CD4+ T cells from elite controllers resist HIV-1 infection by selective upregulation of p21
Huabiao Chen, … , Xu G. Yu, Mathias Lichterfeld
Huabiao Chen, … , Xu G. Yu, Mathias Lichterfeld
Published March 14, 2011
Citation Information: J Clin Invest. 2011;121(4):1549-1560. https://doi.org/10.1172/JCI44539.
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CD4+ T cells from elite controllers resist HIV-1 infection by selective upregulation of p21

Abstract

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.

Authors

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

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Figure 5

p21 inhibition increases multiple early HIV-1 replication steps.

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p21 inhibition increases multiple early HIV-1 replication steps. (A–C) Q...
(A–C) Quantitative analysis of HIV-1 LRT transcripts (A), integrated HIV-1 DNA (B), and HIV-1 mRNA transcripts (C) in CD4+ T cells from elite controllers or HIV-1–negative persons after inhibition of p21. Activated CD4+ T cells were infected with X4- or R5-tropic HIV-1 isolates after electroporation with p21-specific or control siRNA. Alternatively, activated or nonactivated CD4+ T cells were infected with a single-cycle VSV-G–pseudotyped HIV-1 vector in the presence of a small molecule inhibitor of p21 or DMSO as control. Data show mean and SD fold increase of respective copy numbers in p21-deficient cells compared with corresponding control cells from the indicated number of subjects. *P < 0.05; p21 deficient cells versus control cells treated with unspecific siRNA or SMSO; paired Wilcoxon test. (D) Effect of p21 inhibition on HIV-1 mRNA transcription from proviral HIV-1 DNA. Ex vivo activated CD4+ T cells from elite controllers were infected with a VSV-G–pseudotyped HIV-1 vector; YFP+ cells were sorted after 36 hours and exposed to p21 inhibitor. Data are mean and SD of LRT transcripts, integrated HIV-1 DNA, and viral mRNA from sorted YFP+ CD4+ T cells 84 hours after infection. Statistical comparison was performed using paired Wilcoxon test.