HIV-1 latent reservoir size and diversity are stable following brief treatment interruption

Salantes, D. Brenda; Zheng, Yu; Mampe, Felicity; Srivastava, Tuhina; Beg, Subul; Lai, Jun; Li, Jonathan Z.; Tressler, Randall; Koup, Richard A.; Hoxie, James A.; Abdel‐Mohsen, Mohamed; Sherrill-Mix, Scott; McCormick, Kevin; Overton, Edgar Turner; Bushman, Frederic D.; Learn, Gerald H.; Siliciano, Robert F.; Siliciano, Janet M.; Tebas, Pablo; Bar, Katharine J.

doi:10.1172/jci120194

Cited by 95 publications

(143 citation statements)

References 45 publications

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“…To investigate the origin of viral rebound, we compared qVOA outgrowth viruses with in vivo plasma rebound viruses using SGA. Exact matches between qVOA and rebound clones have been reported only very rarely . In these three participants, we observe intermingling between the viral sequences obtained from qVOA and plasma at viral rebound, confirming their close phylogenetic relatedness.…”

Section: Discussionsupporting

confidence: 69%

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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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Section: Discussionsupporting

confidence: 69%

“…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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“…Stochastic simulations (Methods) with a constant VRC01 efficacy against the mutant, indicated that the latent cell pool did not vary significantly over the durations considered (Fig. 3(a)), consistent with experiments 58 . Reactivation leading to the growth of productively infected cells carrying proviruses with the N279K mutation occurred over a duration of a few days to weeks (Fig.…”

Section: Resultssupporting

confidence: 75%

Pre-existing resistant proviruses can compromise maintenance of remission by VRC01 in chronic HIV-1 infection

Saha

Dixit

2020

Preprint

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16Broadly neutralizing antibodies (bNAbs) of HIV-1 hold promise of eliciting long-term HIV-1 17 remission. Surprisingly, the bNAb VRC01, when administered concomitantly with the cessation 18 of successful antiretroviral therapy (ART), failed rapidly in chronic HIV-1 patients. We 19 hypothesized that the failure was due to VRC01-resistant strains that were formed before ART 20 initiation, survived ART in latently infected cells, and were reactivated during VRC01 therapy. 21 Current assay limitations preclude testing this hypothesis experimentally. We developed a 22 mathematical model based on the hypothesis and challenged it with available clinical data. The 23 model integrated within-host HIV-1 evolution, stochastic latency reactivation and viral dynamics 24 with multiple dose VRC01 pharmacokinetics. With a virtual patient population, model predictions 25 quantitatively captured data from two independent clinical trials. Accordingly, we attributed 26 VRC01 failure to single-mutant VRC01-resistant proviruses in the latent reservoir triggering viral 27 recrudescence, particularly during trough VRC01 levels. Accounting for pre-existing resistance 28 may help bNAb therapies maximize HIV-1 remission. 29 30 Antiretroviral therapy (ART) for HIV-1 infection rapidly suppresses viremia to 32 undetectable levels and curtails disease progression but is unable to eradicate the virus. 1 33 Discontinuation of ART, even long after viremic control is established, typically leads to rapid 34 viral rebound, often within days to weeks of discontinuation, and to progressive disease. 2 The 35 rebound is caused by a reservoir of latently infected cells 3 that is formed soon after infection 4 . The 36 reservoir is sustained by cell proliferation 5,6 , which can continue even when ART has stopped new 37 infections, allowing the reservoir to exist long-term 7 . The reservoir can get reactivated 38 stochastically and reignite infection once ART is stopped 8,9 . ART must therefore be administered 39 lifelong. In a remarkable breakthrough, the VISCONTI study showed that when ART is 40 administered early in infection, some individuals can maintain viremic control for many years after 41 the cessation of ART 10 . This study has raised hopes of a functional cure, or long-term remission, 42 of HIV-1, where the viremic control once established by ART can be maintained without lifelong 43 treatment 11 . The success of ART in inducing post-treatment control, however, is small: only ~5-44 15% of the patients treated achieve lasting post-treatment control 12 . Enormous efforts are 45 underway to improve this success rate 11 . 46 One strategy that holds promise is to administer broadly neutralizing antibodies (bNAbs) 47 of HIV-1 for a short period post-ART, i.e., during an analytical treatment interruption (ATI) 13,14 . 48 bNAbs target diverse viral genomic variants 15,16 , and are expected to suppress viremia arising from 49 the reactivation of latently infected cells 17,18 . Simultaneously, they may engage the host immune 50 system 19 , ...

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“…Our large data set of near-full-length HIV-1 provirus sequences allowed for examination of clonal proliferation according to provirus type. Clones were identified as proviruses with identical nucleotide sequences and, if deleted, with identical deletion junctions, as has been done previously (48,58,59). Although definitive assignment of clonality requires integration site analysis, full genome sequence identity provides very strong evidence for clonality (60).…”

Section: Resultsmentioning

confidence: 99%

Longitudinal study reveals HIV-1–infected CD4+ T cell dynamics during long-term antiretroviral therapy

Antar

Jenike

Jang

et al. 2020

Journal of Clinical Investigation

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HIV-1 latent reservoir size and diversity are stable following brief treatment interruption

Abstract: ClinicalTrials.gov NCT02463227FUNDING. Funding was provided by the NIH.

Cited by 95 publications

References 45 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

Pre-existing resistant proviruses can compromise maintenance of remission by VRC01 in chronic HIV-1 infection

Longitudinal study reveals HIV-1–infected CD4+ T cell dynamics during long-term antiretroviral therapy

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