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 4

Inhibition of p21 enhances HIV-1 replication in CD4+ T cells.

Options: View larger image (or click on image) Download as PowerPoint
Inhibition of p21 enhances HIV-1 replication in CD4+ T cells. (A and...
(A and B) Activated CD4+ T cells from elite controllers or HIV-1–negative persons were infected with X4- or R5-tropic primary HIV-1 isolates in the presence of p21-specific or control siRNA; HIV-1 replication was assessed by p24 antigen levels in culture supernatants. (A) Representative example from an HIV-1 elite controller. (B) Fold increase (mean and SD) of p24 levels in p21-deficient versus control cells in indicated persons. (C–F) Flow cytometric assessment of HIV-1 replication in CD4+ T cells after p21 inhibition. CD4+ T cells were infected with GFP-encoding X4- or R5-tropic HIV-1 strains in the presence of p21-siRNA or control siRNA or with a YFP-encoding VSV-G–pseudotyped HIV-1 vector in the presence of a pharmacological p21 inhibitor or the carrier DMSO. (C and D) Representative dot plots from an elite controller. Percentages indicate the proportion of gated CD4+ T cells. (E) Fold increase (mean and SD) in the proportion of GFP+/YFP+ cells or in GFP/YFP mean fluorescence intensity in p21-deficient cells compared with controls. White bar, EC; Grey bar, HIV-1. (F) Correlation between CDKN1A mRNA expression in HLA-DR– CD4+ T cells from elite controllers and HIV-1–negative persons and corresponding fold increases of YFP+ cells after p21 inhibition. *P < 0.05; p21-deficient cells versus control cells treated with unspecific siRNA or SMSO; paired Wilcoxon test. Statistical comparison was performed using Student’s t test.