De novo fatty acid biosynthesis and HIV replication

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ABSTRACT HIV-1 commandeers host metabolism to create a cellular environment favorable to viral replication. We have recently discovered that mammalian fatty acid synthase (FASN) levels increase following HIV-1 infection, and that FASN activity is required for a late step of HIV replication that is subsequent to viral protein expression (e.g. protein trafficking, virion assembly, or virion release). The goal of our proposed research is to determine how FASN activity and resulting de novo fatty acid (FA) production affect a late stage of HIV-1 replication. The product of FASN, palmitate, is a long chain FA that has multiple cellular roles, and can also be trimmed into myristate or extended into other long chain FAs. Long chain FAs have many cellular functions, including roles in membrane structure, energy storage, and regulation of subcellular protein localization. This proposal focuses on two plausible FASN-mediated mechanisms that could interrupt a late stage in the HIV-1 replication cycle: production of lipids for post-translational modification of proteins (AIM 1), and generation of FA to reconfigure cellular lipid composition (AIM 2). If HIV-1 requires FASN activity to facilitate viral protein trafficking or virion assembly, we will have revealed a fundamental mechanism that could explain why many enveloped viruses require FASN activity to replicate.