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Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study.

ABSTRACT: Combination antiretroviral therapy (cART) reduces HIV-associated morbidities and mortalities but cannot cure the infection. Given the difficulty of eradicating HIV-1, a functional cure for HIV-infected patients appears to be a more reachable short-term goal. We identified 14 HIV patients (post-treatment controllers [PTCs]) whose viremia remained controlled for several years after the interruption of prolonged cART initiated during the primary infection. Most PTCs lacked the protective HLA B alleles that are overrepresented in spontaneous HIV controllers (HICs); instead, they carried risk-associated HLA alleles that were largely absent among the HICs. Accordingly, the PTCs had poorer CD8+ T cell responses and more severe primary infections than the HICs did. Moreover, the incidence of viral control after the interruption of early antiretroviral therapy was higher among the PTCs than has been reported for spontaneous control. Off therapy, the PTCs were able to maintain and, in some cases, further reduce an extremely low viral reservoir. We found that long-lived HIV-infected CD4+ T cells contributed poorly to the total resting HIV reservoir in the PTCs because of a low rate of infection of naïve T cells and a skewed distribution of resting memory CD4+ T cell subsets. Our results show that early and prolonged cART may allow some individuals with a rather unfavorable background to achieve long-term infection control and may have important implications in the search for a functional HIV cure.

SUBMITTER: Saez-Cirion A

PROVIDER: S-EPMC3597518 | biostudies-other | 2013 Mar

REPOSITORIES: biostudies-other

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Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study.

Sáez-Cirión Asier A Bacchus Charline C Hocqueloux Laurent L Avettand-Fenoel Véronique V Girault Isabelle I Lecuroux Camille C Potard Valerie V Versmisse Pierre P Melard Adeline A Prazuck Thierry T Descours Benjamin B Guergnon Julien J Viard Jean-Paul JP Boufassa Faroudy F Lambotte Olivier O Goujard Cécile C Meyer Laurence L Costagliola Dominique D Venet Alain A Pancino Gianfranco G Autran Brigitte B Rouzioux Christine C

PLoS pathogens 20130314 3

Combination antiretroviral therapy (cART) reduces HIV-associated morbidities and mortalities but cannot cure the infection. Given the difficulty of eradicating HIV-1, a functional cure for HIV-infected patients appears to be a more reachable short-term goal. We identified 14 HIV patients (post-treatment controllers [PTCs]) whose viremia remained controlled for several years after the interruption of prolonged cART initiated during the primary infection. Most PTCs lacked the protective HLA B alle ...[more]

PMID: 23516360

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Project description:BackgroundLess than 1% of Human Immunodeficiency Virus (HIV)-infected individuals are able to achieve spontaneous viral control without requiring antiretroviral therapy (ART). Whether these HIV controllers (HIC) are at risk of HIV-associated comorbidities and could benefit from ART is debated, but recent studies reported decreased T-cell activation upon ART initiation. We report the frequency of ART initiation, reasons to treat, treatment outcome on immunovirological parameters, and rate of side-effects and treatment discontinuation in the French cohort of HIC.MethodsParticipants included in the French multicenter Agence Nationale de Recherche sur le SIDA et les Hépatites (ANRS) Cohorte des extremes (CODEX) cohort of HIC between July 6, 2007 and January 3, 2018 were prospectively followed. ART initiation, indication, discontinuation, non-Acquired ImmunoDeficiency Syndrome (AIDS)-defining events, side-effects, and immunovirological parameters were recorded. Undetectable HIC (u-HIC) were defined as participants with strictly undetectable viral loads based on routinely used assays throughout the follow-up and blipper HIC (b-HIC) as participants with possible detectable viral loads above the detection threshold during follow-up.FindingsAmong 302 HIC followed for a median of 14.8 years [10.3-20.2], 90 (30%) received ART (7 u-HIC and 83 b-HIC). The main reasons for ART initiation were decreased CD4 T-cell counts (n = 36, 40%), loss of virological control (n = 13, 14%), and non-AIDS-defining events (n = 12, 13%). Sixteen (18%) participants experienced 17 grade 1-2 adverse events. In b-HIC, ART slightly increased the CD4/CD8 ratio (median +0.19, p < 0.0001) and decreased the frequency of circulating CD38+ HLA-DR.+ CD4 and CD8 lymphocytes (median -0.75%, p = 0.003, and -2%, p < 0.0001, respectively), but these changes were not observed for treated u-HIC. Thirteen (14%) participants discontinued ART (5 (38%) because of side-effects, and 10 remained HIC after treatment cessation (median follow-up: 305 days [235-728]).InterpretationOnly 30% of participants in this large cohort of HIC required ART during a median follow-up of 14.8 years. These results show that HIC status is very stable and vouch for a patient-centered treatment decision based on the individual benefit/risk balance.

Project description:Curing HIV will require eliminating the reservoir of integrated, replication-competent proviruses that persist despite antiretroviral therapy (ART). Understanding the burden, genetic diversity, and longevity of persisting proviruses in diverse individuals with HIV is critical to this goal, but these characteristics remain understudied in some groups. Among them are viremic controllers-individuals who naturally suppress HIV to low levels but for whom therapy is nevertheless recommended. We reconstructed within-host HIV evolutionary histories from longitudinal single-genome amplified viral sequences in four viremic controllers who eventually initiated ART and used this information to characterize the age and diversity of proviruses persisting on therapy. We further leveraged these within-host proviral age distributions to estimate rates of proviral turnover prior to ART. This is an important yet understudied metric, since pre-ART proviral turnover dictates reservoir composition at ART initiation (and thereafter), which is when curative interventions, once developed, would be administered. Despite natural viremic control, all participants displayed significant within-host HIV evolution pretherapy, where overall on-ART proviral burden and diversity broadly reflected the extent of viral replication and diversity pre-ART. Consistent with recent studies of noncontrollers, the proviral pools of two participants were skewed toward sequences that integrated near ART initiation, suggesting dynamic proviral turnover during untreated infection. In contrast, proviruses recovered from the other two participants dated to time points that were more evenly spread throughout infection, suggesting slow or negligible proviral decay following deposition. HIV cure strategies will need to overcome within-host proviral diversity, even in individuals who naturally controlled HIV replication before therapy. IMPORTANCE HIV therapy is lifelong because integrated, replication-competent viral copies persist within long-lived cells. To cure HIV, we need to understand when these viral reservoirs form, how large and genetically diverse they are, and how long they endure. Elite controllers-individuals who naturally suppress HIV to undetectable levels-are being intensely studied as models of HIV remission, but viremic controllers, individuals who naturally suppress HIV to low levels, remain understudied even though they too may hold valuable insights. We combined phylogenetics and mathematical modeling to reconstruct proviral seeding and decay from infection to therapy-mediated suppression in four viremic controllers. We recovered diverse proviruses persisting during therapy that broadly reflected HIV's within-host evolutionary history, where the estimated half-lives of the persistent proviral pool during untreated infection ranged from <1 year to negligible. Cure strategies will need to contend with proviral diversity and between-host heterogeneity, even in individuals who naturally control HIV.

Dataset Information

Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study.

Publications

Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study.

Similar Datasets

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