The human brain is an enigma that to date defies comprehensive understanding in the context of homeostasis and disease. Given this, it is not surprising that the role of the central nervous system (CNS) in HIV persistence and pathogenesis during combination antiretroviral therapy (ART) in humans remains uncertain. Since the first descriptions of HIV effects on the CNS over 30 years ago [1,2], widespread use of effective ART in the past two decades has changed the clinical character and pathology of neurologic disease in people living with HIV (PLWH). However, in the context of this successful treatment, new pressing questions have emerged. ART-free HIV remission (control of viral replication and lack of complications in the absence of ART) has become a focus of intense investigative effort given the growing numbers of PLWH worldwide and the personal, public health, and societal challenges of chronic HIV and prolonged ART. To achieve HIV remission, it will be critical to understand to what extent and in what tissues, cell types, and circumstances CNS infection persists during ART.
The purpose of this supplement issue of AIDS is to provide a coherent collection of reports addressing whether the brain and CNS more broadly are sites of viral persistence during ART, the character of this persistence, and the potential role of the CNS as an obstacle to effective HIV remission. Through a collection of original articles, summary reviews, perspectives, and an editorial commentary, this issue highlights key recent findings in animal model and human studies, identifies gaps in knowledge related to the role of the CNS in HIV remission, and provides guidance in definition and study strategies for future coherent studies to understand HIV persistence and ‘cure’ in the CNS.
Simian immunodeficiency virus (SIV) and simian-HIV (SHIV) infection in nonhuman primates (NHPs) leads to infection in CD4+ T cells, monocytes and tissue macrophages providing excellent models to study infection in brain. In this supplement, Hsu et al. report the impact of analytic treatment interruption (ATI) on SHIV infection in the CNS. SHIV-1157ipd3N4 infection of NHPs results in virus in plasma and cerebrospinal fluid (CSF) as well as increased levels of inflammatory cytokines, IL-15 and CCL2 in both compartments. ART rapidly suppressed virus in plasma and CSF, reduced of IL-15, IFNg -induced protein-10, neopterin in plasma and monocyte chemoattractant protein-1 in CSF. ATI resulted in virus rebound in the plasma of all the macaques but not in CSF. However, ATI was associated with mild, localized T-cell infiltrate in brain without detectable SHIV-RNA in CSF or brain or elevation in CSF soluble markers of inflammation. Despite the lack of viral rebound the CSF and brain in this study, continued surveillance of CNS was recommended.
Abreu et al. describe a novel macrophage quantitative viral outgrown assay (mQVOA) similar to the QVOA that measures CD4+ T-cell functional latent reservoir in ART-suppressed individuals. Persistence of latently infected brain macrophages (perivascular macrophages and microglia) in ART-suppressed SIVmac251-infected NHPs reported in this study provides evidence that despite ART the CNS contains latent infectious virus. Using the mQVOA assay, the frequency of latently infected monocytes in ART-suppressed NHPs was 1 in 106 cells, comparable with the frequency of latent CD4+ T cells in suppressed NHPs and humans. In addition, microglia and perivascular macrophages contained a similar frequency of latently infected cells that produced infectious SIV. This report provides compelling evidence that blood monocytes and brain macrophages harbor latently infected cells that have the potential to reactivate infectious virus and constitute an additional latent reservoir in SIV-infected macaques and potentially in HIV-infected humans.
A collection of three articles in this supplement focus on the theme of CSF HIV escape in humans, a condition that indicates a source of HIV replication or release from cells within the CNS despite systemically suppressive ART. Mastrangelo et al. describe the clinical syndrome of ‘symptomatic CSF escape’ wherein detection of CSF escape occurs in the context of progressive diffuse or focal neurological signs and symptoms. The authors review the risk factors for this condition, clinical manifestations, and the response to modifications in ART regimens that have been described through a comprehensive summary of case reports as well description of their own personal experience. Among other treatment-related factors, they discuss the implications of specific treatment approaches, including integrase strand inhibitor-based therapy and dual ART regimens, for the risk of developing symptomatic HIV escape.
In an effort to understand what CSF HIV escape can reveal about the existence of CNS viral reservoirs, Joseph et al. examined the virological character of CSF HIV escape populations as a window into whether these viruses appear to be produced by ‘reservoir’ cells within the CNS. They argue that ‘episodic’ CSF escape (detected intermittently or only once) is likely produced by immune cells trafficking from the blood that release virus locally within the CNS. However, CSF escape viral populations that are detected over multiple time points, are genetically diverse, are macrophage tropic or manifest viral evolution during ART are likely produced by resident CNS cells. Examples of each of these conditions are presented from previously described reports and the author's own experience. The authors conclude that CSF escape is not only often produced by trafficking cells and local viral release but also may be produced by resident cells within the CNS, which appear to include both myeloid lineage cells (macrophages/microglia) and CD4+ T lymphocytes.
In a supplement editorial article for this issue, Winston, et al. propose a set of consensus definitions of CSF HIV escape, in order to provide a foundation for common clinical management and research investigation for this condition. These definitions are based on a review of terminology and determinations used to date in international guidelines and research articles, and on the discussions of an expert panel combined with responsive voting by an open audience at a US National Institute of Mental Health-sponsored symposium on CSF escape held in Pollenzo, Italy. Viral load measurement criteria, symptomatology categories, and indications for clinical management aspects of CSF HIV escape are considered, and for each of these, a summary of the discussion and a consensus recommendation is provided. Despite limitations in our understanding of the biological underpinnings and clinical significance of CSF HIV escape, these initial consensus definitions address some of the questions and controversies surrounding this collection of syndromes and should provide guideposts for further investigation.
The detection of CSF Tat protein and CSF-derived exosomes containing biologically active HIV Tat protein in ART-suppressed PLWH as described in Henderson et al. support other reports in this AIDS supplement that despite ART, there is ongoing viral production (at least viral transcription) in the CNS. In their findings, CSF Tat protein increased after initiation of ART, suggesting that Tat was persistently produced despite treatment. PLWH who were positive for Tat represented 37% of those studied but were distinguished by a history of using drugs of abuse (cocaine and amphetamines) from the TAT-negative group. Thus, this study may provide another CSF measure of HIV ‘escape’ in the CNS in ART-suppressed patients, reveal a potential driver of CNS inflammation and pathogenesis associated with viral persistence, and may identify a subgroup of individuals at heightened risk for HIV persistence in the CNS.
Prior studies suggesting that low CD4+ T-cell nadir and prolonged HIV exposure prior to ART are risk factors for HIV CSF escape and HIV-associated neurocognitive disorder raise the credible hypothesis that early treatment may reduce or prevent persistent HIV within the CNS after ART. Spudich et al. describe the early neuropathogenesis of HIV within the CNS including examples of detection of HIV compartmentalization and viral evolution within the CSF in the first year of infection, suggesting the potential for establishment of sites of HIV persistence in some cases. The authors proceed to describe the evidence for an apparent benefit of early initiation of ART in the CNS on inflammation and neuronal injury, and outline existing information about HIV detection and HIV-specific responses – which are a potential proxy for detection of HIV antigen – after early ART. However, the limitations of our current means of assessment of CNS HIV persistence in the living human are highlighted, providing a rationale for development of novel means to assess for low-level or latent HIV in this compartment during ART.
Finally, two manuscripts provide a broad overview of the implications of HIV persistence during ART in the CNS compartment. Brew et al. describe a spectrum of evidence from multiple approaches that indicate persistent perturbation of the CNS during suppressive ART, and ongoing low level brain infection in a subset of individuals. In particular, they provide a neuropathological perspective based on review of evidence derived from brain tissue of ART-suppressed individuals and animal models, and a summary of cell types (including macrophages, microglia, and astrocytes) that have been considered as sites of HIV persistence. Importantly, the authors discuss controversies regarding these cell types as potential targets for HIV. The implications of persistent HIV in the CNS are considered, in terms of inflammatory and clinical consequences, and the gaps in knowledge of our current understanding, including mechanisms of the neurotoxic effects of persistent HIV.
Chan and Ananworanich provide a final perspective piece on whether and how HIV within the CNS needs to be considered in strategies aimed at HIV remission or eradication (HIV ‘cure’). The authors summarize existing information on how the CNS may be relevant to HIV cure, serving as a potential source of HIV rebound, a site of enhanced inflammation and injury in the setting of viral reactivation, or a protected site with limited penetration or effect of therapeutic molecules and immune interventions. A comprehensive delineation of the information available on CNS effects of remission studies, including antiretroviral treatment interruption and HIV cure interventions, outlines the design or intervention and the CNS outcomes of studies to date. To conclude, they provide a roadmap of approaches to CNS monitoring during future treatment interruption or interventional trials, suggesting that consistency of methods and approaches, even across small studies, can yield key safety, efficacy, and mechanistic information about the implications of CNS HIV persistence for HIV remission and eradication.
Conflicts of interest
There are no conflicts of interest.