Viral Immunopathology - CNRS URA1930  

  MEMBERSDr BUSEYNE Florence / DURRIEU Ludovic / GODON Ophélie

  Annual Report

Our major goal is to study the role of viral-specific T cell responses in two human infections, Human Immunodeficiency Virus type-1 (HIV-1), and Hepatitis C Virus (HCV).

CTL and Pediatric infection (coll. : S. Blanche, C. Rouzioux, D.Scott-Algara, J.Warszawski). Our study of memory HIV-specific cytotoxic T lymphocytes (CTL) response has established that CTL response is associated with a better clinical course and lower viral replication in untreated children. Our first study of interaction between HIV-specific CD8+T cells and HAART was performed during early HAART era, measuring memory CTL. The activity of HIV-specific CTL per se was associated with a greater reduction of plasma viremia in the presence of antiretroviral treatment, at least during the early HAART era, when the combined therapy was sub-optimal for infected children. This data supports a synergy between both antiviral mechanisms. In this initial study a significant number of children had partial virologic suppression that was associated with increased Gag-specific CTL response when compared to children with either full or no viral suppression. Thus, as shown for adult patients, persistence of reduced viral replication allowed partial immune recovery and improvement of memory HIV-specific CTL responses. In the HAART-treated children, the frequency of ex vivo IFN-γproducing HIV-specific CD8 + T cells was positively associated with plasma viremia in two cross-sectional studies. The frequencies of HIV-specific CD8+ T cells increase with age in untreated children. Importantly, we observed almost no response in children who initiated HAART during their first months of life. These data support that therapeutic vaccination expanding the HIV-specific CD8+ T cell pool might be useful for young children with suppressed viremia, which have the lowest antiviral response.

Animal model: DNA based immunization in macaque (coll. with M.L. Michel). Immunization with hybrid DNA encoding hepatitis B surface antigen fused to antigenic domains of simian/human immunodeficiency virus (SHIV 89.6P) induced both effector and long-lasting precursor T cells. Following boosting with a recombinant modified vaccinia Ankara producing full-length SIV and HIV antigens, it appeared that priming with hybrid DNA had increased virus-specific T-cell responses in terms of both the number of virus-specific IFN-γ-secreting T-cells, and lymphoproliferation. After intrarectal challenge with SHIV 89.6P, immunized animals demonstrated early control of SHIV 89.6P replication and stable CD4+ T cell counts. After SHIV challenge, vaccine-induced CD8+ T cells were recalled during acute infection. Most of the SIV-specific CD4+ T-cell responses became undetectable in peripheral blood or lymph nodes even after in vitro peptide stimulation, whereas we persistently detected CD4+ T-cell responses specific for control recall antigens in infected animals. These results show that SHIV89.6P challenge results in functional impairment of vaccine-induced SHIV-specific CD4+ T cells and suggest that attention should be paid to CD4+ T cell responses when designing vaccines.

Role of HCV-specific T cell responses in HCV-infection (coll. : S. Pol and M-L. Chaix). HCV-core-specific responses were characterized after in vitro stimulation of PBMC from chronically infected subjects. 45% of patients studied present a core-specific response directed to the N-terminal and central parts. There was no relationship between T cell responses and parameters of disease evolution (serum alanine transaminase levels, and histologic hepatic damage), but a positive relationship between the presence of a core-specific T cell responses and the viremia. This suggests that a high viral antigen load is required for the maintenance of a core-specific memory T cell.


Publications 2006 of the unit on Pasteur's references database

Activity Reports 2006 - Institut Pasteur
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