A Cell-Intrinsic Inhibitor of HIV-1 Reverse Transcription in CD4+ T Cells from Elite Controllers

•Effective HIV-1 reverse transcription depends on host cyclin-dependent kinase 2•HIV-1 reverse transcriptase is a substrate for CDK2-dependent phosphorylation•CDK2-dependent phosphorylation increases RT stability and viral fitness•Upregulation of the CDK inhibitor p21 in controllers indirectly blocks HIV-1 RT

SummaryHIV-1 reverse transcription represents the predominant target for pharmacological inhibition of viral replication, but cell-intrinsic mechanisms that can block HIV-1 reverse transcription in a clinically significant way are poorly defined. We find that effective HIV-1 reverse transcription depends on the phosphorylation of viral reverse transcriptase by host cyclin-dependent kinase (CDK) 2 at a highly conserved Threonine residue. CDK2-dependent phosphorylation increased the efficacy and stability of viral reverse transcriptase and enhanced viral fitness. Interestingly, p21, a cell-intrinsic CDK inhibitor that is upregulated in CD4+ T cells from “elite controllers,” potently inhibited CDK2-dependent phosphorylation of HIV-1 reverse transcriptase and significantly reduced the efficacy of viral reverse transcription. These data suggest that p21 can indirectly block HIV-1 reverse transcription by inhibiting host cofactors supporting HIV-1 replication and identify sites of viral vulnerability that are effectively targeted in persons with natural control of HIV-1 replication.

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