Role des molecules de l'hote incorporees dans l'enveloppe du VIH-1: Signalisation cellulaire et implications dans le processus de la transmission et la replication virale dans les organes lymphoides ex-vivo (French text)

We and others have demonstrated that HIV-1 incorporates several foreign glycoproteins. However, the biological significance of these incorporated molecules in HIV-1 budding is now only beginning to be unrevealed. The primary objective of this thesis is to establish a specific causative relationship among incorporated host proteins (CD80, CD86, ICAM-1) in infectivity, signaling events, HIV transmission and CD4+ T-cell depletion in mature lymphoid tissue. Our results indicate that the physical presence of CD80 and CD86 proteins increases virus infectivity in a CD28/B7-dependent manner. Furthermore, we indicate that incubation of human T lymphoid cells with virions bearing host-derived B7-2 proteins and anti-CD3 antibody can potently activate HIV-1 LTR-driven gene expression. This upregulating effect necessitates the involvement of nuclear factor-kappa B (NF-κB) and nuclear factor of activated T cells (NFAT). We have extended the study to investigate the role played by adhesions molecules acquired by HIV-1 envelope in viral progression within human lymphoid tissue. Indeed, we optimized an experimental model ex-vivo using human histoculture tonsillar tissue. Our results show that the presence of ICAM-1 in HIV-1 envelope highly increases viral infectivity in human tonsils ex vivo, and induces consequently a strong depletion of CD4+ T cells. Furthermore, we provide evidence that ICAM-1 - LFA-1 association was found to be a more efficient transmission factor than the combined gp120 - DC-SIGN and ICAM-3 - DC-SIGN interactions. These results suggest that the nature of the host proteins incorporated in HIV-1 envelope could influence the process of the viral transmission. This additional knowledge gained on the factors affecting HIV-1 infectivity, will help in the design of new treatment of HIV-1 infection and also in the development of new vaccine formulations.