While SIV infected Asian macaque monkeys develop disease very similar to humans infected with HIV, SIV infected African mangabey monkeys do not develop disease. Defining the mechanisms that distinguish disease susceptibility and resistance is the goal of our studies. Loss of CD4+ T cells accompanied by loss of appropriate CD4+ T cell function is the hallmark of pathogenic HIV-1 infection and SIV infection of select Asian species of nonhuman primates (NHP), such as rhesus macaques (RM). However, some NHP species, such as sooty mangabeys (SM) that are natural hosts of SIV, do not experience similar CD4+ T cell dysfunction and do not develop disease despite relatively high viral loads that are comparable to those present in SIV infected rhesus macaques that develop AIDS like disease. The precise mechanism(s) that lead to such loss of CD4+ T cells function has yet to be defined, but one of these mechanisms is a development of massive susceptibility of the both infected and non-infected - bystander""""""""- CD4+ T cells - to undergo immune mediated SIV induced dysfunction leading to the decrease in T cell responses, while, at the same time lymphocytes from SIV infected SM do not show similar CD4+ T cell dysfunction and maintain proper T cell responses. It was also documented that HIV and SIV virions incorporate wide range of host cell derived proteins that may play an important role in virus induced pathology. We submit that the differential clinical outcome of SIV infection in RM and SM provides for a unique tool to define and distinguish those mechanisms that are critical for the development of or resistance to SIV induced disease in RM or SM, respectively. The objective of this proposal therefore is focused first on the analysis of the SIV particles and host derived proteins associated with SIV in RM and SM and their role in the induction of SIV induced CD4+ T cell dysfunction. Subsequently we will characterize the roles of Akt and Cox2 signaling, two signaling pathways that are critical for multiple T cell functions, in SIV mediated T cell dysfunction. And lastly, the studies will evaluate DMA methylation as a downstream regulatory mechanism elicited by SIV induced T cell signaling and its role the dysfunction of the CD4+ T cells SIV infection. These proposed studies address in a stepwise fashion the potential effects that SIV may exhibit on each stage of the signal transduction machinery from the engagement of the receptor on cell surface down to the epigenetic regulation of transcription of critical effector genes at the promoter level. The approach of the utilization of the two NHP models of SIV infection will allow for the characterization of those SIV effects or cellular mechanisms that are critical for those pathogenic and, conversely, it may lead to the characterization of those mechanisms that antagonize these virus induced defects and contribute to resistance to lentivirus induced immune dysfunction and disease observed in SM. ? ?
