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Perspective on potential impact of HIV central nervous system latency on eradication

Chan, Phillipa; Ananworanich, Jintanata,b,c,d

doi: 10.1097/QAD.0000000000002264
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Given the challenges of life-long adherence to suppressive HIV antiretroviral therapy (ART) and possibilities of comorbidities, such as HIV association neurocognitive disorder, HIV remission and eradication are desirable goals for people living with HIV. In some individuals, there is evidence that HIV persists and replicates in the CNS, impacting the success of HIV remission interventions. This article addresses the role of HIV CNS latency on HIV eradication, examines the effects of early ART, latency-modifying agents, antibody-based and T-cell enhancing therapies on the CNS as well as ART interruption in remission studies. We propose the integration of CNS monitoring into such studies in order to clarify the short-term and long-term neurological safety of experimental agents and treatment interruption, and to better characterize their effects on HIV CNS persistence.

aSEARCH, Thai Red Cross AIDS Research Centre, Bangkok, Thailand

bU.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring

cHenry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda , Maryland, USA

dDepartment of Global Health, Amsterdam Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Correspondence to Jintanat Ananworanich, Bill & Melinda Gates Medical Research Institute, 245 Main Street, Cambridge, MA 02142, USA. E-mail: Jintanat@gatesmri.org

Received 19 May, 2018

Revised 11 April, 2019

Accepted 11 April, 2019

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Introduction

Antiretroviral therapy (ART) has transformed HIV-1 infection from a life-threatening disease to a manageable yet sometimes complex chronic illness. Latent HIV-1 resides mostly in long-lived memory CD4+ T-lymphocytes in blood and lymphoid tissues, and poses a barrier to curing HIV-1. Reactivation of replication-competent virus in these cells can fuel a new round of cell infection in the absence of ART. HIV-1 cure is an important goal, given the challenges of lifelong ART adherence, the financial burden to healthcare systems, chronic immune activation [1,2], and non-AIDS related comorbidities including HIV-associated neurocognitive disorders (HAND) despite successful therapy [3–6].

The ultimate and nearly impossible goal of HIV-1 cure research is sterilizing cure or eradication, which aims to abolish all cells that harbor replication-competent provirus within the host cellular DNA. A functional cure or sustained virologic remission is a challenging yet more attainable goal. It is the ability to maintain plasma viral load below detection limit without ART despite the persistence of replication-competent HIV-1. The potential HIV-1 eradication in the Berlin patient and possibly, the London patient, required extreme means of cancer treatment and CCR5-negative stem cell transplantation [7–9]. Remission cases are unusual and mostly described in people who initiated ART during acute HIV-1 infection (AHI). There are several investigative approaches to reduce and control latently infected cells, namely, early ART, latency reactivation or suppression, and immune-based, cell-based and gene-editing therapies [10].

This article addresses three questions relating to the role of the HIV-1 central nervous system (CNS) latency on HIV-1 eradication. First, how is HIV-1 CNS infection and persistence relevant to HIV-1 cure efforts? Second, how do HIV-1 remission strategies affect the CNS? Third, what future investigations could be considered in HIV-1 remission studies?

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How is HIV-1 central nervous system infection and persistence relevant to HIV-1 cure efforts?

HIV-1 clearly involves the CNS. Millions living with HIV-1 suffer from HAND that affects their lives in substantial ways. Although ART has dramatically reduced HIV-associated dementia, milder forms of HAND are prevalent in 15–55% of people with HIV [4,5,11]. Moreover, new onset and ongoing deterioration of cognitive impairment occur despite ART [6,12,13]. HIV-1 RNA is readily detected in cerebrospinal fluid (CSF) samples within days of infection [14,15]. Even under viral suppression with ART, some individuals have elevated soluble inflammatory biomarkers in the CSF [16]. Microglial activation on PET can also be observed in treated individuals and is associated with lower cognitive performance [17].

Whether the HIV-1 virions in the CNS are replication-competent is unproven. However, some treated individuals with plasma viral suppression have low levels of HIV-1 RNA in their CSF [18]. In the systemic circulation, infected CD4+ T-lymphocytes with defective HIV-1 DNA generate incomplete RNA transcripts that contribute to persistent immune activation [19,20]. Future studies should clarify if such phenomenon co-exists in the CNS as HIV-1 DNA is frequently present in the brain cells of people who have been on years of suppressive ART [21].

Controlling CNS infection and persistence is integral to the efforts in curing HIV-1. First, HIV-1 remission strategies should reduce frequencies of HIV-infected cells in the CNS. HIV-1-infected brain cells are long lived residential cells including perivascular macrophages, microglia and astrocytes. Pathological studies suggest their ability to harbor HIV-1 DNA with or without the development of HIV encephalitis [22–27], and the frequencies of HIV-1 DNA+ cells correlate with reduced cognitive function [28,29]. Despite long-term suppressive ART, brain macrophages/microglia from simian immunodeficiency virus (SIV)-infected macaques still harbor replication-competent virus that could be reactivated by latency-reversing agents (LRA) [30,31].

Second, strategies should improve control of viral replication in the CNS. CNS viral escape is when HIV-1 RNA is detected only in the CSF, or CSF viremia is at least 1log10copies/ml above a fairly well controlled HIV-1 RNA in blood [32–34]. Although mostly asymptomatic, CNS viral escape is linked to elevated CSF soluble inflammatory markers [18,33,35]. Moreover, patients with symptomatic CNS viral escape can present with a spectrum of neurologic issues ranging from a mild headache or sensory disturbance to encephalopathy or coma [36–38]. Symptomatic viral escape typically responds to ART adjustment guided by genotyping of CSF HIV-1, or by selecting ART regimens with higher CNS penetration-effectiveness (CPE) scores [36,39]. However, the latter does not necessarily improve the cognitive outcome of individuals with HAND [40–42]. Furthermore, studies have reported ART-resistant strains in the CSF of treated individuals with plasma viral suppression [36,38,39].

Third, remission strategies should target viral quasispecies that may be different in CSF compared with blood. HIV-1 CNS compartmentalization can occur as early as the first year of infection in untreated individuals [43]. In one report, HIV-1 CNS compartmentalization persists during ART and returns during viral rebound post-ART interruption [44]. The repertoires of HIV-specific CD8+ T-lymphocyte receptors are different between CSF and blood even at AHI [45]. Such phenomenon could affect the responses to immune-based HIV-1 remission strategy.

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How do HIV remission and cure strategies affect the central nervous system?

Table 1 summarizes human and nonhuman primate (NHP) studies that evaluate the CNS outcomes of stand-alone treatment interruptions and remission strategies with or without treatment interruptions .

Table 1

Table 1

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Early antiretroviral therapy

ART initiated during AHI markedly reduces frequencies of cells that harbor HIV-1 DNA in blood and lymphoid tissues [46,47], and associates with higher CD4+ T lymphocytes and CD4+/CD8+ ratio [48]. Compared with ART initiation at chronic infection, early ART leads to lower levels of CSF microglial activation [49] and neuronal damage markers [50], and normalization of intracranial inflammation in magnetic resonance spectroscopy (MRS) studies [51,52]. People received early ART (20–132 estimated days of exposure) also have markedly reduced CSF HIV-1 antibody levels likely because of shorter HIV-1 antigen exposure [53]. In short, early ART initiation could contribute to a dramatic reduction in systemic, and likely, CNS reservoirs. Together with the preserved adaptive immunity, early treated individuals could be better candidates for HIV-1 remission strategies.

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Latency reversal agents

Latency reversal is part of the ‘shock and kill’ concept [54]. It aims to ‘shock’ infected cells out of latency, forcing them to express viral antigens and thereby exposing them to killing by direct viral cytopathic action and HIV-specific cytotoxic T-lymphocytes (CTLs). Early trials combining anti-CD3 antibody and recombinant human IL-2 that induced global T-lymphocyte activation validated the concept of latency reversal but also induced significant toxicity from cytokine release [55,56]. Subsequent research has focused on small molecule LRAs that do not cause overt T-lymphocytes activation and cytokine release [57].

Such LRAs include histone deacetylation inhibitors (HDACi) that block the epigenetic control of proviral gene silencing (e.g. vorinostat, panobinostat and romidepsin); protein kinase C (PKC) agonists that induce transcription factor NF-κB (e.g. prostratin, bryostatin-1, and ingenol compounds); and toll-like receptor (TLR) agonists that reactivate viral latency through cellular signaling [58,59].

Most LRAs appear to be nontoxic to primary CNS cells at therapeutic concentrations [60]. Some LRAs, including romidepsin, JQ-1, and panobinostat, can induce viral transcription in infected astrocytes in vitro[60–62]. One study shows bryostatin-1 to reactivate infected astrocytes with p24 antigen upregulation [62] and yet another LRA study shows bryostatin-1 fails to reactivate the latency of infected astrocytes after initial active viral productive phase [63]. In-vitro macrophage/microglia studies demonstrate that combination of LRA reactivates latent virus with increased HIV-1 mRNA and protein levels [64,65].

Non-human primate (NHP) studies provide insight into the viral dynamics of the HIV-1 reservoir in the CNS. After administration Ingenol-B and vorinostat, one out of two SIV-infected macaques on long-term suppressive ART developed SIV encephalitis with neurological symptoms; subsequent CSF examination showed a viral load 10-fold higher than that in plasma [30]. Postnecropsy investigations suggest that the CSF viral transcripts originate from resident CD68+ macrophages/microglia within the occipital lobe of the brain. Importantly, replication-competent virus was isolated from infected brain macrophages in seven out of eight macaques under similar experimental conditions [31]. Therefore, a balance between CNS-desired effects and safety requires careful consideration.

More than 15 clinical trials have evaluated LRAs, and some showed a modest increase in blood cell-associated and plasma HIV RNA after LRAs without a decrease in cell-associated HIV DNA [59]. Two assessed the CNS outcomes and showed no adverse effects [66,67]. One panobinostat study exhibited undetectable CSF HIV-1 RNA in 11 participants despite six having measurable plasma HIV-1 RNA after the last dose of LRA [68]. There were also no changes in CSF inflammatory and neuronal injury markers. Perhaps these findings are unsurprising given the undetectable CSF levels of panobinostat. Our group previously examined the effect of vorinostat, hydroxychloroquine and maraviroc (VHM) in 10 acutely treated AHI participants who have maintained viral suppression for at least 48 weeks [67]. VHM was given under ART coverage, followed by ART interruption. Low-grade CSF HIV-1 viremia was detected in two out of eight CSF samples (25 and 42 copies/ml) at systemic viral rebound (plasma HIV RNA 25796 and 329 copies/ml respectively) after treatment interruptions . There was no adverse CNS outcome observed from serial neuropsychiatric tests, CSF inflammatory markers measurements and MRS.

Multiple factors could affect the outcomes of LRAs. Apart from CNS penetration, LRAs may alter the blood–brain barrier (BBB) permeability and immune cell functions [69]. Moreover, inconsistent reactivation responses [61] and LRAs-induced reactivation of defective HIV-1 provirus reservoir [20,70] may hinder the efficacy of subsequent killing of the ‘true’ reservoir.

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Latency suppression agents

The improved understanding of HIV-1 latency also gives rise to the ‘block and lock’ strategy that aims to disarm the reactivation ability of the HIV-1 reservoir. HIV-1 transactivator of transcription (Tat) protein, which expresses early in the viral life cycle and promotes subsequent HIV transcription, appears to be a potential target for intervention because of the absence of a human homolog. Didehydro-cortistatin A (dCA) is an analog of the natural compound cortistatin A. It potently inhibits Tat production from infected CD4+ T-lymphocytes isolated from viraemic and aviraemic patients [71]. In combination with ART, dCA potentiates the inhibition of viral production during cellular expansion in comparison to ART alone [72]. dCA further inhibits viral reactivation in T-lymphocytes exposed to LRAs and ART interruption [72,73]. dCA crosses the BBB in animal models and inhibits Tat uptake in microglia-like and astrocytes cell lines [74].

In the CNS, Tat may directly contribute to HAND through pro-inflammatory and direct cytotoxic effects [75]. Tat induces neurobehavioral deleterious effects in an animal model [76]. It upregulates platelet-derived growth factor in astrocytes [77], which eventually leads to CCL2 secretion and monocyte infiltration across BBB [78]. It may also cause direct neuronal loss through astrocytosis-related excitotoxicity [79]. As a result, if dCA shows a similar inhibition of latency reactivation in CNS-infected cells, it may alleviate intracerebral immune activation and perhaps offer a viable alternative for HIV remission.

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Immune-based therapies

Aside from the complexity of the CNS response during ‘shock,’ the lack of an effective ‘kill’ mechanism marks another major obstacle to a cure. Human and NHP trials have evaluated interventions to enhance antibody and T-cell functions. Their mechanisms and study outcomes were recently reviewed [80].

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Broadly neutralizing antibodies

Broadly neutralizing antibodies (bNAbs) can neutralize diverse, multiclade, circulating HIV-1 strains. BNAbs bind cell-free virus, block new infection [81], and reduce infected cells through Fcυ receptor-dependent mechanisms in animal models [82]. The effect of bNAbs in CNS is unclear. First, bNAbs are theoretically too large to cross the BBB and gain access to locally infected cells. Second, bNAbs may not target virus-containing compartments in monocyte-derived macrophages according to in-vitro experiments [83,84]. Antibody-treated macrophages remain infectious and could transmit HIV-1 to CD4+ T lymphocytes via macrophage-T-lymphocytes virological synapse [83,85]. The role of bNAbs in reducing infection in microglia and astrocytes requires further studies. Our group did not observe changes in neuropsychological tests or MRI parameters in acutely treated participants who either received VRC01 bNAb or placebo at the time of treatment interruptions [86]. A subset with CSF samples did not reveal viremia posttreatment interruptions despite detectable plasma viremia [86,87].

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Antiα4β7 integrin Ab

α4β7 integrin is a gut-homing receptor and target of HIV-1 gp120 [88,89]. It is extensively expressed on memory CD4+ T-lymphocytes [90], resulting in massive infection and depletion of gut α4β7+ CD4+ T lymphocytes during productive HIV-1 infection. Sustained SIV remission has been reported in macaques treated with primatized α4β7 integrin monoclonal antibody (mAb) in addition to ART during primary infection [91]. Vedolizumab, an approved α4β7 integrin mAb treatment for inflammatory bowel diseases, is being investigated for HIV remission in chronically HIV-infected people (NCT02788175 and NCT03147859). Vedolizumab does not affect T-lymphocyte migration to the CNS like the α4β1 mAb (Natalizumab) [92]. Although vedolizumab is not anticipated to impact CNS immune surveillance and cause neurologic diseases, CNS safety monitoring is prudent as being performed in one study (NCT03147859).

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T lymphocyte-enhancing strategies

Boosting T-lymphocyte immunity against HIV-infected cells is another killing strategy. Learning from the cancer field, several agents including dual affinity retargeting molecules (DARTs), immune checkpoint inhibitors and therapeutic vaccines are now being investigated for HIV-1 infection.

DARTs are bispecific, antibody-based molecules that recognize two different epitopes and redirect T cells to target cells [93]. Applications of DARTs in hematological malignancies are actively explored [94], but little is known about their effects on the CNS residential cells including macrophages, microglia and astrocytes.

Immune checkpoint inhibitors aim to reverse the immune exhaustion and dysfunction of HIV-specific CD8+ T-lymphocytes during chronic HIV-1 infection. Antiprogrammed death ligand 1 (PD-L1) mAb was well tolerated in a phase 1 trial involving eight HIV-1 infected individuals on suppressive ART [95] but one developed asymptomatic hypophysitis 266 days after the infusion. Endocrine complications including hypophysitis and hypothyroidism/thyroiditis are observed in cancer trials with immune checkpoint inhibitors, such as anticytotoxic T-lymphocyte-associated molecule 4 (8 and 6%, respectively, n = 256) [96], and to a lesser extent, anti-PD-L1 [97]. Neurological complications such as myopathy, neuropathies and cerebellar ataxia were reported in 2.9% of cancer patients (n = 347) who received anti-PD-L1 mAb [98]. Given these infrequent but severe toxicities, close systemic and CNS monitoring is warranted in trials using immune checkpoint inhibitors.

Therapeutic vaccinations induce systemic immune responses against target cells including brain cells. Dendritic cell-based vaccines show promising results in cancer trials of CNS glioma and glioblastoma [99,100]. Severe immune-related toxicity is less frequent in dendritic cell vaccines compared with antibody-based treatment for cancers [99]. HIV-1 antigen-pulsed dendritic cell vaccines can induce HIV-specific T-lymphocytes responses in HIV-infected individuals on suppressive ART [101]. Boosted dendritic cells may also reactivate latent HIV-1 provirus [102,103]. In one study, 4 out of 10 participants on ART had a transient increase in plasma HIV-1 RNA levels following autologous dendritic cell vaccines [104]. Although the vaccination did not prevent viral rebound during ART interruption, it showed a modest reduction in peak plasma viremia [104]. Other therapeutic HIV-1 vaccine combinations, such as ChAdV63.HIVcons and MVA.HIVconsv showed potential in viremic control potential among participants who started ART within first year of HIV-1 infection [105].

The chimeric antigen receptor (CAR) engineered T-lymphocytes offer a new option for difficult-to-treat cancers and possibly HIV-1. FDA-approved CD19-targeted CAR-T therapy in 2017 for relapsed or refractory B-cell acute lymphoblastic leukemia and lymphoma. First generation CAR-T therapy for HIV used CD8+ T cells CAR expressing CD4+ infused with a CD3+ zeta-signaling domain. It showed good safety profile and partial effect on plasma viremia [106–108]. Second generation CAR-T therapy is based on bNAb expression to enhance specific killing of infected cells, and disruption of CCR5 to reduce cell infectivity [109]. Primary human T-cell model of bNAb CARs shows elimination of HIV-infected CD4+ T lymphocytes in the absence of active viral replication [109]. The induced mutation of CCR5 locus protects these CAR-T cells from HIV-1 infection [109]. Phase I/II CAR-T study in chronically HIV-infected individuals is ongoing (NCT03240328). Toxicities are less likely to happen in HIV-infected individuals than in cancer patients as they have large tumor burden and hence a higher risk of cytokine releasing syndrome [110]. The incidence of neurotoxicity in cancer settings ranges from 0 to 50% [111]. Their manifestations are diverse and nonlocalizing, including headaches, confusion, and occasionally life-threatening convulsions [111].

Taken together, both antibody-based and T-lymphocyte-enhancing strategies offer compelling evidence to decrease HIV-1 reservoirs and promote virologic remission [82,91,112,113]. The potential for antibodies to affect CNS viral latency is uncertain given their general lack of CNS penetration. Enhanced T-lymphocytes could readily cross the BBB and perhaps target the infected CNS cells. Whether they are beneficial in eliminating HIV-infected cells in the CNS remains to be clarified. Regardless, the extent and duration of such T-lymphocyte-driven cytotoxicity need monitoring.

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What future investigations could be considered in HIV remission studies?

There are two primary goals to perform CNS investigations in HIV remission studies. First is to determine whether experimental agents and treatment interruptions are well tolerated. Second is to understand the effects of remission interventions on CNS HIV persistence.

Experimental agents in HIV remission trials can have direct or indirect effects on the CNS. Those that cross the BBB may reactivate or kill target-infected cells resulting in localized immune activation. The systemic effects of agents that do not cross BBB could indirectly affect the CNS through systemic viremia and immune activation. Treatment interruption is included in remission trials to measure the efficacy of interventions because there are no biomarkers for posttreatment control. Short treatment interruptions with frequent HIV-1 RNA monitoring have been proven to be clinically safe [67,86,114], but severe complications could occur in rare cases. Both Boston patients with CCR5+ allogeneic stem cell transplantation from HIV-uninfected donors had low-level CSF viremia during systemic viral rebound posttreatment interruptions, but one subsequently developed HIV-meningitis [115]. The lack of preexisting HIV-1 immunity likely contributed to the meningitis. Furthermore, life-threatening encephalitis secondary to massive immune activation and CD8+ T-lymphocyte infiltration can occur after CNS viral escape in unplanned treatment interruptions [116], highlighting the crucial role of CNS monitoring in remission studies.

We propose CNS monitoring based on our experience conducting four HIV-1 remission trials with treatment interruptions at the Thai Red Cross AIDS Research Centre in Bangkok, Thailand.

All participants initiated ART during AHI and sustained at least 12 months of viral suppression before entering the remission trials, which included shock and kill (NCT02475915, n = 14), VRC01 bNAb infusion (NCT03036709, n = 18), and very early ART initiation in Fiebig 1 AHI (NCT02614950, n = 8). Plasma viral load was monitored every 3–7 days in these trials. ART was resumed for confirmed plasma viral load greater than 1000 copies/ml, fall in CD4+ T-lymphocyte count, development of clinical HIV disease or acute retroviral syndrome, pregnancy, or at volunteer request. No participant experienced severe neurological adverse events or change in cognitive function as a result of interventions and treatment interruptions . CSF viremia and elevated inflammatory markers during ATI were uncommon despite detectable plasma viremia [67,86,114].

HIV remission studies should incorporate clinical neurologic monitoring at a minimum. This includes self-reported questionnaires, standardized neurological examination, and neuropsychological testing. Serial CSF sampling before and after intervention as well as after treatment interruptions is ideal but may not be acceptable to some participants. The most important sampling time-point depends on the intervention and the research question. In LRA trials, CSF sampling shortly after serial LRA dosing when maximum activity is expected would be informative to understand possibly deleterious CNS effects from viral activation. In people who achieve remission post treatment interruptions, CSF sampling during plasma viral suppression off ART maybe helpful to understand if viral escape has occurred. In immune interventional trials with long treatment interruptions, CSF sampling could be done after plasma viral set-point or at the time point prior to ART resumption to understand if the rebound virus in the blood vs. the CSF are phylogenetically different; therefore, compartmentalized. Measurement of immune markers in both plasma and CSF samples would help to clarify whether people in remission have heightened immune activation similar to elite controllers, which is linked to unfavorable clinical outcomes [117,118] and cognitive decline in neurodegenerative diseases [119]. Plasma and CSF neurofilament light chain protein (NFL) assay could provide additional information for subclinical neuronal damage [120].

Neuroimaging could be used for neurological monitoring given the noninvasiveness and likely superior sensitivity for preclinical changes. MRI sequences, such as MRS and diffusion-tensor imaging (DTI) are useful to detect intracerebral inflammation and microstructure change, respectively. Another potential MRI technique includes diffusion basis spectrum imaging (DBSI), which provides paired axonal integrity and pathological information through additional evaluation of vasogenic edema and cellularity [121,122].

Figure 1 illustrates the proposed CNS data acquisition at different phases of a remission study: preintervention preparation: document baseline neurologic functions, neuroimaging, CSF viremia, immune activation markers and viral sequences, during and postintervention: assess changes from baseline for clinical and laboratory markers, measure concentration of experimental agents if appropriate, posttreatment interruptions: evaluate neurologic functions for safety, and measure CSF viremia and inflammatory markers in individuals who experience plasma viral load rebound, and in those with sustained aviremia. Phylogenetic analysis can be performed in CSF viremic individuals to compare with pre-ART or baseline sequences, which will inform the source of rebound viremia and possible selective immune pressure from interventions, and post-ART resumption and viral resuppression: safety monitoring to ensure that any neuropsychiatric manifestations, CSF viremia, and inflammation normalizes or return to baseline values.

Fig. 1

Fig. 1

Given the multisystem involvement of HIV and the impracticability of multitissue sampling (especially the brain) for disease evaluation, priority should be given to developing noninvasive methods to measure HIV disease activity. Molecular imaging using PET has been increasingly used in HIV research. An immuno-PET study in SIV-infected monkeys used 64Cu-labeled SIV Gp120-specific antibody ligand to locate infected cells throughout the body except the brain because the antibody did not penetrate the BBB [123]. PET imaging based on 18 kDA translocator protein (TPSO)-targeted ligand measures activation of microglia activation and has become a valid choice for neuroinflammation research [17,124]. Vascular PET that evaluates atherosclerotic vascular inflammation [125,126] could be helpful for predicting long-term comorbidities. Dual-tracer PET imaging [127] in HIV infection should be explored given its success in cancer research.

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Conclusion

HIV persistence in the CNS is an obstacle to curing HIV. Strategies towards a remission and cure should reduce the frequencies of HIV-infected cells, improve control of viral replication and target unique viral quasispecies within the CNS. HIV remission trials include experimental agents and treatment interruptions that can directly and indirectly impact the CNS, but CNS monitoring is often not done. Latency-modifying agents, therapeutic vaccines and cell-based therapies can cross the BBB, and potentially target infected cells resulting in local immune activation. Antibody-based therapies generally do not cross the BBB but its systemic effects on viremia and immune activation could affect the CNS. Therefore, HIV remission studies should incorporate CNS investigations to determine if experimental agents and treatment interruptions are safe, and to understand the effects of interventions on CNS HIV persistence.

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Acknowledgements

We thank Drs Serena Spudich, Eugene Kroon, and Donn Colby for the helpful discussions and advice on this article, Ms. Ellen Turk for editorial assistance and Ms. Oratai Butterworth for administrative support. J.A. was funded in part by the U.S. National Institute of Health (R01NS084911-01 and UM1AI126603).

Disclaimer: The views and opinions expressed in the article are solely those of the authors and are not intended to represent those of the US Army or the Department of Defense, or the National Institutes of Health, Department of Health and Human Services, USA.

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Conflicts of interest

P.C. declares no conflict of interest. J.A. has participated in advisory boards for ViiV Healthcare and Gilead, and meetings for Merck, and served as a consultant for Roche and AbbVie.

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    Keywords:

    antiretroviral interruption; central nervous system compartmentalization; central nervous system latency; HIV cure

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