Mechanisms of abrupt loss of virus control in a cohort of previous HIV controllers
Rosás Umbert, Miriam (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Llano Montero, Anuska (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Bellido, Rocío (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Olvera, Alex (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Ruiz-Riol, Marta (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Rocafort, Muntsa (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Fernández, Marco A. (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Cobarsi, Patricia (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Crespo Casal, Manuel (Complexo Hospitalario Universitario de Vigo)
Dorrell, Lucy (Nuffield Department of Medicine, University of Oxford)
Del Romero, Jorge (Centro Sanitario Sandoval, Madrid)
Alcami, Jose (Instituto de Salud Carlos III)
Paredes, Roger (Universitat Autònoma de Barcelona. Departament de Medicina)
Brander, Christian (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Mothe, Beatriz (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)

Fecha:	2019
Resumen:	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. 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.
Ayudas:	European Commission HIVACAT/681137-EAVI2020 Instituto de Salud Carlos III RD06/0006/0035
Nota:	Altres ajuts: FIPSE grant 360737-09; AELIX Therapeutics
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	HIV-1 control ; HIV-1 progression ; Cell tropism ; Host genetics ; In vitro virus inhibition ; Loss of control
Publicado en:	Journal of Virology, Vol. 93 (february 2019) , ISSN 1098-5514

DOI: 10.1128/JVI.01436-18
PMID: 30487276

15 p, 676.0 KB

El registro aparece en las colecciones:
Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Artículos > Artículos de investigación
Artículos > Artículos publicados