Dataset Information

Impact of CD4 and CD8 dynamics and viral rebounds on loss of virological control in HIV controllers.

ABSTRACT:

Objective

HIV controllers (HICs) spontaneously maintain HIV viral replication at low level without antiretroviral therapy (ART), a small number of whom will eventually lose this ability to control HIV viremia. The objective was to identify factors associated with loss of virological control.

Methods

HICs were identified in COHERE on the basis of ?5 consecutive viral loads (VL) ?500 copies/mL over ?1 year whilst ART-naive, with the last VL ?500 copies/mL measured ?5 years after HIV diagnosis. Loss of virological control was defined as 2 consecutive VL >2000 copies/mL. Duration of HIV control was described using cumulative incidence method, considering loss of virological control, ART initiation and death during virological control as competing outcomes. Factors associated with loss of virological control were identified using Cox models. CD4 and CD8 dynamics were described using mixed-effect linear models.

Results

We identified 1067 HICs; 86 lost virological control, 293 initiated ART, and 13 died during virological control. Six years after confirmation of HIC status, the probability of losing virological control, initiating ART and dying were 13%, 37%, and 2%. Current lower CD4/CD8 ratio and a history of transient viral rebounds were associated with an increased risk of losing virological control. CD4 declined and CD8 increased before loss of virological control, and before viral rebounds.

Discussion

Expansion of CD8 and decline of CD4 during HIV control may result from repeated low-level viremia. Our findings suggest that in addition to superinfection, other mechanisms, such as low grade viral replication, can lead to loss of virological control in HICs.

SUBMITTER: Chereau F

PROVIDER: S-EPMC5381858 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

Impact of CD4 and CD8 dynamics and viral rebounds on loss of virological control in HIV controllers.

Chereau Fanny F Madec Yoann Y Sabin Caroline C Obel Niels N Ruiz-Mateos Ezequiel E Chrysos Georgios G Fidler Sarah S Lehmann Clara C Zangerle Robert R Wittkop Linda L Reiss Peter P Hamouda Osamah O Estrada Perez Vicente V Leal Manuel M Mocroft Amanda A Garcia De Olalla Patricia P Ammassari Adriana A D'Arminio Monforte Antonella A Mussini Cristina C Segura Ferran F Castagna Antonella A Cavassini Matthias M Grabar Sophie S Morlat Philippe P De Wit Stéphane S Lambotte Olivier O Meyer Laurence L

PloS one 20170405 4

<h4>Objective</h4>HIV controllers (HICs) spontaneously maintain HIV viral replication at low level without antiretroviral therapy (ART), a small number of whom will eventually lose this ability to control HIV viremia. The objective was to identify factors associated with loss of virological control.<h4>Methods</h4>HICs were identified in COHERE on the basis of ≥5 consecutive viral loads (VL) ≤500 copies/mL over ≥1 year whilst ART-naive, with the last VL ≤500 copies/mL measured ≥5 years after HIV ...[more]

PMID: 28380038

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Project description:Elite and viremic HIV controllers are able to control their HIV infection and maintain undetectable or low-level viremia in the absence of antiretroviral treatment. Despite extensive studies, the immune factors responsible for such exclusive control remain poorly defined. We identified a cohort of 14 HIV controllers that suffered an abrupt loss of HIV control (LoC) to investigate possible mechanisms and virological and immunological events related to the sudden loss of control. The in-depth analysis of these subjects involved the study of cell tropism of circulating virus, evidence for HIV superinfection, cellular immune responses to HIV, as well as an examination of viral adaptation to host immunity by Gag sequencing. Our data demonstrate that a poor capacity of T cells to mediate in vitro viral suppression, even in the context of protective HLA alleles, predicts a loss of viral control. In addition, the data suggest that inefficient viral control may be explained by an increase of CD8 T-cell activation and exhaustion before LoC. Furthermore, we detected a switch from C5- to X4-tropic viruses in 4 individuals after loss of control, suggesting that tropism shift might also contribute to disease progression in HIV controllers. The significantly reduced inhibition of in vitro viral replication and increased expression of activation and exhaustion markers preceding the abrupt loss of viral control may help identify untreated HIV controllers that are at risk of losing control and may offer a useful tool for monitoring individuals during treatment interruption phases in therapeutic vaccine trials.IMPORTANCE A few individuals can control HIV infection without the need for antiretroviral treatment and are referred to as HIV controllers. We have studied HIV controllers who suddenly lose this ability and present with high in vivo viral replication and decays in their CD4+ T-cell counts to identify potential immune and virological factors that were responsible for initial virus control. We identify in vitro-determined reductions in the ability of CD8 T cells to suppress viral control and the presence of PD-1-expressing CD8+ T cells with a naive immune phenotype as potential predictors of in vivo loss of virus control. The findings could be important for the clinical management of HIV controller individuals, and it may offer an important tool to anticipate viral rebound in individuals in clinical studies that include combination antiretroviral therapy (cART) treatment interruptions and which, if not treated quickly, could pose a significant risk to the trial participants.

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Dataset Information

Impact of CD4 and CD8 dynamics and viral rebounds on loss of virological control in HIV controllers.

Objective

Methods

Results

Discussion

Publications

Impact of CD4 and CD8 dynamics and viral rebounds on loss of virological control in HIV controllers.

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