Nef-Host Interactions in Virus Replication

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DESCRIPTION (provided by applicant): Nef is an accessory viral gene product that has been shown to be required for high titer virus replication and AIDS pathogenesis in a monkey model. Furthermore, infection with nef-defective strains of HIV-1 has been associated with the absence of disease progression in humans. While Nef appears crucial for efficient virus replication in vivo, the mechanism by which it acts is poorly understood. In cell culture, Nef can be shown to down-regulate CD4 and MHC class I from the cell surface, to modulate the cellular activation state, and to directly enhance the infectivity of progeny virions. Our preliminary results now establish that HIV-1 Nef interacts in a highly specific manner with the ubiquitously expressed GTPase dynamin 2, which is essential for clathrin-mediated endocytosis and mediates the fission step during endocytic vesicle budding. Our results also imply that this interaction is crucial for the enhancement of viral infectivity by Nef, since we find that this function can be specifically inhibited by dominant-negative dynamin 2 but not dynamin 1. Because of the involvement of dynamin 2 in endocytosis, our results further suggest that the down-regulation of an as yet unidentified factor from the cell surface by Nef may be required for optimal HIV-1 infectivity. Our goals are to elucidate what enables Nef to interact with dynamin 2 but not with closely related isoforms, to understand the relevance of the interaction for HIV-1 infectivity and replication, and to identify the downstream target of Nef and dynamin 2. An understanding of the role of dynamin 2 in the infectivity enhancement of Nef may ultimately provide promising new targets for anti-viral therapy, particularly since the known function of dynamin 2 suggests the involvement of a cell surface protein.