Title: The effect of different viral strains on thymocyte development during HIV-1 infection

Ping Ye and Denise E Kirschner, University of Michigan, Ann Arbor, MI

The thymus is the central lymphoid organ which provides a specialized microenvironment for thymocyte development. Although the thymus undergoes a gradual involution during aging, substantial thymic output is still detectable in adults. A number of clinical and experimental data have demonstrated that the thymus can be infected by different HIV-1 strains, suggesting thymocyte development may be interrupted by HIV-1. This may contribute to the CD4 T cell depletion that occurs during HIV-1 infection, thus accelerating disease progression to AIDS. As expected, this phenomenon is more evident in pediatric patients in whom the thymus is at its peak of function and is the primary source of newly generated T cells. Several critical factors have been identified as contributing to suppression of thympoiesis including: HIV-1 strain, viral coreceptor expression level on thymocytes, and cellular factors favoring HIV-1 replication. We have developed a mathematical model to illustrate the dynamic interactions between thymocytes and virus to understand how and when HIV-1 causes disruption of thymocyte development. Our hyptothesis is that a viral strain switch from R5 to X4 results in thymic function failure and further depletes the peripheral T cell pool. Through our analysis of the steady states of virus-free and various infection scenarios, our model demonstrates that thymic output alters the peripheral T cell pattern, including CD4 T cellcounts, CD4/CD8 T cell ratios in adults, and is also responsible for both CD4, CD8 T cell depletion observed in a subset of pediatric patients who have a faster disease progression to AIDS.