Listeria monocytogenes as a vaccine vector for the delivery of HIV antigens

AIDS has been established as the fourth leading cause of death worldwide while the development of an effective vaccine has remained elusive. A major hallmark of HIV infection is the selective depletion of CD4+ T cells, leading to an impaired immune system that leaves the host susceptible to opportunistic infections. A number of studies have indicated a correlation between the presence of HIV-specific CTLs and non-progression of HIV positive individuals to AIDS. In addition, it has been suggested that in response to HIV-1 infection Th1 type cells, which induce cell mediated immunity, are protective whereas Th2 type cells, which result in humoral immunity, may be detrimental to the induction of protective responses. Thus, attempts to develop HIV vaccines, in recent years, have focused on approaches that induce strong cell mediated immunity. L. monocytogenes is a gram-positive facultative intracellular bacterium that lives and grows in the cytoplasm of the host cell. The immune response to L. monocytogenes antigens have been shown to be restricted to a Th1 CD4+ cell response and CD8+ response. Thus, L. monocytogenes may be the ideal vector for boosting the Th1 CD4+ and CD8+ T cell responses to HIV proteins and a unique system to prime the cellular immune response as a potential vaccine against HIV. In order to characterize the immune response to HIV proteins delivered by L. monocytogenes we have expressed HIV Gag in L. monocytogenes in secretable form. We are using these recombinant organisms (Lm-Gag) to generate HIV specific immune responses in the mouse, which we are characterizing in vivo and in vitro. We have shown strong CTL and Th1 helper responses that appear to be directed to the p24 gene product and have identified epitopes in two different strains of mice. Furthermore, immunization of mice with Lm-Gag protects them from a challenge with a vaccinia construct expressing Gag. Such protection is abrogated upon depletion of both CD4+ and CD8 + T cells, suggesting that the Gag-specific T cell immune response induced by the Lm-Gag vaccine is protective