Although an effective AIDS vaccine is the best hope for containing the world-wide AIDS epidemic, thefailure of the T-cell-based Merck vaccine has highlighted our lacunae in knowledge about the correlates ofvaccine protection. There is currently renewed emphasis on the necessity for more basic research onmechanisms of AIDS pathogenicity and development of therapeutic strategies in the nonhuman primate model.Natural hosts of the simian immunodeficiency virus (SIV) have co-evolved with the virus for millions of yearsand adapted to SIV in a way that disease progression does not occur or is markedly slowed down despitepersistent viremia. Understanding mechanisms that allow nonpathogenicity in natural hosts is highly relevantfor basic AIDS research and can expand the scope of AIDS vaccine research beyond the goal of achievingsterile protection, to developing additional novel therapeutic strategies. In recent studies we have shown thatacute events following SIV infection in rhesus macaques (RM) differ from those occurring in the natural hostsooty mangabeys (SM) with regards to the presence of CD4+ T lymphocyte apoptosis and increase in TNF-receptor associated apoptosis-inducing ligand (TRAIL) We hypothesize that increased TRAIL productionleading to increased CD4+ T lymphocyte apoptosis initiates bystander T lymphocyte activation and is critical tothe development of chronic immune activation and AIDS progression following pathogenic lentiviral infection.In this grant we propose to examine whether inhibition of TRAIL will result in alteration of the outcome of SIVinfection in rhesus macaques. We also propose to perform a detailed examination of differences in the earlyhost response to immunogens in SM and RM using a herpes simplex virus (HSV)-based vaccine approachexpressing SIV immunogens.
Our Specific Aims are:
Specific Aim #1 : Investigate the hypothesis that anacute increase in TRAIL production is a cardinal feature of pathogenic lentiviral infection and causally linked toinduction of CD4+ T lymphocyte apoptosis and development of AIDS.
Specific Aim #2 : Determine whethersooty mangabey and rhesus macaque CD4+ T lymphocytes differ in their susceptibility to TRAIL-mediatedapoptosis in the absence or presence of SIV infection.
Specific Aim #3 : Investigate differences in the earlyinnate and adaptive host response to SIV immunogens in vaccinated sooty mangabeys and rhesus macaques.
The goal of this project is to better define differences in the early host responseto SIV in pathogenic and nonpathogenic SIV infection with the aim of developinginterventional therapeutic strategies that attenuate disease progression to AIDS.Differences in the early innate and adaptive host response to SIV will be studied in SIVinfected and vaccinated sooty mangabeys and rhesus macaques.
