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Biography

Jean-Marie Andrieu, M.D., is currently an Emeritus Professor at the University of Paris-Descartes, Paris, France and has published 50 papers and 3 books on HIV/SIV pathogenesis, treatment and vaccine development

Abstract

Since CD4+ T cell activation drives the initial burst of HIV/SIV replication in vivo, we explored in macaques whether an oral vaccine comprised of Lactobacillus plantarum (LP), a commensal bacterium that favors immune tolerance, and inactivated (i) SIVmac239 would induce CD4+T-cell unresponsiveness toward SIV antigens and thereby prevent the establishment of SIV infection. SIV mac239 was produced in CEM174 cells and inactivated with aldrithiol-2 and heating. LP was cultured to reach a concentration of 1010 cfu/ml. Sixteen macaques of Chinese origin were intragastrically administered over 5 days, 35 doses of 30 ml of 4x107 copies/ml of iSIV plus 3x109cfu/ml of living LP in maltodextrin (20%) solution. Eight animals received LP alone, and 8 animals received iSIV alone according to the same protocol. Specific antibody and CTL responses were tested by standard methods. The activation status (Ki 67+) of Gag positive CD4+T-cells was tested in the presence or absence of autologous or allogeneic CD8+T- cells of vaccinated and control macaques. To deplete macaques of CD8+T-cells in vivo, they were given an i.v. injection of a chimeric CD8 monoclonal antibody on days 0, 4, and 7. The vaccine induced a class of non cytotoxic MHC-Ib/E-restricted CD8+ regulatory T cells (Tregs) which have not been described previously. These CD8+Tregs suppressed the activation of SIV positive CD4+T-cell and the ex vivo SIV replication in 15 of 16 animals without inducing SIV specific antibodies or CTLs. Of 16 macaques that were intrarectally challenged with SIVmac239 or a heterologous strain (SIVB670), 15 were sterilely protected while the 16 controls were infected. In four macaques that were rechallenged intravenously, plasma SIV levels peaked slightly and then dropped to undetectable levels, although the animals subsequently harbored intracellular SIV DNA. Infusion of CD8 antibodies confirmed the role of this new class of CD8+ Tregs in suppressing SIV in vivo. Given that SIV and HIV require activated CD4+T-cells in which to replicate, this preventive SIV vaccine should likely be transferable in humans. Moreover, the induction of this class of CD8+T- regulatory cells could potentially be used therapeutically to suppress HIV replication in already infected patients. Finally, the tolerogenic vaccine approach described here could be exploited in the management of a wide range of immune disorders and is likely to have profound implications across the whole of immunology

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