Viral Immunopathology - Institut Pasteur, URA CNRS 3015  


  HEADYves Rivière / yves.riviere@pasteur.fr
  MEMBERSF. Buseyne Assistant Professor / S. Gohebel Master 2, Paris 7 / P. Louche Technician / C. Marnata Master 2, Versailles Saint Quentin/ T. Montange Technician / Y. Rivière Associate Professor / J. Villeneuve Secretary


  Annual Report

1 .Cytotoxic T Lymphocytes (CTL) and Pediatric HIV-1 infection, Collaboration with S. Blanche and C. Rouzioux, Necker Hospital, Paris and J. Warszawski, INSERM, Bicêtre, D. Scott Algara, Institut Pasteur, Paris.

The paediatric HIV infection differs from infection during adulthood by several points: the immaturity of the immune system of the infant at time of infection; the bimodal disease evolution; the persistence of high level plasma viremia during the first years of life; the high thymic activity allowing an efficient replenishment of destroyed CD4+T lymphocytes.

Our initial contribution was to show that CD8+CTL were present in a majority of infected children. Thus, perinatal exposure to HIV did not induce immune tolerance of T lymphocytes.Despite the relative immaturity of the immune system at time of infection, most HIV-infected children were able to mount an HIV-specific CTL response.Memory HIV-specific CTL response HIV-infected children was associated with a better clinical course, lower viral replication, and better viral response to treatment.Our data have added further support to the major role of functional HIV-specific CD8+T lymphocytes in controlling HIV replication.

The frequency of ex vivo HIV-specific IFN-gproducing CD8 lymphocytes was shown to increase with age and to be dependent upon active viral replication. Importantly, these data suggest 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 CD8+response.

The HIV-DNA level in PBMC has recently been shown to be a predictor of disease progression, independent of the HIV RNA Level. In untreated HIV-1 infected children, we observed that (1) higher frequencies of HIV-specific CD8 lymphocytes were associated to lower levels of infected cells; (2) higher percentages of activated CD4+HLA-DR+ lymphocytes were associated to higher levels of infected cells, in contrast to the elevated percentages of activated CD8+CD38+lymphocytes that were associated to higher cell-free virus levels; (3) total CD4 depletion was associated to higher levels of infected cells, whereas CD4 memory depletion was associated to higher levels of cell-free HIV particles.Our study supports that cell-free virus and infected cells play independent roles in HIV-1 immunopathogenesis.

The aims of our currentresearch (ANRS-EP38-IMMIP study) are to assess the immune status of patients infected by HIV-1 in the perinatal period and older than 15 yrs and to study the associations between the immune markers and the (a) the current virological, clinical, and therapeutic status; (b) the duration of exposition to active virus replication dependent upon treatment history, and (c) patient virological/clinical and immunological status at time of HAART initiation.

2- HCV-specific immune responses in HCV-uninfected individuals, collaboration with O. Launay and S. Pol, CIC and Hepatology Unit, Cochin hospital, M-L. Chaix and J-L. Bresson CHU Necker, D. Benomar EFS, Paris.

In an initial study we were able to detect a HCV-core-specific cellular immune response in a control group of volunteers not infected by HCV. The presence of a virus–specific T cell response in uninfected and presumably unexposed individuals could be due to an under-estimation of the frequency of a previous resolutive HCV infection, as most cases of acute HCV infection are clinically silent.An alternative not mutually exclusive hypothesis is the existence of a cross-reactivity between HCV antigens and other viral or common antigens present in the general population as reported previously by a few investigators. This result would modify our current concept of HCV prevalence. The goal of the current study is to estimate the presence of HCV-specific cellular immune responses in uninfected individuals without any known risk of a viral exposition (professional, nosocomial, familial, sexual) with a negative HCV PCR assay and humoral response by commercial assay. In 28 uninfected volunteers without any known risk of HCV exposition, HCV-specific circulating effector T lymphocytes responses have been studied using interferon γ-Elispot and a CFSE proliferation assays from fresh PBMC. A panel of HCV-core-specific peptides was used for HCV-specific stimulation, and of SIV Gag or Nef-specific peptides as negative control. A core-specific T cell response was fully characterized with both assays (proliferation and γIFN-Elispot) in one out of the 28 volunteers tested. Part of this work has been presented during the 43rd Annual Meeting of the European Association for the Study of the Liver, Milan, Italy, April 23-27, 2008[Rivière Y et al., HCV-Specific Immune Responses In Uninfected Individuals With No Known Risk For HCV Exposition].

Keywords: HIV-1, pediatric infection, T lymphocytes, HCV



  Publications

  1. Buseyne, F., Le Chenadec, J., Burgard, M., Bellal, N., Mayaux, MJ., Rouzioux, C., Rivière, Y. and S. Blanche. In HIV type 1-infected children cytotoxic T lymphocyte responses are associated with greater reduction of viremia under antiretroviral therapy.AIDS Res.Hum.Retroviruses. 21:719-27, 2005.

  2. Janvier, G., Chaix, ML., Fontaine, H., Bresson, JL., Pol, S., and Y. Riviere. The core-specific precursor T cell response is directed to the N-terminal and central parts of the protein and positively correlates to the viral load in chronically HCV-infected patients. Virology, 340:318-25, 2005.

  3. Buseyne, F., Scott-Algara, D., Bellal, N., Burgard, M., Rouzioux, C., Blanche, S. and Y. Riviere. The frequency of HIV-specific interferon-γ-producing CD8 T cells is associated with both age and level of antigenic stimulation in HIV-1-infected children. J Infect Dis., 192:1781-6, 2005.

  4. Buseyne, F., Scott-Algara, D., Corre, B., Porrot, F., Monchatre, E., Bellal, N., Burgard, M., Rouzioux, C., Blanche, S. and Y.Rivière. Poor recognition of HIV-1 Nef protein by CD8 T cells from HIV-1-infected children: impact of age. Virology, 354 :271-279, 2006

  5. Buseyne, F., S. Blanche, M. Burgard, C. Milliancourt, D. Scott-Algara, C. Rouzioux, and R. Riviere, The frequency of HIV-specific CD8 T lymphocytes is inversely correlated to HIV DNA levels in untreated infected children Retrovirology, 2008, 5(Suppl 1):O22





Activity Reports 2009 - Institut Pasteur
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