Certain inbred mouse strains are resistant to retrovirus-induced disease induced by E-55+ murine leukemia virus (MuLV) despite the fact that they become persistently infected. This resistance appears to be the result of the genetic control of events associated with virus infection including but not limited to anti-virus immune responses. In these studies, we will use microsatellite-based genome mapping to localize and identify genes involved in resistance to virus-induced disease. Our previous studies have demonstrated that the immune response to retrovirus-infected cells is in part responsible for this resistance. This protective immune response is bimodal with respect to time after viral infection. The early immune response results in a dramatic decrease in the number of virus-infected cells within 4-8 weeks after infection. This decrease in virus-infected cells occurs in immunocompetent mice from strains which are either resistant (C57BL/10-H- 2k) or susceptible (BALB/c-H-2k) to retrovirus-induced disease. Subsequently, susceptible mice which rapidly progress to virus-induced disease (leukemia/thymic lymphoma) develop an increase in virus-infected cells whereas no increase in infected cells occurs in resistant mice despite the fact that they have a persistent infection (long-term survivors). Our working hypothesis for these studies is that protection from virus-induced disease in long-term survivors is the result of the development of an effective late immune response in genetically resistant mice which inhibits the expression of virus-infected cells. In this manner, the number of virus-infected cells and, thus, the virus burden, is kept very low in these persistently infected mice. The studies described in this proposal establish a role for CD8+ cells in the long term survival of mice persistently infected with retrovirus. In addition, phenotypes contributing to long-term survival will be identified and mapped. These studies should provide new and important information regarding the genetic basis for resistance to virus-induced disease, including (but not limited to) the immune response mediated by CD8+ lymphocytes. Information from these studies may be helpful in understanding a genetic basis for long-term survival vs. rapid progression to AIDS in HIV infected individuals.
