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.
View: Text | PDF
Research Article AIDS/HIV

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

×

Figure 6

p21 inhibits enzymatic activity of CDK9 and affects HIV-1 transcriptional elongation.

Options: View larger image (or click on image) Download as PowerPoint
p21 inhibits enzymatic activity of CDK9 and affects HIV-1 transcriptiona...
(A) Whole protein lysates of CD4+ T cells from elite controllers were precipitated with anti-CDK9, anti–cyclin T, or unspecific anti-IgG control antibodies and subsequently interrogated with p21-specific antibodies using Western blotting. Shown is 1 representative experiment of 2. (B) Assessment of the enzymatic activity of CDK9 in CD4+ T cells from elite controllers electroporated with p21-specific or control siRNA. CDK9 isolated from electroporated CD4+ T cells was mixed with a recombinant, GST-tagged protein representing the CTD of human RNA polymerase II serving as a substrate for CDK9. Phosphorylation of CTD polymerase II was detected by phospho-Ser2–specific antibodies in 3 representative patients. Cumulative data from 6 patients per group are also shown. Statistical comparison was performed using paired Wilcoxon test. (C) Influence of p21 on transcription of proximal and distal HIV-1 mRNA transcripts. CD4+ T cells from elite controllers were infected with VSV-G–pseudotyped HIV-1 after treatment with p21 inhibitor or DMSO as control. Data are mean and SD fold increase in expression of proximal, intermediate, and distal HIV-1 mRNA transcripts in p21-deficient relative to control cells. Statistical comparison between expression intensity of different mRNA transcripts was performed using Mann-Whitney U test.