0 INSTITUT PASTEURELSEVIER Paris 1997 Res. Virol. 1997, 148, 23-81 5th FORUM IN VIROLOGY THE ROLE OF NEF IN THE PRIMATE LENTIVIRUS LIFE CYCLE Organized by Y. Collette Towards a consensus for a role of Nef in both viral replication and immunomodulation? Y. Collette Cance’rologie et thbrapeutiques expe’rimentales, Inserm V119, Institut Paoli Calmettes, 27, Bd LA Roure, 13009 Marseille (France) The human immunodeficiency viruses 1 and 2 (HIVl, -2) and their simian counterparts (SIV) define a group of lentiviruses that induce in their host chronic and productive infections associated with severe and fatal immunodeficiency. Following the early primary infection (and its set of early clin- ical signs) during which the virus disseminates to various sites, the natural host generally proceeds through an asymptomatic phase that might be pro- longed for up to 15 years before the onset of AIDS disease in humans. Although multiple signs for the existence of a significant immune response are noted soon after infection, the virus efficiently per- sists in its host for several years and induces a chronic and productive infection. Given that a clear understanding of this aspect in the lentivirus life cycle is of utmost importance in our attempt to defeat HIV productive chronicity and pathogenesis, we must identify the molecular bases enabling these viruses to evade immune clearance along with the known phenomenon of immune selection of resist- ant variants. The recent calculation by Ho and col- leagues of viral parameters within HIVl-infected patients unexpectedly revealed an extraordinary dynamic balance of newly produced viral particles and cell generation per day (Perelson et al., 1996), thus indicating that one “immune escape” mecha- nism for HIV1 probably consists of overwhelming the immune system. Moreover, several animal viruses have been shown to encode for proteins with a function of counteracting the efficiency of the host antiviral response (Gooding, 1992; Marrack and Kappler, 1994). While deletion of open reading frames coding for these proteins often barely affects the replicative efficiency of the virus in vitro, simi- lar deletions severely impair the infectious process in viuo and modulate replicative efficiency and/or pathogenesis. Lentiviruses have evolved complex mechanisms to evade the efficiency of the host anti- viral response (Joag and Narayan, 1993). These include (1) dissemination of the virus within the very cells implicated in the immune response, (2) silent infection followed by sudden distribution of newly produced viral particles in novel cellular