Anatomic Compartments as a Barrier to HIV Cure

Yukl, Steven A.; Wong, Joseph K.

doi:10.1007/978-1-4614-9610-6_435-1

Cited by 4 publications

(5 citation statements)

References 214 publications

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“…The persistence of virus or viral remnants in nearly all tissues studied (Table 1)[144] has important implications for viral pathogenesis and for cure. Given the diversity of cell types and anatomic environments where HIV reservoirs simultaneously persist, it is questionable whether single interventions and modalities will suffice to eliminate all possible viral reservoirs.…”

Section: Discussionmentioning

confidence: 99%

Tissue reservoirs of HIV

Wong

Yukl

2016

Current Opinion in HIV and AIDS

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195

161

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Purpose Tissue reservoirs of HIV may promote the persistent immunopathology responsible for non-AIDS morbidity and data support multifocal reactivation from tissues as the source of viral rebound during ART interruption. The heterogeneity of tissue reservoirs and incomplete knowledge about their composition are obstacles to an HIV cure. Recent findings In addition to the higher concentration of infected CD4+ T cells found in both central lymphoid tissues and gut, specific subsets of CD4+ T cells appear to play a disproportionate role in HIV persistence. Recently, a subset of central memory T cells enriched in lymphnode germinal centers called T-follicular helper cells have been identified that express more viral RNA and occupy an anatomic niche inaccessible to CTL killing. Additional observations suggest that ARV concentrations may be lower in some tissues raising the possibility for localized, low-level viral replication. Finally, some recent data implicate the persistence of infected, non-CD4+ T cell types in tissues during ART. Summary The retention of infected cells in a wide variety of tissues, often with distinct viral and cellular characteristics, underscores the importance of studying tissue reservoirs in the development and assessment of cure strategies. Both inhibitory ARVs and latency reversing drugs must reach these sites and novel strategies may be needed to attack virus in cells as variable as Tfh and macrophages.

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Section: Discussionmentioning

confidence: 99%

Tissue reservoirs of HIV

Wong

Yukl

2016

Current Opinion in HIV and AIDS

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195

161

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“…Detailed HIV reservoir measurements of different tissues are reviewed elsewhere (Yukl and Wong, 2015;Barton et al, 2016;Churchill et al, 2016;Wong and Yukl, 2016). For the purposes of this review, we consider both defined and potential anatomic reservoir sites (Figure 1) in the context of current and emerging reservoir assays.…”

Section: The Hiv Reservoir: Anatomic Sites Of the Reservoirmentioning

confidence: 99%

“…However, there are many long-lived cell types, such as other tissue resident macrophages in other sites (e.g., microglia), astrocytes, hematopoietic progenitor cells, among others, in which HIV DNA or RNA has been detected but replicationcompetent HIV has not (Carter et al, 2010;Canaud et al, 2014;Yukl and Wong, 2015;Al-Harti et al, 2018;Ko et al, 2019;Wong et al, 2019) (Figure 1). Therefore, we consider tissues with these cell types as potential reservoir sites.…”

Section: The Hiv Reservoir: Anatomic Sites Of the Reservoirmentioning

confidence: 99%

“…This diversity is primarily attributed to the absence of a proofreading mechanism in the HIV reverse transcriptase enzyme, as well as high levels of viremia and recombination (van Zyl et al, 2018). Other factors that contribute to this diversity include: host immune response (APOBEC enzyme hypermutations) (Bruner et al, 2016), length of infection (accumulation of mutations and depletion of CD4 T cell targets) (Arrildt et al, 2015;Zhou et al, 2016), viral compartmentalization (Yukl and Wong, 2015;van Zyl et al, 2018;Miller et al, 2019), and selection for viral quasispecies that are able to evade killing by host immune mechanisms (Phillips et al, 1991;Wei et al, 2003;Kearney et al, 2009;van Zyl et al, 2018).…”

Section: The Hiv Reservoir: Spectrum Of Viral Expression Diversity mentioning

confidence: 99%

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New Frontiers in Measuring and Characterizing the HIV Reservoir

et al. 2019

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A cure for HIV infection remains elusive due to the persistence of replication-competent HIV proviral DNA during suppressive antiretroviral therapy (ART). With the exception of rare elite or post-treatment controllers of viremia, withdrawal of ART invariably results in the rebound of viremia and progression of HIV disease. A thorough understanding of the reservoir is necessary to develop new strategies in order to reduce or eliminate the reservoir. However, there is significant heterogeneity in the sequence composition, genomic location, stability, and expression of the HIV reservoir both within and across individuals, and a majority of proviral sequences are replication-defective. These factors, and the low frequency of persistently infected cells in individuals on suppressive ART, make understanding the reservoir and its response to experimental reservoir reduction interventions challenging. Here, we review the characteristics of the HIV reservoir, stateof-the-art assays to measure and characterize the reservoir, and how these assays can be applied to accurately detect reductions in reservoir during efforts to develop a cure for HIV infection. In particular, we highlight recent advances in the development of direct measures of provirus, including intact proviral DNA assays and full-length HIV DNA sequencing with integration site analysis. We also focus on novel techniques to quantitate persistent and inducible HIV, including RNA sequencing and RNA/gag protein staining techniques, as well as modified viral outgrowth methods that seek to improve upon throughput, sensitivity and dynamic range.

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“…In this process, HIV establishes reservoirs throughout the body including in the CNS, lymphoid tissues (spleen, thymus, lymph nodes, gut-associated lymphoid tissue), bone marrow, lungs, kidneys, liver, adipose tissue, gastrointestinal tract, and genitourinary systems (5). The persistence of replication-competent HIV in these ana-tomical sites, even in the setting of longstanding, potent antiretroviral therapy (ART) that suppresses HIV replication, is the main barrier to curing HIV (6).…”

Section: Introductionmentioning

confidence: 99%

HIV persists throughout deep tissues with repopulation from multiple anatomical sources

Chaillon¹,

Gianella²,

Dellicour³

et al. 2020

Journal of Clinical Investigation

172

154

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BACKGROUND. Understanding HIV dynamics across the human body is important for cure efforts. This goal has been hampered by technical difficulties and the challenge of obtaining fresh tissues. METHODS. This observational study evaluated 6 individuals with HIV (n = 4 with viral suppression using antiretroviral [ART] therapy; n = 2 with rebound viremia after stopping ART), who provided serial blood samples before death and their bodies for rapid autopsy. HIV reservoirs were characterized by digital droplet PCR, single-genome amplification, and sequencing of fulllength (FL) envelope HIV. Phylogeographic methods were used to reconstruct HIV spread, and generalized linear models were tested for viral factors associated with dispersal. RESULTS. Across participants, HIV DNA levels varied from approximately 0 to 659 copies/10 6 cells (IQR: 22.9-126.5). A total of 605 intact FL env sequences were recovered in antemortem blood cells and across 28 tissues (IQR: 5-9). Sequence analysis showed (a) the emergence of large, identical, intact HIV RNA populations in blood after cessation of therapy, which repopulated tissues throughout the body; (b) that multiple sites acted as hubs for HIV dissemination but that blood and lymphoid tissues were the main source; (c) that viral exchanges occurred within brain areas and across the blood-brain barrier; and (d) that migration was associated with low HIV divergence between sites and greater diversity at the recipient site. CONCLUSION. HIV reservoirs persisted in all deep tissues, and blood was the main source of dispersal. This may explain why eliminating HIV susceptibility in circulating T cells via bone marrow transplants allowed some individuals with HIV to experience therapy-free remission, even though deeper tissue reservoirs were not targeted. TRIAL REGISTRATION. Not applicable.

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Anatomic Compartments as a Barrier to HIV Cure

Cited by 4 publications

References 214 publications

Tissue reservoirs of HIV

Tissue reservoirs of HIV

New Frontiers in Measuring and Characterizing the HIV Reservoir

HIV persists throughout deep tissues with repopulation from multiple anatomical sources

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