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 1

Reduced susceptibility of CD4+ T cells from elite controllers to HIV-1 infection.

Options: View larger image (or click on image) Download as PowerPoint
Reduced susceptibility of CD4+ T cells from elite controllers to HIV-1 i...
(A) p24 antigen production in activated CD4+ T cells from elite controllers (EC), viremic controllers (VC), HIV-1–negative persons (HIV-), and HIV-1 progressors (Prog) after exogenous HIV-1 infection with the X4-tropic primary isolate 92HT599 and the primary R5-utilizing strain 91US056. Data were obtained on day 7 after infection; similar patterns of p24 antigen production were observed on days 3 and 5 after infection (Supplemental Figure 1). Baseline p24 levels in autologous cells without exogenous HIV-1 infection were subtracted as background. Significance was tested using Mann-Whitney U test. (B–E) Flow cytometric assessment of HIV-1 replication in activated CD4+ T cells from elite controllers and HIV-1–negative persons on day 4 after infection with GFP-encoding X4- and R5-tropic HIV-1 isolates. (B and D) Representative flow cytometry dot plots from 1 elite controller and 1 HIV-1–negative person. Percentages indicate the respective proportions of gated GFP+ CD4+ cells. (C and E) Proportion of GFP+ CD4+ T cells from the indicated subjects. Bounds of boxes denote interquartile range; lines within boxes denote median; whiskers indicate range.