Elucidation of HIV Env acquisition strategies

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DESCRIPTION (provided by applicant): A requisite step for the creation of an infectious HIV-1 particle is incorporation of the surface fusion glycoprotein (for retroviruses, referred to as Env) This incorporation only occurs if Env traffics to the precise patch of membrane in the cell that serves as the viral assembly site. The features of the viral assembly site that facilitate this translocation of viral glycoproteins remain a mystery. We have demonstrated that glycoproteins from diverse families of viruses are efficiently recruited to human immunodeficiency virus (HIV-1) assembly sites but that most host proteins are not. We hypothesize that enveloped viruses utilize a common mechanism to facilitate the redistribution of viral glycoproteins to viral assembly sites. Because many of the viral glycoproteins recruited to HIV-1 assembly sites contain no sequence similarity with the native HIV-1 glycoprotein (HIV-1 Env), it is unlikely that foreign glycoprotein recruitment is facilitated by a direct protein-protein interaction between HIV 1 structural protein (Gag) and the glycoprotein. The central objectives of this proposal, therefore, are (1) to identify the feature(s) in viral glycoproteins that dictate their attraction o viral assembly sites and (2) to identify the feature(s) of the viral assembly site that facilitate his attraction. This proposal contains four specific aims. Aim 1: Determine whether diverse viral glycoproteins co-package into the same viral particles. Aim 2: Utilize retroviral mutagenesis libraries to ascertain what features in viral glycoproteins dictate their attraction to viral assemly sites. Aim 3: Perform quantitative imaging of glycoprotein acquisition in real time. Aim 4: Apply positive selection to identify determinants of compatibility between Gag and glycoprotein CTDs. These aims will help define the interactions that modulate this critical step in the HIV-1 lifecycl.