Elite controllers represent a unique group of HIV-1–infected persons with undetectable HIV-1 replication in the absence of antiretroviral therapy. However, the mechanisms contributing to effective viral immune defense in these patients remain unclear. Here, we show that compared with HIV-1 progressors and HIV-1–negative persons, CD4+ T cells from elite controllers are less susceptible to HIV-1 infection. This partial resistance to HIV-1 infection involved less effective reverse transcription and mRNA transcription from proviral DNA and was associated with strong and selective upregulation of the cyclin-dependent kinase inhibitor p21 (also known as cip-1 and waf-1). Experimental blockade of p21 in CD4+ T cells from elite controllers resulted in a marked increase of viral reverse transcripts and mRNA production and led to higher enzymatic activities of cyclin-dependent kinase 9 (CDK9), which serves as a transcriptional coactivator of HIV-1 gene expression. This suggests that p21 acts as a barrier against HIV-1 infection in CD4+ T cells from elite controllers by inhibiting a cyclin-dependent kinase required for effective HIV-1 replication. These data demonstrate a mechanism of host resistance to HIV-1 in elite controllers and may open novel perspectives for clinical strategies to prevent or treat HIV-1 infection.
Huabiao Chen, Chun Li, Jinghe Huang, Thai Cung, Katherine Seiss, Jill Beamon, Mary F. Carrington, Lindsay C. Porter, Patrick S. Burke, Yue Yang, Bethany J. Ryan, Ruiwu Liu, Robert H. Weiss, Florencia Pereyra, William D. Cress, Abraham L. Brass, Eric S. Rosenberg, Bruce D. Walker, Xu G. Yu, Mathias Lichterfeld
Inhibition of p21 enhances HIV-1 replication in CD4+ T cells.