The overall goal of this proposal is to improve our understanding of the molecular mechanisms which control assembly and exit of human and feline immunodeficiency viruses (HIV-1 and FIV, respectively). Though the internal structural proteins of retroviruses, the so-called Gag proteins, can form membrane-enveloped particles in the absence of other viral components, the viral envelope glycoproteins (Env) are implicated in controlling where and how much virus is released from infected cells. Their position in the viral life cycle is thus pivotal not only because they control virus attachment and entry but also because they regulate where exactly newly assembled particles exit from cells during the late phase of the viral replication cycle. Spatially restricted, directional release of retrovirus may be particularly important when infected cells contact potential target cells, e.g. when immunodeficiency viruses cross epithelial barriers or during their migration from the periphery to lymphoid organs and the central nervous system. The regulation of virus egress is thus likely to influence substantially the course of virus dissemination and pathogenesis. As such it also presents a potential target for therapeutic intervention. We propose a molecular dissection of late events of the lentiviral (HIV-1; FIV) replication cycle using cell-biological, biochemical and virological methods. Our focus is on the role of Env during viral assembly and release and we will put emphasis on studying the interactions of Env with host-cell proteins and with viral Gag.
The specific aims ofthis proposal are 1) to further define signals in lentiviral Env (HIV-1; FIV) that are necessary for its association with proteins of the cellular trafficking machinery and thus for the characteristics of the post-Golgi routing of Env; 2) to test the hypothesis that the transport of Env to specific subcellular sites, as defined in Specific Aim 1, is responsible for directional virus release and to test if mistargeting of particle shedding impairs virus propagation. A thorough assessment of virus-host interactions, which control the asymmetry of virus release, will also provide the necessary groundwork for further studies aiming at the identification of additional Env late functions implicated in virus spread and pathogenicity.
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| Nydegger, Sascha; Foti, Michelangelo; Derdowski, Aaron et al. (2003) HIV-1 egress is gated through late endosomal membranes. Traffic 4:902-10 |
