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Co-adaptation Between HIV and CD8 Cellular Immunity

2016-09-01 14:53:21 | BioPortfolio

Summary

Our objective here is to characterize the viral evolution and viral factors determining HIV virulence, the evolution of the HIV reservoir in PBMC and the co-evolution of anti-HIV CD8 T cell repertoires. The coordinated study of virus evolution, host responses and identification of genetic determinants of virulence should allow to better understand mechanisms of HIV pathogenicity and persistence of mutations in viral reservoirs.

Description

The importance of the still unmet challenges raised by researches on the eradication of the HIV reservoirs and by the need for developing efficient vaccines against HIV, imposes a much deeper understanding the molecular mechanisms regulating the co-evolution and the co-adaptation between HIV and its host during the natural course of the disease an during treatment. The unique cell collection established 27 years ago in an ANRS cohort and the new methods of ultradeep sequencing, or " next generation sequencing", allow to produce innovative analysis of the HIV variability and of reservoirs as well as of the repertoires used by CD8 T cells responses to provide new insights in the very long term relationships between the virus and its host. Our objective is to progress at unprecedented levels in the understanding of these mechanisms thanks to the unique opportunity offered by this Immunoco cohort initially composed of 152 patients infected by HIV, most of them untreated when recruited from 1991 to 97 at Pitié-Salpêtrière, with 28 subjects still followed in our hospital and efficiently treated for the last 15 years. This cohort had initially been set up to study the characteristics of the cytotoxic T lymphopcyte (CTL) responses to HIV with disease progression. This exceptional and still available 1991-97 cell collection enriched of extra samples from 1988 to nowadays, allow us to perform a retrospective longitudinal analysis over 27 years in the 28 patients still followed-up, with a new blood sampling in 2015. Our project involves 5 highly experienced teams and aims at characterizing in parallel: 1) the viral evolution and viral factors determining virulence, as markers predicting progression of infection, by performing an ultradeep sequencing of the whole HIV genome and of viral variants archived in blood mononuclear cells (PBMC), and 2) the evolution of the reservoir in PBMC and of the distribution of variants archived in those reservoirs over time, in relationship with exposure to the various selective pressures due to CTL or ARV, 3) the co-evolution of anti-HIV CD8 T cell repertoires: we will test the hypothesis that the emergence of new CD8 T clonotypes displaying a great sensibility for variant antigens, or a cross-reactivity able to recognize similarly wild-type and mutant epitopes allow an efficient long term control of viral replication, and that cell loss by clonal exhaustion is associated to disease progression. The coordinated study of virus evolution, host responses and identification of genetic determinants of virulence should allow to better understand mechanisms of HIV pathogenicity and persistence of mutations in viral reservoirs, especially of defective mutants or resistant mutants to ARV, as well as the co-adaptation of CD8 T cell repertoires and of viral variability determining the capacities of viral control by anti-HIV CD8 T cells. Altogether these results should open new strategies for inhibiting viral replication and for controlling viral reservoirs for therapeutic and vaccinal perspectives.

Study Design

Observational Model: Cohort

Conditions

HIV Infection

Intervention

Non interventionnal study

Status

Not yet recruiting

Source

French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inser

Results (where available)

View Results

Links

Published on BioPortfolio: 2016-09-01T14:53:21-0400

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