Clonal CD4+ T cells in the HIV-1 latent reservoir display a distinct gene profile upon reactivation

Cohn, Lillian B.; Silva, Israel Tojal da; Valieris, Renan; Huang, Amy S.; Lorenzi, Julio C. C.; Cohen, Yehuda Z.; Pai, Joy A.; Butler, Allison L.; Caskey, Marina; Janković, Mila; Nussenzweig, Michel C.

doi:10.1038/s41591-018-0017-7

Cited by 123 publications

(159 citation statements)

References 49 publications

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“…There remains quite some discussion about the value of qVOA when investigating the HIV reservoir, due to rather poor correlations with rebound sequences as described here and by others . One potential explanation is that qVOA is limited to the blood compartment and does not take into account rebound coming from other anatomical reservoirs.…”

Section: Discussionmentioning

confidence: 82%

Rapid viral rebound after analytical treatment interruption in patients with very small HIV reservoir and minimal on‐going viral transcription

et al. 2020

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Introduction Viral remission after analytical treatment interruption (ATI), termed post‐treatment control, has been described in a small proportion of HIV‐positive patients. This phenomenon has been separately associated to both low levels of HIV‐1 proviral DNA as well as cell‐associated RNA. We investigated whether the combination of both parameters could help predict delayed viral rebound after treatment interruption (TI). Methods We conducted an open single‐arm ATI study in four Belgian HIV reference centres from January 2016 to July 2018. Eligible participants were adults who had fewer than 50 HIV‐1 RNA copies/mL for more than two years, more than 500 CD4 cells/µL for more than three months, and were in general good health. Consenting participants who had fewer than 66 copies total HIV‐1 DNA (t‐DNA) and fewer than 10 copies cell‐associated HIV‐1 unspliced RNA (US‐RNA) per million peripheral blood mononuclear cells (PBMCs), interrupted therapy and were monitored closely. Antiretroviral therapy (ART) was resumed after two consecutive viral loads exceeding 1000 copies or one exceeding 10,000 copies/mL. The primary outcome was the proportion of participants with fewer than 50 HIV‐1 RNA copies/mL 48 weeks after TI. Secondary outcomes were time to viral rebound, the frequency of serious adverse events (AEs) and evolution of t‐DNA and US‐RNA after TI. Results All 16 consenting participants who interrupted therapy experienced rapid viral rebound two to eight weeks after TI. No serious AEs were observed. Levels of t‐DNA and US‐RNA increased after TI but returned to pre‐ATI levels after treatment restart. None of the studied demographic, clinical and biological parameters were predictive of time of viral rebound. Conclusions The combination of low levels of t‐DNA and US‐RNA in PBMCs, corresponding respectively to a small and transcriptionally silent viral reservoir, is not predictive of viral remission after TI in patients on ART.

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Section: Discussionmentioning

confidence: 82%

Rapid viral rebound after analytical treatment interruption in patients with very small HIV reservoir and minimal on‐going viral transcription

et al. 2020

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“…To determine whether the intact sequences isolated from antigen-responsive cells are replication competent, we compared the sequences obtained from antigen or SEB responsive cells to those obtained from single-cell viral outgrowth cultures (Q 2 VOA) from 5 of the individuals for whom such data was available (Cohn et al, 2018;Mendoza et al, 2018). B207 and 9247 had identical matches between Q 2 VOA sequences and proviral sequences isolated from either CMV-pp65-or HIV-gag-responsive cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, in vitro studies showed that cell division and latency are not mutually exclusive (Wang et al, 2018;Hosmane et al, 2017;Pinzone et al, 2019). Finally, isolation of productively infected cells ex vivo (Cohn et al, 2018) and paired full-length viral sequencing and integration site analysis (Einkauf et al, 2019) provided definitive evidence for the existence of expanded clones of CD4 + T cells harboring intact latent proviruses.…”

Section: Discussionmentioning

confidence: 99%

Antigen responsive CD4⁺T cell clones contribute to the HIV-1 latent reservoir

Mendoza

Jackson

Oliveira

et al. 2020

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AbstractAntiretroviral therapy suppresses but does not cure HIV-1 infection due to the existence of a long-lived reservoir of latently infected cells. The reservoir has an estimated half-life of 44 months and is largely composed of clones of infected CD4+ T cells. The long half-life appears to result in part from expansion and contraction of infected CD4+ T cell clones. However, the mechanisms that govern this process are poorly understood. To determine whether the clones might result from, and be maintained by exposure to antigen, we measured responses of reservoir cells to a small subset of antigens from viruses that produce chronic or recurrent infections. Despite the limited panel of test antigens, clones of antigen responsive CD4+ T cells containing defective or intact latent proviruses were found in 7 out of 8 individuals studied. Thus, chronic or repeated exposure to antigen may contribute to the longevity of the HIV-1 reservoir by stimulating the clonal expansion of latently infected CD4+ T cells.

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“…; Bolton et al, 2017; Martrus et al, 2016). Two recent publications have also examined HIV latency using scRNA-seq of a primary cell model (Golumbeanu et al, 2018) and from sorted patient samples (Cohn et al, 2018), yielding important insights. In particular, Golumbeanu et al (2018) observed two clusters of cells in a primary cell model system that exhibited distinct transcriptional phenotypes, associated with different levels of viral gene expression.…”

Section: Discussionmentioning

confidence: 99%

Single-Cell Analysis of Quiescent HIV Infection Reveals Host Transcriptional Profiles that Regulate Proviral Latency

et al. 2018

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SUMMARY A detailed understanding of the mechanisms that establish or maintain the latent reservoir of HIV will guide approaches to eliminate persistent infection. We used a cell line and primary cell models of HIV latency to investigate viral RNA (vRNA) expression and the role of the host transcriptome using single-cell approaches. Single-cell vRNA quantitation identified distinct populations of cells expressing various levels of vRNA, including completely silent populations. Strikingly, single-cell RNA-seq of latently infected primary cells demonstrated that HIV downregulation occurred in diverse transcriptomic environments but was significantly associated with expression of a specific set of cellular genes. In particular, latency was more frequent in cells expressing a transcriptional signature that included markers of naive and central memory T cells. These data reveal that expression of HIV proviruses within the latent reservoir are influenced by the host cell transcriptional program. Therapeutic modulation of these programs may reverse or enforce HIV latency.

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Clonal CD4+ T cells in the HIV-1 latent reservoir display a distinct gene profile upon reactivation

Cited by 123 publications

References 49 publications

Rapid viral rebound after analytical treatment interruption in patients with very small HIV reservoir and minimal on‐going viral transcription

Rapid viral rebound after analytical treatment interruption in patients with very small HIV reservoir and minimal on‐going viral transcription

Antigen responsive CD4⁺T cell clones contribute to the HIV-1 latent reservoir

Single-Cell Analysis of Quiescent HIV Infection Reveals Host Transcriptional Profiles that Regulate Proviral Latency

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Clonal CD4+ T cells in the HIV-1 latent reservoir display a distinct gene profile upon reactivation

Cited by 123 publications

References 49 publications

Rapid viral rebound after analytical treatment interruption in patients with very small HIV reservoir and minimal on‐going viral transcription

Rapid viral rebound after analytical treatment interruption in patients with very small HIV reservoir and minimal on‐going viral transcription

Antigen responsive CD4+T cell clones contribute to the HIV-1 latent reservoir

Single-Cell Analysis of Quiescent HIV Infection Reveals Host Transcriptional Profiles that Regulate Proviral Latency

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Antigen responsive CD4⁺T cell clones contribute to the HIV-1 latent reservoir