T cell epitope ontogeny in AIDS-virus infected cells

More than 25 million people have died from HIV/AIDS since its discovery in 1981, making the epidemic one of the deadliest in history. With greater than 95% of the infections occurring in countries unable to afford antiretroviral therapy, the development of a prophylactic HIV vaccine remains one of the world's top health priorities. Unfortunately, conventional vaccine approaches to HIV have failed, highlighting the need for novel vaccine modalities. Multiple studies have demonstrated the important role of CD8+ T cells in controlling HIV and SIV infections and, accordingly, research is now underway to develop vaccines, which elicit effective CD8+ T cells. However, there is no clear consensus as to which viral proteins should be used for vaccination.; We approached this problem by investigating the kinetics of CD8 + T cell epitope presentation in cells infected with Simian Immunodeficiency Virus (SIV). For maximal anti-viral efficacy, vaccine-induced CD8+ T cells should recognize infected cells early enough to prevent the production of progeny virus particles. To test this concept, we designed a novel synchronous infection technique and examined the ontogeny of T cell epitopes in synchronously infected CD4+ T cells. We initially hypothesized that CD8+ T cell epitopes would be presented in the order in which their parent proteins were synthesized after infection. However, we found that epitopes derived from viral proteins, which accompany the infecting retroviral genome into the cytoplasm of the target cell, are efficiently presented as early as 2 hours post-infection. Additionally, CD8 + T cells directed against these "early" presented structural proteins effectively eliminated infected cells prior to the production of progeny virions. These data suggest that CD8+ T cells capable of recognizing epitopes derived from the incoming viral particle gain a kinetic advantage in recognition and elimination of infected cells and, therefore, may play an important role in containment of viral replication.