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 whereby 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 called apoptosis. We asked whether apoptosis occurs in organs of infected people and made a surprising discovery-this cell death occurs predominantly in healthy bystander 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.