This Proposal results from translational HIV research by the Applicants, ranging from basic research on signal transduction in lymphocytes that has firmly established cyclic AMP (cAMP) / protein kinase A type I alpha as a major inhibitor of antigen-specif ic activation; to basic clinical studies showing that cAMP is increased in T cells from HIV-infected patients and that vaccination responses in these patients are less effective than in HIV seronegative controls. Our hypothesis is that increased producti on of prostaglandin E2 (PGE2) by inflammation-induced cyclooxygenase-2 (COX-2) locally in a lymphoid tissue microenvironment could be a major cause of elevated cAMP in T cells, PGE2 being a potent inducer of cAMP. This mechanism could also certainly be a consequence of the detrimental hyperimmune activation in chronic HIV infection.Two consecutive exploratory clinical trials testing COX-2 inhibitors in HIV-infected patients ultimately demonstrated in a recently completed third trial at our Hospital that 12 weeks of COX-2 inhibitor treatment in randomized patients without antiretroviral treatment developed better T cell-dependent immune responses to the vaccine antigens than controls and also reduced immune hyperactivation markers (CD38, PD-1) that best r elate to disease progression of HIV. These promising clinical results warrants further investigation to address a number of key questions concerning the potential for COX-2 inhibitors in HIV. In general, new, alternative immunmodulating strategies and adj uvant immunostimulants for combination with vaccines should currently be evaluated in chronic HIV, based on several recent disappointments in developing effective HIV vaccines.Many key questions will be addressed by completion of a randomized four-arm st udy with COX-2 inhibitor for 24-48 weeks in two arms and two control arms, each arm receiving vaccines at different time points, with careful sampling of clinical and laboratory efficacy and safety data.