Novel therapeutic strategies for immunostimulation in HIV targeting CD25+ T-regulatory cells.

Regulatory T cells (Treg) represent 5-10% of the CD4 T cells and are identified by constitutively expressing CD25. Treg are subdivided into naturally occuring Treg devolped in the thymus, and adaptive Treg that are induced in the periphery from naïve CD4 T cells. Naturally occuring Treg are intstrumental in suppressing autoreactive T cells and thereby prevent autoimmune diseases. Adaptive Treg that are induced in the periphery, suppress immune responses to exogenous antigens and tumor antigens. We have re cently demonstrated that regulatory T cells inhibit virus-specific immune responses in chronic viral infections. The molecular mechanism of the suppressive function of regulatory T cells is not yet elucidated. Based on our unpublished observations, the hy pothesis of the present application is that adaptive regulatory T cells develop from naïve T cells as a result of continuous antigen stimulation by HIV antigens in the vicinity of antigen presenting cells. Adaptive regulatory T cells express COX-2 that le ad to production of prostaglandins, including PGE2 that binds to G-protein coupled receptors on normal T cells engaged in the immune response against the virus. PGE2 leads to production of cAMP that activates an inhbitory signal pathway that involves prot ein kinase A (PKA) in the T cells which suppress the anti-viral immune response. Therapeutic strategies devised to target the COX-2 - PGE2 - cAMP - PKA - inhibitory pathway may have application as immunomodulatory treatment for HIV. Disrupting the pathway may enhance the immune response against the virus, reduce the need for antiviral treatment, reduce the incidence of opportunistic infections and potentially enable the immune system to eradicate the virus.