IMPACT OF AGING ON IMMUNE CONTROL OF A PERSISTENT VIRUS

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With the increasing longevity of the human population, it is urgent that we define the consequences of aging on immunity and develop preventative or therapeutic strategies to counteract age-associated immune decline. Immune control of persistent viral infections is a problem associated with aging, as illustrated by the well-documented example of reactivation of the alpha-herpesvirus, varicella-zoster, in the elderly, causing postherpetic neuralgia (Shingles). The human garnma-herpesviruses, Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus, are important human pathogens, associated with lymphoproliferative disorders and various maligancies, including Burkitt's lymphoma, Hodgkin's disease, nasopharyngeal carcinoma and Kaposi's sarcoma. Continual immunesurveillance is required to maintain latency and prevent viral reactivation. It is therefore critical that we understand the ability of aged individuals to control these infections. In the current proposal, we will exploit a well-characterized mouse model, murine gamma-herpesvirus-68, MHV-68, to study the impact of aging on immune control of this important class of oncogenic viruses. Accumulating data suggest that CD4+ T cells, CD8+ T cells and antibodies all contribute to immune control of viral latency. Our preliminary data show that there is a progressive decline in neutralizing antibodies in aged mice, and that aged mice are compromised in their ability to control viral latency. These data justify a thorough analysis of virus-specific humoral and cellular immunity. Therefore, in Aim 1, we will determine whether the decline in neutralizing antibody titers in aged mice results in compromised humoral immunity, and whether there is a change in isotype profile or viral specificity with age, as has been shown for EBV. In Aim 2, we will monitor numbers, phenotype and function of virus-specific T cells for seven different lytic and latent CD4 and CD8 epitopes, and determine whether there is a decline in cellular immunity in aged mice. Finally, in Aim 3, we will assess how physiological perturbation of the immune system impacts immune control of persistent gamma-herpesviruses in the aged. These studies will be the first systematic analysis of the impact of aging on control of persistent gamma-herpesvirus infections.