Global Dysfunction of CD4 T-Lymphocyte Cytokine Expression in Simian-Human Immunodeficiency Virus/SIV-Infected Monkeys Is Prevented by Vaccination

CD4+ T lymphocytes are critical for a functional immune system, providing the signals required for the development of antigen-specific responses by both B and CD8+ T lymphocytes. CD4+ T lymphocytes provide the cytokine environment and second signals necessary for the development of antibody responses and are also required for the generation and maintenance of effective cytotoxic T lymphocytes (CTL) (3, 6, 7, 12, 29). In fact, loss of CD4 help results in a reduced capacity of CTL to protect against new viral infections and results in a failure of immune control of the replication of viruses, such as Epstein-Barr virus and cytomegalovirus, that cause clinical infection (5, 13, 14). Abnormalities in CD4+ T lymphocytes have been described in human immunodeficiency virus (HIV)-infected individuals that profoundly affect the global competency of their immune function. A reduction in the proliferative capacity of CD4+ T lymphocytes in response to HIV antigens has been demonstrated (9, 15, 18, 19, 23, 24). HIV type 1 (HIV-1) replication also inhibits antigen-specific CD4+ T-lymphocyte progression through the cell division cycle (26). Finally, a loss of the CD4+ T lymphocytes' ability to secrete cytokines in response to viral antigen stimulation has been described in infected individuals (9, 17). Since activated CD4+ T cells are infected and destroyed by HIV-1, these sequelae of infection are not surprising (8, 27). However, we know little about the early status and temporal evolution of CD4+ T-lymphocyte abnormalities during the course of an immunodeficiency virus infection. Cohorts of HIV-infected individuals have been described who do not develop progressive clinical disease, maintaining effective HIV-specific CTL, as well as CD4+ T lymphocytes that demonstrate robust proliferation and cytokine secretion in response to viral antigens (10, 23). Moreover, we and others have demonstrated that prior vaccination can alter the clinical outcome of an immunodeficiency virus infection, protecting against the evolution of CD4+ T-lymphocyte loss (2, 25). Although difficulties have been encountered in eliciting immunity with prototype vaccines that is likely to prevent HIV infection following exposure to the virus, these types of observations suggested the feasibility of prior vaccination delaying progressive clinical AIDS in individuals who become infected. The biologic mechanisms underlying the protection afforded by vaccine-elicited immune responses remain unknown. In the present studies, we have assessed the functional capacity of CD4+ T lymphocytes in rhesus monkeys both prospectively during the course of a simian immunodeficiency virus (SIV) infection and in a cohort of SIV/SHIV-infected animals with nonprogressive disease. We have also evaluated the protection against functional CD4+ T-lymphocyte dysfunction seen in monkeys who are vaccinated prior to an immunodeficiency virus infection. These studies suggest that preserved CD4+ T-lymphocyte function may be central to the control of disease progression following immunodeficiency virus infection.