Longitudinal Genetic Characterization Reveals That Cell Proliferation Maintains a Persistent HIV Type 1 DNA Pool During Effective HIV Therapy

Stockenström, Susanne von; Odevall, Lina; Lee, Eun-Ok; Sinclair, Elizabeth; Bacchetti, Peter; Killian, Martin; Epling, Lorrie; Shao, Wei; Hoh, Rebecca; Ho, Terence; Faria, Nuno Rodrigues; Lemey, Philippe; Albert, Jan; Hunt, Peter W.; Loeb, Lisa; Pilcher, Christopher D.; Poole, Lauren; Hatano, Hiroyu; Somsouk, Ma; Douek, Daniel C.; Boritz, Eli; Deeks, Steven G.; Hecht, Frederick M.; Palmer, Sarah

doi:10.1093/infdis/jiv092

Cited by 134 publications

(206 citation statements)

References 19 publications

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“…S2), which is consistent with other reports [5,6,10,13]. A small proportion of sequences had stop codons not obviously due to G-to-A hypermutation (average 3%, range 0-12%) .…”

Section: Hypermutated Sequences Are Frequent In Hiv-1 Reservoirssupporting

confidence: 91%

“…The quantitative virus outgrowth assay (QVOA) represents the "gold standard" [4][5][6], but this assay underestimates the true size of the functional reservoir due to incomplete induction by PHA stimulation. Ho et al [7] showed that the functional HIV-1 reservoir may be 60-fold larger than originally estimated.…”

Section: Introductionmentioning

confidence: 99%

“…PCR based assays are also commonly used for quantifying the HIV-1 reservoir, but these assays overestimate the size of the functional reservoir because they cannot distinguish between replication-competent and defective viral genomes. Quantification of the HIV-1 reservoir by PCRbased methods typically give at least 100-fold higher numbers that the QVOA because of defective proviruses [4][5][6]. Many defective proviruses have large internal deletions [7,8].…”

Section: Introductionmentioning

confidence: 99%

“…Siliciano et al [16] documented a half-life of 44 months for latently infected cells capable of producing replicationcompetent virus in the QVOA. Similarly, HIV-1 DNA levels and genetic compositions are very stable in patients on long-term suppressive ART [5,13,[17][18][19][20][21]. Most studies indicate that the HIV-1 reservoir is maintained by the physiological homeostasis of CD4 memory that in part involves occasional expansions and contractions of individual CD4 cell clones [5,12,22].…”

Section: Introductionmentioning

confidence: 99%

“…Similarly, HIV-1 DNA levels and genetic compositions are very stable in patients on long-term suppressive ART [5,13,[17][18][19][20][21]. Most studies indicate that the HIV-1 reservoir is maintained by the physiological homeostasis of CD4 memory that in part involves occasional expansions and contractions of individual CD4 cell clones [5,12,22]. However, some studies have suggested that persistent virus replication may be an important contributor to the maintenance of the HIV-1 reservoir [23,24].…”

Section: Introductionmentioning

confidence: 99%

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Establishment and stability of the latent HIV-1 DNA reservoir

Brodin

Zanini

Thebo

et al. 2016

Preprint

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HIV-1 infection currently cannot be cured because the virus persists as integrated proviral DNA in long-lived cells despite years of suppressive antiretroviral therapy (ART). To characterize establishment, turnover, and evolution of viral DNA reservoirs we deep-sequenced the p17gag region of the HIV-1 genome from samples obtained from 10 patients after 3-18 years of suppressive ART. For each of these patients, whole genome deep-sequencing data of HIV-1 RNA populations before onset of ART were available from 6-12 longitudinal plasma samples spanning 5-8 years of untreated infection. This enabled a detailed analysis of the dynamics and origin of proviral DNA during ART. A median of 14% (range 0-42%) of the p17gag DNA sequences were overtly defective due to G-to-A hypermutation. The remaining sequences were remarkably similar to previously observed RNA sequences and showed no evidence of evolution over many years of suppressive ART. Most sequences from the DNA reservoirs were very similar to viruses actively replicating in plasma (RNA sequences) shortly before start of ART. The results do not support persistent HIV-1 replication as a mechanism to maintain the HIV-1 reservoir during suppressive therapy. Rather, the data indicate that viral DNA variants are turning over as long as patients are untreated and that suppressive ART halts this turnover.

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“…S2), which is consistent with other reports [5,6,10,13]. A small proportion of sequences had stop codons not obviously due to G-to-A hypermutation (average 3%, range 0-12%) .…”

Section: Hypermutated Sequences Are Frequent In Hiv-1 Reservoirssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Establishment and stability of the latent HIV-1 DNA reservoir

Brodin

Zanini

Thebo

et al. 2016

Preprint

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Mechanisms of CD8⁺ T cell‐mediated suppression of HIV/SIV replication

2018

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In this article, we summarize the role of CD8 T cells during natural and antiretroviral therapy (ART)-treated HIV and SIV infections, discuss the mechanisms responsible for their suppressive activity, and review the rationale for CD8 T cell-based HIV cure strategies. Evidence suggests that CD8 T cells are involved in the control of virus replication during HIV and SIV infections. During early HIV infection, the cytolytic activity of CD8 T cells is responsible for control of viremia. However, it has been proposed that CD8 T cells also use non-cytolytic mechanisms to control SIV infection. More recently, CD8 T cells were shown to be required to fully suppress virus production in ART-treated SIV-infected macaques, suggesting that CD8 T cells are involved in the control of virus transcription in latently infected cells that persist under ART. A better understanding of the complex antiviral activities of CD8 T cells during HIV/SIV infection will pave the way for immune interventions aimed at harnessing these functions to target the HIV reservoir.

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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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Longitudinal Genetic Characterization Reveals That Cell Proliferation Maintains a Persistent HIV Type 1 DNA Pool During Effective HIV Therapy

Abstract: Memory T cells maintained a relatively constant HIV-1 DNA integrant pool that was genetically stable during long-term effective ART. These integrants appear to be maintained by cellular proliferation and longevity of infected cells, rather than by ongoing viral replication.

Cited by 134 publications

References 19 publications

Establishment and stability of the latent HIV-1 DNA reservoir

Establishment and stability of the latent HIV-1 DNA reservoir

Mechanisms of CD8⁺ T cell‐mediated suppression of HIV/SIV replication

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

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Longitudinal Genetic Characterization Reveals That Cell Proliferation Maintains a Persistent HIV Type 1 DNA Pool During Effective HIV Therapy

Abstract: Memory T cells maintained a relatively constant HIV-1 DNA integrant pool that was genetically stable during long-term effective ART. These integrants appear to be maintained by cellular proliferation and longevity of infected cells, rather than by ongoing viral replication.

Cited by 134 publications

References 19 publications

Establishment and stability of the latent HIV-1 DNA reservoir

Establishment and stability of the latent HIV-1 DNA reservoir

Mechanisms of CD8+ T cell‐mediated suppression of HIV/SIV replication

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

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Mechanisms of CD8⁺ T cell‐mediated suppression of HIV/SIV replication