animal models and histopathologic studies in humans, the HIV-1 virus is thought to initially traverse the stratified squamous epithelium of mucosal membranes, such as the vaginal canal or cervix, infecting CD4+ cells and Langerhan’s cells in these tissues.¹² Within two to three days, these immune cells spread hematogenously to gut-associated lymphoid tissue where the virus rapidly multiplies. Primary gut mucosal CD4+T cells have increased susceptibility to HIV infection due to their increased expression of C-C chemokine receptor type 5 (CCR5) and resultant T-cell activation.¹³ Rapid viral replication is accomplished via mass infection of these non-circulating CD4+ T-cells, which corresponds to Fiebig stage I when HIV RNA PCR first becomes detectable. This gut lymphoid tissue invasion also causes a clinically significant and irreversible reduction in the level of CD4+ T-cells in the body. With further migration of infected T lymphocytes into the blood stream, secondary amplification of virus also occurs in various other tissues including bone marrow, lymph nodes, and spleen [Figure 1]. It is also at this point that the RNA reversed-transcribed HIV-1 DNA is integrated into replicating resting or memory T-cell genomes, leading to viral latency and formation of reservoirs.¹⁴ Selective genome mutations can occur in isolation in these regional tissues, leading to uniquely resistant viral populations in these tissues that are not present in circulating virus [Figure 1].¹⁵

Pathophysiology of HIV CNS infection

HIV-1 is a neurotropic virus, with 40–70% of all patients developing neurologic manifestations at some point in their disease course, and 90% demonstrating neurologic disease on autopsy.^16,17 As infected CD4+ T-lymphocytes and macrophages mobilize from the gut and other lymphoid tissues, hematogenous spread to the brain is thought to occur via adherence of immune-cells to the vascular endothelium of the blood brain barrier (BBB). While not fully understood, virus-containing immune cells are believed to penetrate into BBB endothelial cells through emperiopolesis, and subsequently transfer viral particles to microgial cells and macrophages in the brain [Figure 1].¹⁸ While neurons and oligodendrocytes are not directly infected, they can be damaged secondary to cytokines released by infected cells nearby. Astrocytes may also be infected. However, they incompletely express the proteins needed for robust viral replication, so astrocytes are thought to act only as a reservoir and not to contribute substantially to ongoing systemic infection.¹⁹

Timing and markers of CNS HIV infection

It is still unknown how quickly CNS reservoirs can form in AHI in humans. In HIV models of simian immunodeficiency virus (SIV) in macaques, viral RNA has been shown in brain tissue as early as 10 days after infection,²⁰ with additional studies showing that ART started 12 days after infection does not reduce SIV DNA levels in brain tissue. Early CNS invasion is more likely to occur when the mode of transmission is mucosal as opposed to intravenous because viral entry via mucosa selects for and amplifies CCR5-tropic virions which have a predisposition to cross the BBB.¹⁹ However, in one case report of a man who received zidovudine immediately after an iatrogenic IV inoculation of HIV-infected white blood cells, autopsy revealed HIV nucleotides present by PCR in brain tissue 15 days after inoculation but not in several other organs (and one day after first positive HIV blood culture on day 14).²¹ Additional small studies have demonstrated HIV RNA in the CSF as early as 8 days after estimated inoculation,¹⁹ though at lower levels than in plasma. CSF and plasma HIV RNA levels trend toward equalization in chronic infection.^14,19

Inflammatory markers such as CSF light subunit of neurofilament protein (NF-L) or CSF neopterin may be more valuable indicators of early CNS infection than RNA or DNA burden and have been identified in people living with HIV (PLWH) with neurologic symptoms within three months of presumed infection.^22,23 Levels of these inflammatory markers in CSF have also been shown to be similar to those with chronic HIV infection as soon as two months after infection, even while CSF HIV RNA remains at a much lower level than in plasma, indicating early blood brain barrier breakdown.²⁴ Early CNS changes can also be seen on a macroscopic scale. Imaging of patients <100 days from time of estimated infection demonstrated decreased parenchymal volume on brain MRI and reduced white matter integrity on diffusion tensor imaging.²⁵ Another study of patients within one year of presumed HIV-1 infection also demonstrated reductions in neuronal integrity, mild brain atrophy, and a reduction in cerebral blood volume.²⁶ These changes have been shown to correlate with levels of CSF inflammatory markers like neurofilament light chain, even in asymptomatic patients, and demonstrate that structural CNS changes likely begin even in AHI.²³

CNS as a reservoir of HIV

Even after initiation of ART and reduction of CSF RNA viral burden, CSF HIV DNA levels and inflammatory markers can remain constant, suggesting AHI may establish a CNS reservoir early in the disease that facilitates a persistent inflammatory state in the CNS in spite of treatment.²⁷ Early and persistent CNS infection is often evaluated through CNS compartmentalization, in which sequences of HIV-1 RNA from blood are compared to that of CNS HIV-1 RNA. Genetic variability in the CSF is used to extrapolate that CNS cells are producing HIV virions in a distinct population from those in the serum. Small studies indicate that this can happen as early as months after initial infection.^28,29

In the most extreme cases, HIV RNA can be detected in the CSF even with undetectable systemic peripheral viral loads, a phenomenon known as CNS escape. In several small studies of individuals with new neurologic symptoms but sustained serum HIV levels <50 copies/mL, CSF HIV RNA was detected at an average of greater than 800–3,000 copies/mL.^30,31 Initial hypotheses surrounding CNS escape centered on concern for poor CNS penetration of ART.³² However, in the studies referenced above, almost all samples of CSF HIV RNA demonstrated resistance-associated mutations, indicating CNS compartmentalization as a likely additional driver. Individuals in these studies also demonstrated elevated CSF white blood counts, neopterin, and, in a few subjects, CD8+ lymphocytes on brain pathology, indicating an association of active inflammation with CNS viral escape.³¹

Time to treatment initiation likely plays a role in viral escape; a recent study comparing CSF viral load in patients initiated on ART within 4 months of primary infection compared to those initiated on ART >14 months after primary infection found lower molecular diversity in CSF HIV DNA as well as reduced CSF inflammatory markers in the early treatment group, although both groups still demonstrated some individuals with HIV DNA compartmentalization.³³ While there is some evidence that transient elevations in CSF HIV RNA can occur in as many as 30% of HIV patients,³⁴ recent calculations of the prevalence of CNS escape estimate it to be between 1–7%.^35–38 Neurologic conditions such as HAND and encephalitis have been associated with CSF compartmentalization and escape.^39,40

Neurologic presentations of acute HIV infection

Because there are often delays between initial HIV infection and symptom onset or diagnostic testing, few primary studies have described the early neurologic manifestations of AHI. However, approximately 70% of patients will experience a clinical syndrome at the time of HIV seroconversion, and in 10% of patients this may be associated with neurological symptoms.¹⁶ These neurologic symptoms have been shown in several studies to be associated with higher CSF HIV RNA levels than those found in patients without neurologic manifestations of AHI.^41–43

Aseptic meningitis, generally presenting with headache and meningeal signs, is the most common CNS manifestation of AHI and can be seen in as many of 25% patients. It can occur within 2 weeks of infection, even prior to seroconversion.⁴² Other less commonly reported CNS presentations include transverse myelitis^44–46, unilateral⁴⁷ or bilateral^48,49 optic neuropathy, fulminant encephalopathy,⁵⁰ and acute disseminated encephalomyelitis.^51,52 One recent study also found that subtle extrapyramidal signs, such as bradykinesia, were among the most common signs observed on neurologic exam within twelve weeks of HIV infection [Table 1].⁴¹

Table 1:

Neurologic Manifestations of Acute HIV Infection

Clinical Presentation	Diagnosis/Comments	Treatment*	References
Aseptic meningitis	Often occurs in the setting of acute retroviral syndrome CSF studies typically show a lymphocytic pleocytosis + elevated protein	Supportive	40
Peripheral neuropathy	Symmetric distal sensory polyneuropathy Small fiber predominant Often painful requiring neuropathic pain agents	Neuropathic pain agents	39, 62
Cognitive dysfunction/Encephalopathy	May include deficits in memory, concentration or speech. May persist despite early antiretroviral therapy initiation and successful viral load suppression Basic studies from CSF often normal or with mild pleocytosis and/or elevated protein	Supportive	39, 41, 48
Bell’s Palsy	Can be unilateral or bilateral (rare) May be associated with aseptic meningitis	Steroids +/− acyclovir	51–54
ADEM	Diagnosed by abnormal MRI and CSF	Steroids**	49, 50
AIDP	Clinically indistinguishable from AIDP unrelated to HIV CSF may show a pleocytosis in addition to elevated protein	IVIG	55–58
Meningoradiculitis	EMG shows demyelination	Supportive	59
Transverse myelitis	HIV should only be considered the etiology infectious/inflammatory workup is completed and is unrevealing	Steroids, IVIG**	42–44
Brachial neuritis	Usually unilateral and monophasic Clinically indistinguishable from cases unrelated to HIV	Supportive	60, 61
Optic neuropathy	Can be unilateral or bilateral (rare) Broad infectious workup should be undertaken to exclude other causes such as CMV, TB and neurosyphilis	Steroids	45–47
Extrapyramidal signs	Include tremors, bradykinesia	Supportive	39

^*Supportive treatment indicates ART as well as symptom management

^**Unclear clinical utility

Peripheral nervous system manifestations of HIV can also be seen in acute infection. Isolated cranial nerve 7 (Bell’s) palsy has been identified as an early, and even first, presenting symptom.⁵³ Several cases of bilateral Bell’s palsy have also been described,^54–56 with a median onset of 15 days after clinical disease presentation and always together with aseptic meningitis.⁵⁴ Acute inflammatory demyelinating polyneuropathy (AIDP) has also been well described in AHI, and unlike in classic forms of AIDP, a CSF pleocytosis is often found.^57–60 While HIV-associated radiculopathy is generally associated with the later stages of the disease and concomitant CMV infection, cases of meningoradiculitis⁶¹ and brachial neuritis^62,63 have also been reported in AHI, although these are very rare [Table 1].

In a recent study performed in Thailand, the most common objective neurologic symptom observed by physicians in the first 12 weeks of HIV infection was a length-dependent neuropathy, seen in 26% of all participants.⁴¹ Another study found that signs of peripheral neuropathy were detected by neurologic exam in 35% of patients within 1 year of primary HIV infection, with a median time to symptoms of 3.5 months.⁶⁴

Though previously discussed mainly in chronic HIV, cognitive symptoms may also be common early neurologic manifestations of HIV infection. In the study performed in Thailand, 53% of study participants reported one or more neurologic symptoms within the first 12 weeks following HIV diagnosis, and half of all individual neurologic complaints were self-reported cognitive symptoms such as memory, concentration, or speech.⁴¹ Additionally, in a study with a median time since HIV infection of 19 days, approximately 25% of participants demonstrated objective mild deficits on neuropsychological cognitive testing.⁴³

Treatment of neurologic complications of acute HIV

Fulminant neurologic disorders seen in association with AHI are generally treated similarly to presentations of these diseases in HIV-uninfected individuals. For example, Bell’s palsy can be treated with a short corticosteroid course and acyclovir, though this has not been systematically studied,⁵⁴ and AIDP is treated with a course of IVIG.^57,65 There are no clear guidelines for treatment of CNS disorders such as myelopathy or ADEM associated with AHI, but ART, antibiotics, and steroids are often trialed in the course of diagnosis and treatment.⁴⁴ Prevention of these acute neurologic disorders is difficult since they can occur early in the disease course and may even be the presenting sign of HIV infection; however, there is hope that with early diagnosis and treatment with ART their prevalence may be reduced.

Unfortunately, much like other neurodegenerative disorders, there are no effective medical treatments for HAND. While most data come from patients with chronic HIV infection, studies indicate that even in patients who have been treated with successfully suppressed systemic viral loads, as many as 62% still experience cognitive impairment.^66,67 Few studies have directly examined the correlation between CNS HIV nucleotide levels, early treatment, and involvement of cognitive symptoms in AHI. However, in a recent study which found that the two earliest neurologic symptoms in AHI were distal neuropathy and subjective cognitive impairment, 90% of neurologic findings present at diagnosis remitted after 4 weeks of treatment.⁴¹ In this study, neurologic symptoms at onset were associated with higher plasma HIV RNA levels at diagnosis. However, while another small trial also demonstrated higher CSF HIV RNA in patients with AHI and cognitive symptoms, it was found that early treatment with ART did not reverse cognitive impairment.⁴³

Given early viral CNS penetration and the phenomenon of CNS escape, the question remains whether early initiation of ART might help prevent the cognitive changes seen in chronic HIV infection. In the past decade there have been several trials which have demonstrated benefit on prevention of long-term cognitive deficits, with initiation of ART at higher CD4 cell counts compared to the prior practice of waiting for CD4 cell counts to fall below a defined threshold before initiating ART.⁶⁸ However, later studies have demonstrated conflicting results with only some sub-populations of patients showing significant benefit,⁶⁹ and the effect of very early ART in AHI on preventing cognitive outcomes has been less well-defined. In a recent clinical trial that compared neuropsychologic testing in patients randomized to immediate ART vs ART delayed for 24 weeks, less significant improvement was seen on cognitive domains such as processing speed in the deferred treatment group, indicating that early treatment may help prevent cognitive decline.⁷⁰ As discussed above, however, it is unclear if even very early ART can prevent CSF HIV penetration and compartmentalization. Neurocognitive impairment has been shown to be more frequent in patients with CSF escape compared to those without,³⁷ and CSF viremia alone has also been correlated with worse neurocognitive performance.⁷¹ However, some evidence indicates that HIV viral presence alone, in the absence of associated inflammation on post-mortem brain tissue analysis, is not correlated with worse cognitive function prior to death.⁷² Therefore, early treatments in AHI targeted at preventing CNS viral entry, compartmentalization, escape and associated inflammation may be a target for preventing the development of HAND, though this hypothesis remains unproven.

Future directions: looking towards a cure

Early CNS involvement in AHI has many implications for future treatment strategies. As discussed, in addition to the gut, bone marrow, and lymphoid tissue, the brain is thought to be an anatomical reservoir for HIV viral DNA, which is integrated into host DNA and from which viral RNA replication and re-infection can occur even after effective ART treatment.⁷³ As goals of HIV management shift towards disease cure rather than just viral suppression, these anatomical reservoirs are an important consideration in the development of treatment strategies.

Barriers to disease eradication

A clear barrier to disease cure is the rapid rate at which HIV can penetrate the CNS and other reservoir tissues, even in asymptomatic patients. Studies of early ART initiation in humans have indicated that measures of HIV-1 RNA are lower in both blood and anatomical reservoirs such as the gut in patients begun on early ART treatment when compared to historical data from participants starting ART in chronic infection.⁷⁴ Additional data have also shown that early ART reduces markers of CNS HIV infection such as HIV-specific antibodies.⁷⁵ While recent case reports have even demonstrated no detectible HIV-1 RNA or DNA in reservoirs like CSF, gut, and lymph nodes with very early ART initiation, all participants in these small studies have still demonstrated later rebound of viral load and disease with treatment interruption.^76,77 Information from post-mortem pathology also indicates that HIV RNA and DNA persist in the brain even in asymptomatic patients with systemic virological suppression.⁷⁸

In addition to early viral invasion of the CNS complicating disease eradication efforts, the immune cell populations primarily involved in acute CNS HIV infection may differ from those which are responsible for latent disease reservoirs. While T cells are thought to play the principle role in early CNS HIV infection, perivascular macrophages and microglia – and possibly astrocytes – are considered the primary cells that harbor latent HIV,⁷⁹ and current treatments may not effectively address these cell populations.⁸⁰ Furthermore, the low rate of replication of infected memory T cells makes them stable and long-lived and difficult to target with current treatment strategies. Estimates indicate it could take over 70 years of effective ART to eradicate these latent HIV-infected cells.⁸¹

The concept of a genetically unique reservoir of HIV infection raises concern that therapies targeting cure may activate or release this latent CNS population which may result in acute neurologic symptoms. The phenomenon of HIV virologic escape causing fulminant neurologic disorders such as encephalitis^82,83 as well as more subacute symptoms such as ataxia, vision changes, weakness, and tremor³¹ has been described. It is therefore possible that new therapies being studied to activate latent HIV with the goal of cure may put patients at risk of activating HIV CNS disease and causing neuronal injury.⁷³ However, large-scale studies have yet to be performed.

Current strategies for HIV cure under investigation

Bone marrow transplantation (BMT) as a method of HIV cure has been under investigation since the Berlin Patient was declared cured after BMT with cells with a CCR5 receptor deletion mutation.⁸⁴ The goal of this treatment is to replace a patient’s immune cells with CCR5-mutated stem cells that will be resistant to HIV infection. While in 2019, apparent disease cure was also seen in a second patient,⁸⁵ consistent replication of this finding has thus far been unsuccessful. Additionally, the high risk and medically complex nature of BMT makes it unlikely to be a scalable treatment strategy given the relative efficacy and tolerability of current ART [Table 2].

Table 2:

Treatment Strategies for Acute HIV

Approach to Treatment	Stage	Comments	Barriers	References
Bone Marrow Transplant	Case studies	Transplant cells with CCR5 receptor mutation	High morbidity	82, 83
Shock and Kill:reactivation and eradication of latent HIV	Animal models, small Clinical trials	Targets: histone methyltransferase inhibitors, protein kinase C agonists, bromodomain inhibitors, and inhibitor of apoptosis proteins	Failure to activate reservoirs, reduced ability of patients to clear HIV after reactivation, potential for treatment to incite cerebral edema	84–91
HIV Genome editing	In vitro	DNA editing of HIV genome to reduce replication	Unclear targets, method of delivery for gene editing	79

The “shock and kill” strategy for HIV cure has also begun to be studied in humans. In this method, a therapy is used to re-activate latent HIV so that it can be targeted for immune clearance. Examples of these latency reactivating agents which have been tested in cell culture and animal models include histone deacetylase inhibitors⁸⁶, histone methyltransferase inhibitors^87,88, protein kinase C agonists⁸⁹, bromodomain inhibitors⁹⁰, and inhibitor of apoptosis protein antagonists⁹¹. Several small clinical trials of histone deacetylase inhibitors^92,93 have demonstrated that HIV reservoirs can be activated, but they have not demonstrated reservoir clearance in subjects. Even if reservoirs can be effectively cleared after activation, barriers to this treatment strategy include reduced ability of patients with chronic HIV infection to clear viral reservoirs once activated, variable degree of viral re-activation both between and within patients, and unclear in vivo effectiveness of current agents. As discussed above, CNS reservoirs may provide a particularly unique barrier to this treatment, as activation of HIV generates viral particles which can be damaging to neurons and glia⁸¹ [Table 2].

Several other potential cure strategies are currently being investigated in vitro, although they remain far from human testing. While targeting the HIV genome with DNA editing to reduce its replication has been proposed, it remains unclear which HIV genome sequences are optimal to target, what the consequences in off-target gene editing and RNA editing may be, and how to deliver the gene editing system in vivo.⁸¹ Some preliminary data have also indicated that targeting latent HIV to epigenetically induce an inactive or silent state could be effective if this effect can be made to persist even when ART is discontinued. Recently, heat shock protein 90 inhibition has been studied as a method to prevent HIV reactivation in cell culture,⁹⁴ though studies of other similar targets, such as inhibition of the HIV Tat protein, have failed to demonstrate similar findings in in vivo models.⁹⁵ It is unknown what the best epigenetic targets for these treatments are, if multiple targets are needed, and if these strategies will prevent HIV reactivation in the long term.⁸¹

Conclusions

Limited POC diagnostic testing for AHI and delayed recognition of infection continue to lead to under-recognition and under-reporting of neurologic manifestations of AHI. AHI should be on the differential for a broad range of acute neurological conditions, however, from classically HIV-associated conditions such as Bell’s palsy, peripheral neuropathy, and aseptic meningitis, to more rare manifestations such as ADEM, AIDP, meningoradiculitis, transverse myelitis, and brachial neuritis. Treatment for these conditions involves early initiation of ART and then standard disease-specific treatments (i.e. IVIG for AIDP). Current HIV cure strategies under investigation include bone marrow transplantion, viral reservoir re-activation and eradication, and genome and epigenetic viral targeting. However, CNS penetration by HIV-1 occurs early on in the disease course, and the CNS reservoir of HIV virus is an important limiting factor for these therapies.