A systems biology approach to understanding cellular dynamics during HIV-1 infection and progression to AIDS.

The mechanisms by which HIV-1 infection gradually depletes CD4 + T cells eventually leading to AIDS still remain unknown. Key players in the immune response to HIV-1 infection, CD8+ T cells and dendritic cells (DCs), exhibit compromised function during infection. Although these cell populations are primarily measured in the blood, the majority of infection events occur in lymph nodes (LNs). To understand cellular-viral dynamics within LNs during HIV-1 infection, I construct multi-compartment mathematical models describing blood and LN dynamics. The first model captures CD4+ T-cell interactions with virus, simulating various infection patterns dependent upon both viral and host factors. Using this model, I assess current therapies and suggest new treatment regimens. Visualization of residual virus below the level of detection and in the LNs during treatment allows first-time analysis of patient responsiveness to drugs. In a second multi-compartment model, I explore the differentiation of CD8+ T cells to cytotoxic T cells (CTLs). I find that both DCs, the primary antigen presenting cells in HIV 1 infection, and CD4+ T-cell help play crucial roles in the successful activation of virus-specific CTLs. Furthermore, CTL differentiation is dependent upon full activation of DCs within the LN. However, I determined that enhanced recruitment of DCs and elevated immune activation are directly correlated to CD4+ T-cell decline. I develop a third model to specifically address the dual role of DCs in CD4+ and CD8+ T-cell activation versus infection via cell-associated virus. Model results indicate that full activation of DCs and CTLs is a multistep process, influenced by several sequential cell-cell interactions. Due to the heterogeneity of these interactions within the LN, I develop a fourth model to encompass the effect of LN structure and composition on overall infection dynamics. I apply an agent-based modeling technique to capture stochastic processes involved in antigen presentation and HIV-1 infection among DCs and CD4+ and CD8+ T cells within a single human LN. Results highlight various factors governing spatio-temporal events such as cell motility and virus propagation. Various implementations of the systems biology approach highlight multiple mechanisms in the host-virus interaction responsible for CD4+ T-cell depletion and progression to AIDS.Ph.D.Applied SciencesBiomedical engineeringHealth and Environmental SciencesImmunologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/124733/2/3163749.pd