HIV-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. © 2014 Elsevier Inc.
Leng, J., Ho, H. P., Buzon, M. J., Pereyra, F., Walker, B. D., Yu, X. G., … Lichterfeld, M. (2014). A cell-intrinsic inhibitor of HIV-1 reverse transcription in CD4 + T cells from elite controllers. Cell Host and Microbe, 15(6), 717–728. https://doi.org/10.1016/j.chom.2014.05.011