Cellular fatty acid synthase is required for late stages of HIV-1 replication.
BACKGROUND: Like all viruses, HIV-1 relies on host systems to replicate. The human purinome consists of approximately two thousand proteins that bind and use purines such as ATP, NADH, and NADPH. By virtue of their purine binding pockets, purinome proteins are highly druggable, and many existing drugs target purine-using enzymes. Leveraging a protein affinity media that uses the purine-binding pocket to capture the entire purinome, we sought to define purine-binding proteins regulated by HIV-1 infection. RESULTS: Using purinome capture media, we observed that HIV-1 infection increases intracellular levels of fatty acid synthase (FASN), a NADPH-using enzyme critical to the synthesis of de novo fatty acids. siRNA mediated knockdown of FASN reduced HIV-1 particle production by 80%, and treatment of tissue culture cells or primary PBMCs with Fasnall, a newly described selective FASN inhibitor, reduced HIV-1 virion production by 90% (EC50 = 213 nM). Despite the requirement of FASN for nascent virion production, FASN activity was not required for intracellular Gag protein production, indicating that FASN dependent de novo fatty acid biosynthesis contributes to a late step of HIV-1 replication. CONCLUSIONS: Here we show that HIV-1 replication both increases FASN levels and requires host FASN activity. We also report that Fasnall, a novel FASN inhibitor that demonstrates anti-tumor activity in vivo, is a potent and efficacious antiviral, blocking HIV-1 replication in both tissue culture and primary cell models of HIV-1 replication. In adults, most fatty acids are obtained exogenously from the diet, thus making FASN a plausible candidate for pharmacological intervention. In conclusion, we hypothesize that FASN is a novel host dependency factor and that inhibition of FASN activity has the potential to be exploited as an antiretroviral strategy.
Kulkarni, MM; Ratcliff, AN; Bhat, M; Alwarawrah, Y; Hughes, P; Arcos, J; Loiselle, D; Torrelles, JB; Funderburg, NT; Haystead, TA; Kwiek, JJ
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