THE INTEGRIN-TRIGGERED RESCUE OF T-LYMPHOCYTE APOPTOSIS IS BLOCKED INHIV-1-INFECTED INDIVIDUALS

HIV infection is associated with a disease status-dependent impairment of Ag-specific T cell responses, resulting in anergy or unchecked apo ptotic cell death, beta(1) integrins play an important role in the ind uction of T lymphocyte responses to antigenic challenge by providing a T cell costimulatory signal, and have been shown to rescue various ce ll types from undergoing apoptosis. We examined the integrin-triggered cell survival signal and associated pathways in CD3(+) T cells derive d from 69 HIV-1-infected individuals in comparison with healthy contro ls. We found beta(1) integrin-mediated costimulation of TCR-induced T cell proliferation and protection from aberrant cell death to be absen t in the majority of patients with AIDS, but intact in asymptomatic, i nfected individuals. The lack of integrin-mediated rescue may be partl y due to an early impairment of TCR/integrin-costimulated secretion of IFN-gamma, a type 1 lymphokine that protects against TCR-induced apop tosis of T cells from HIV-seropositive donors, but not loss of integri n expression. The mechanism of integrin hyporesponsiveness appeared to correlate with a failure of the integrin-generated signal to induce p p125(FAK) mRNA and protein expression. Protein kinase C activation in CD3(+) T cells following integrin stimulation was also impaired in HIV -infected individuals, mostly among the symptomatic/AIDS patients. Pro tein kinase C inactivation in T cells was shown to have a destabilizin g effect in vitro on pp125(FAK) mRNA that contains an AUUUA motif in t he 3'-untranslated region, a consensus sequence for the AU-rich elemen ts responsible for mRNA destabilization. These aberrant changes in pp1 25(FAK) expression may have direct significance to the overall immunop athogenesis during infection with HIV-1.