The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time

Josefsson, Lina; Stockenström, Susanne von; Faria, Nuno Rodrigues; Sinclair, Elizabeth; Bacchetti, Peter; Killian, Martin; Epling, Lorrie; Tan, Alice J.; Ho, Terence; Lemey, Philippe; Shao, Wei; Hunt, Peter W.; Somsouk, Ma; Wylie, Will; Douek, Daniel C.; Loeb, Lisa; Custer, Jeff; Hoh, Rebecca; Poole, Lauren; Deeks, Steven G.; Hecht, Frederick M.; Palmer, Sarah

doi:10.1073/pnas.1308313110

Cited by 249 publications

(333 citation statements)

References 58 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%

“…This is at variance with a recent report by Lorenzo-Redondo et al [25] and a few earlier reports [23,24], but agrees with several other earlier studies [5,13,[17][18][19][20][21]. Lorenzo-Redondo et al [25] compared genetic diversity in samples HIV-1 RNA in plasma at start of therapy with HIV-1 DNA sequences obtained from blood and tissues at baseline, three and six months after the start of treatment.…”

Section: Discussionsupporting

(Expert classified)

“…Another difference is that LorenzoRedondo et al [25] investigated HIV-1 DNA sequences in tissue as well as PBMC samples whereas we only studied PBMC samples. However, tissue and blood HIV-1 DNA variants should be well-mixed over the time frame that we investigate [5,13,25]. Both Lorenzo-Redondo et al [25] and we studied DNA sequences in HIV-1 reservoirs, which are known to contain a high proportion of defective virus.…”

Section: Discussionmentioning

confidence: 99%

“…Early ART reduces the size and the genetic complexity of the reservoir [12][13][14][15]. Siliciano et al [16] documented a half-life of 44 months for latently infected cells capable of producing replicationcompetent virus in the QVOA.…”

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%

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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: Discussionsupporting

(Expert classified)

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Establishment and stability of the latent HIV-1 DNA reservoir

Brodin

Zanini

Thebo

et al. 2016

Preprint

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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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Size of HIV‐1 reservoir is associated with telomere shortening and immunosenescence in early‐treated European children with perinatally acquired HIV‐1

et al. 2021

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IntroductionPersistence of HIV‐1, causing chronic immune activation, is a key determinant of premature senescence. Early antiretroviral therapy (ART) has been associated with a reduced HIV‐1 reservoir in children with perinatally acquired HIV‐1 (PHIV), but its impact on the senescence process is an open question. We investigated the association between HIV‐1 reservoir and biological and immune ageing profile in PHIV enrolled in the multicentre cross‐sectional study CARMA (Child and Adolescent Reservoir Measurements on early suppressive ART) conducted within the EPIICAL (Early treated Perinatally HIV Infected individuals: Improving Children's Actual Life) consortium.MethodsBetween September 2017 and June 2018, CARMA enrolled 40 PHIV who started ART before 2 years of age and had undetectable viremia for at least 5 years before sampling date. Samples from 37 children with a median age of 13.8 years were available for this study. HIV‐1 DNA copies on CD4 cells, relative telomere length (marker of cellular senescence) and levels of T‐cell receptor rearrangement excision circle (TREC, marker of thymic output) on CD4 and CD8 cells were quantified by qPCR. Immunological profile was assessed by flow cytometry. Associations between molecular and phenotypic markers, HIV‐1 reservoir and age at ART initiation were explored using a multivariable Poisson regression.ResultsHigher HIV‐1 reservoir was associated (p<0.001) with telomere shortening (incidence rate ratio [IRR] = 0.15 [0.13–0.17]), immunosenescence (CD28–CD57+, IRR = 1.23 [1.21–1.26]) and immunoactivation (CD38+ HLADR+, IRR = 7.29 [6.58–8.09]) of CD4 cells. Late ART initiation (after 6 months of age) correlated with higher HIV‐1 reservoir levels (552 [303–1001] vs. 89 [56–365] copies/106 CD4 cells, p = 0.003) and percentage of CD4 senescent cells (2.89 [1.95–6.31] vs. 1.02 [0.45–2.69, p = 0.047). TREC levels in CD8 cells were inversely associated with HIV‐1 reservoir (IRR = 0.77 [0.76–0.79]) and were significantly lower in late treated PHIV (1128 [486–1671] vs. 2278 [1425–3314], p = 0.042).ConclusionsLater ART initiation is associated with higher HIV‐1 reservoir size, which correlates with increased telomere shortening and senescence of CD4 cells. Timing of ART initiation in infancy has long‐term consequences on the immune and biological ageing profile of children with perinatally acquired HIV‐1.

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The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time

Cited by 249 publications

References 58 publications

Establishment and stability of the latent HIV-1 DNA reservoir

Establishment and stability of the latent HIV-1 DNA reservoir

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

Size of HIV‐1 reservoir is associated with telomere shortening and immunosenescence in early‐treated European children with perinatally acquired HIV‐1

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