Nithianandan Selliah

FOXP3 inhibits HIV-1 infection of CD4 T-cells via inhibition of LTR transcriptional activity.

FOXP3 is a necessary transcription factor for the development and function of CD4+ regulatory T-cells (Tregs). The role of Tregs in HIV-1 infection remains unclear. Here, we show that expression of FOXP3 in primary human CD4 T-cells significantly inhibits HIV-1 infection. Since FOXP3 inhibits NFAT activity, and NFAT proteins contribute to HIV-1 transcription, we explore a transcriptional repressive function of HIV-1 LTR by FOXP3. Over-expression of FOXP3 in primary CD4 T-cells inhibits wild-type HIV-1 LTR reporter activity, and truncation mutants demonstrate that repression of the LTR by FOXP3 requires the dual proximal NF kappaB/NFAT binding sites. Interestingly, FOXP3 decreases binding of NFAT2 to the HIV-1 LTR in vivo. Furthermore, FOXP3 does not inhibit infection of HIV-1 NL4-3 which is mutated to disrupt transcription factor binding at either proximal NFAT or NF kappaB binding sites. These data suggest that resistance of Tregs to HIV-1 infection is due to inhibition of HIV-1 LTR transcription by FOXP3.

T cell signaling and apoptosis in HIV disease

Groundbreaking research has led to an understanding of some of the pathogenic mechanisms of HIV-1 infection. Surprisingly, an unanswered question remains the mechanism(s) by which HIV-1 inactivates or kills T cells. Our goals are to define candidate T cell signaling cascades altered by HIV infection and to identify mechanisms where by HIV-infected cells escape the apoptosis triggered by this aberrant signaling. In earlier work, we found that HIV reprograms healthy T cells to self-destruct by a process alled apoptosis. We asked whether apoptosis occurs in organs of infected people and made a surprising discovery—this cell death occurs predominantly in healthy by stander cells and only rarely in infected cells. We hypothesize that HIV may be doubly diabolical—healthy T cells are killed in HIV infection, while infected cells resist killing. Thus, the virus protects its viral factory and allows HIV to turn the cell into a “Trojan Horse,” with the virus in hiding or “latent.” In this review, we discuss the role of viral and cellular proteins in HIV-induced T cell anergy and death. We also discuss mechanisms by which HIV may protect infected T cells from apoptosis. These studies will yield new insights into the pathogenesis of AIDS, identify cellular targets that regulate HIV-1 infection, and suggest novel therapeutic approaches to cure HIV infection.