HIV Rebound Is Predominantly Fueled by Genetically Identical Viral Expansions from Diverse Reservoirs

Scheerder, Marie‐Angélique De; Vrancken, Bram; Dellicour, Simon; Schlub, Timothy E.; Lee, Eun-Ok; Shao, Wei; Rutsaert, Sofie; Verhofstede, Chris; Kerre, Tessa; Malfait, Thomas; Hemelsoet, Dimitri; Coppens, Marc; Dhondt, Annemieke; Looze, Danny De; Vermassen, Frank; Lemey, Philippe; Palmer, Sarah; Vandekerckhove, Linos

doi:10.1016/j.chom.2019.08.003

Cited by 131 publications

(169 citation statements)

References 74 publications

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“…One potential explanation is that qVOA is limited to the blood compartment and does not take into account rebound coming from other anatomical reservoirs. As shown by De Scheerder et al rebound is heterogeneous and can be fuelled by any infected cell in any anatomical reservoir, making it difficult to have an in vitro proxy [37]. Another potential explanation is the dynamic nature of the viral reservoir, which implicates that sequences between different time points and the observed clones might wax and wane [36,38].…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…Interestingly, the group of Sarah Palmer indicated that analytical treatment interruption (ATI) activated proviruses with similar sequence between plasma and intestinal lamina propria mononuclear cells (Barton et al, 2016), indicating that intestinal HIV-1 reservoir is contributing to viremia following ATI. A recent study by the group of Linos Vandekerckhove confirmed the heterogeneous source of viral rebound from distinct anatomical reservoirs in HIV-1 individuals undergoing treatment interruption, showing that genetically-identical viral expansions play a significant role in viral rebound (De Scheerder et al, 2019). In a study presented by Oliveira et al (CROI 2019, Poster 327-Characterizing the HIV DNA reservoirs in wholebody tissues in the "Last Gift" cohort), HIV-1 DNA was detected in most body tissues with a nice distribution and compartmentalization of HIV-1 reservoir between tissues from the Last Gift cohort enrolling altruistic, terminally-ill persons living with HIV-1.…”

Section: Hiv-1 Diversity Within the Latent And Reactivated Reservoirsmentioning

confidence: 95%

Current Status of Latency Reversing Agents Facing the Heterogeneity of HIV-1 Cellular and Tissue Reservoirs

Aït-Ammar

Kula

Darcis³

et al. 2020

Front. Microbiol.

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Quantitative polymerase chain reaction; QVOA, quantitative viral outgrowth assays; Rev, regulator of virion expression; RNA, ribonucleic acid; RNAPII, RNA polymerase II; RT-ddPCR, teverse transcription droplet digital PCR; SAHA, suberoylanilide hydroxamic acid; SIV, simian immunodeficiency virus; SMAC, second mitochondrial activator of caspases; SMYD2, SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (Myeloid-Nervy-DEAF1) domain-containing protein 2; Sp1, specificity protein 1; STAT5, signal transducer and activator of transcription 5; Suv39H1, Suppressor of variegation 3-9 homolog 1

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“…Current combination antiretroviral therapy (cART) can successfully control human immunodeficiency virus type 1 (HIV-1) infection and prevent disease progression to the acquired immunodeficiency syndrome (AIDS). However, a cure is not generally achievable due to the establishment of a latent reservoir of proviral HIV-1 DNA which remains dormant and fuels viral rebound upon treatment interruption [1][2][3][4]. Therefore, better insight into the mechanisms regulating HIV-1 latency is crucial in order to interfere with this latency state and to develop cure strategies.…”

Section: Introductionmentioning

confidence: 99%

Underestimated effect of intragenic HIV-1 DNA methylation on viral transcription in infected individuals

et al. 2020

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Background: The HIV-1 proviral genome harbors multiple CpG islands (CpGIs), both in the promoter and intragenic regions. DNA methylation in the promoter region has been shown to be heavily involved in HIV-1 latency regulation in cultured cells. However, its exact role in proviral transcriptional regulation in infected individuals is poorly understood or characterized. Moreover, methylation at intragenic CpGIs has never been studied in depth.Results: A large, well-characterized HIV-1 patient cohort (n = 72), consisting of 17 long-term non-progressors and 8 recent seroconverters (SRCV) without combination antiretroviral therapy (cART), 15 early cART-treated, and 32 late cART-treated patients, was analyzed using a next-generation bisulfite sequencing DNA methylation method. In general, we observed low level of promoter methylation and higher levels of intragenic methylation. Additionally, SRCV showed increased promoter methylation and decreased intragenic methylation compared with the other patient groups. This data indicates that increased intragenic methylation could be involved in proviral transcriptional regulation. Conclusions:Contrasting in vitro studies, our results indicate that intragenic hypermethylation of HIV-1 proviral DNA is an underestimated factor in viral control in HIV-1-infected individuals, showing the importance of analyzing the complete proviral genome in future DNA methylation studies.

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HIV Rebound Is Predominantly Fueled by Genetically Identical Viral Expansions from Diverse Reservoirs

Cited by 131 publications

References 74 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

Current Status of Latency Reversing Agents Facing the Heterogeneity of HIV-1 Cellular and Tissue Reservoirs

Underestimated effect of intragenic HIV-1 DNA methylation on viral transcription in infected individuals

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