The Biology of the HIV-1 Latent Reservoir and Implications for Cure Strategies

Cohn, Lillian B.; Chomont, Nicolas; Deeks, Steven G.

doi:10.1016/j.chom.2020.03.014

Cited by 189 publications

(208 citation statements)

References 138 publications

(168 reference statements)

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“…Viral sequencing has also revealed many intact proviruses within clonally expanded populations, particularly within the Tem and Th1 subsets, and those expressing Ox40 or CD161 (De Scheerder et al, 2019;Hiener et al, 2017;Kuo et al, 2018;Lee et al, 2017;Li et al, 2019). These and many other studies (Cohn et al, 2020;Liu et al, 2020) have solidified the view that clonal expansion plays a major role in maintaining the longlived HIV reservoir.…”

Section: Introductionmentioning

confidence: 67%

“…5C). To assess the extent of clonal expansion, a major driver of HIV persistence (Cohn et al, 2020;Liu et al, 2020), we determined the proportions of expanded identical sequences (EIS). EIS were prominent in both populations, but the proportions of EIS with intact p24 sequences were consistently higher in the enriched ones ( Fig.…”

Section: Markers Of Knn Latent Cells Enrich For the Replication-compementioning

confidence: 99%

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The Atlas of the In Vivo HIV CD4 T Cell Reservoir

Neidleman

Luo

Frouard

et al. 2020

Preprint

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The latent reservoir is a main barrier for curing HIV. But because latently-infected cells cannot be phenotyped directly, the features of the in vivo reservoir have remained elusive. Here, we describe a method that leverages high-dimensional phenotyping using CyTOF to trace latently-infected cells reactivated ex vivo to their original pre-activation states. Our results suggest that contrary to common assumptions, the reservoir is not randomly distributed among cell subsets, and is remarkably conserved between individuals. However, reservoir composition differs between tissues and blood, as do cells successfully reactivated by different latency reversing agents. Most importantly, by selecting 8-10 of our 39 original CyTOF markers, we were able to isolate highly purified populations of unstimulated in vivo latent cells, thereby validating the PP-SLIDE approach for reservoir characterization. These purified populations were highly enriched for replication-competent and intact provirus, transcribed HIV, and displayed clonal expansion. The ability to isolate unstimulated latent cells from infected individuals enables previously impossible studies of HIV persistence.

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Section: Introductionmentioning

confidence: 67%

Section: Markers Of Knn Latent Cells Enrich For the Replication-compementioning

confidence: 99%

The Atlas of the In Vivo HIV CD4 T Cell Reservoir

Neidleman

Luo

Frouard

et al. 2020

Preprint

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“…An important aspect of how HIV persists in individuals on long-term ART is through the evasion of immune recognition, predominately thought to be achieved through the maintenance of strict viral latency, with an additional aspect of anatomical sequestration. This perception that the reservoir is entirely latent has begun to shift lately, in response both to a new understanding of the dynamic nature of the HIV reservoir (driven by the clonal expansion of infected cells), and to new insights into ongoing viral transcriptional activity on ART (15,38). (43), and ii) the substantial majority of HIV-specific T-cells that remain detectable after years of ART target epitopes for which escape is not fixed in corresponding reservoir viruses (44,45).…”

Section: Discussionmentioning

confidence: 99%

“…Most notably, unspliced, and sometimes multiply spliced, HIV transcripts are readily detectable in peripheral blood mononuclear cells (PBMCs) of individuals on durable ART (12,13). These observations have recently led some to propose amendments to the "latent reservoir" model, by introducing the idea of a continuum ranging from "deep latency" (no RNA produced) through to an "active reservoir" (14,15). A key unresolved question, however, is whether these transcripts result in HIV-protein production, and thus enable immune recognition.…”

Section: Introductionmentioning

confidence: 99%

HIV-specific T-cell responses reflect substantive in vivo interactions with infected cells despite long-term therapy

Stevenson

Ward

Truong

et al. 2020

Preprint

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Antiretroviral therapies (ART) durably suppress HIV replication to undetectable levels – however, infection persists in the form of long-lived reservoirs of infected cells with integrated proviruses, that re-seed systemic replication if ART is interrupted. A central tenet of our current understanding of this persistence is that infected cells are shielded from immune recognition and elimination through a lack of antigen expression from proviruses. Efforts to cure HIV infection have therefore focused on reactivating latent proviruses to enable immune-mediated clearance, but these have yet to succeed in driving reductions in viral reservoirs. Here, we revisited the question of whether HIV reservoirs are predominately immunologically silent from a new angle, by querying the dynamics of HIV-specific T-cell responses over long-term ART for evidence of ongoing recognition of HIV-infected cells. We show that T-cell responses to autologous reservoir viruses persist over years, and that the maintenance of HIV-Nef-specific responses was uniquely associated with residual frequencies of infected cells. These responses disproportionately exhibited a cytotoxic, effector functional profile, indicative of recent in vivo recognition of HIV-infected cells. These results indicate substantial visibility of the HIV reservoir to T-cells on stable ART, presenting both opportunities and challenges for the development of therapeutic approaches to curing HIV infection.

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“…43,44 A variety of other agents (e.g., sirolimus, an IL-21 superagonist, and anti-IFNa/b receptor antibodies) are also being tested for their ability to reduce HIV-associated inflammation, hoping to thereby improve HIV-specific immune responses. [45][46][47] Targeting the HIV replication cycle…”

Section: Immune Modulationmentioning

confidence: 99%