QUANTITATIVE ANALYSIS OF IMMUNITY TO VIRAL IMMUNOGENS

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Viral infections are important pathogens in the elderly. Immune response play a major role in protecting individuals from lethal infection with viruses. Evidence suggests that T cell function is compromised in both old rodents and humans. Our hypothesis is that dietary restriction (DR) can prevent the deficiencies induced by aging. We will, therefore, utilize novel, quantitative analyses to test this hypothesis in a relevant primate model, the rhesus macaque. Thus, we will quantitate the cellular immune response to vaccination in young, control (old) an dietary restricted (DR) rhesus macaques. Over the last five years of NIH support, we have increased the value of the rhesus macaque as a non-human primate model for studying the immune response to important human pathogens by defining the alleles and loci of the major histocompatibility complex (MHC) and developing sequence-based MHC typing of the rhesus-macaque MHC class I and II alleles. We have also developed technologies for the analysis of virus-specific cytotoxic T lymphocytes (CTLs) and Dr. Altman has developed a novel technology for determining CTL precursor frequencies. We are uniquely positioned to test important hypotheses concerning the effect of aging and DR on the cellular immune response to virus infection in vivo. We will, therefore, use these novel technologies for analyzing the T cell response in immunized rhesus macaques to understand the effects of age and DR on the cellular immune response to virus infection. The unique cohort of animals provided by the core represents an invaluable resource of animals that will allow us to test hypotheses concerning the role of aging and DR on the immune response of primates in virus infection. In Specific Aim I, we will describe the CD8+ T cell response to the simian immunodeficiency virus (SIV) in ten healthy, young MHC class I-defined rhesus macaques. This will result in the description of at least 4 new immunodominant CTL epitopes that bind to common rhesus MHC class I molecules. We will use these epitopes in the construction of immunogens in Specific Aim II. In Specific Aim II, we will quantitate the CD8+ T cell response to CTL epitope vaccination. We will also monitor the proliferative and antibody response to the hepatitis B virus (HBV) core antigen. This will allow us to assess the effect of aging and DR on the CD8, CD4 and B cell compartment in young, control (old) and restricted animals. In these control and restricted cohorts of animals in groups 1, 2 and 3 we will, therefore, determine whether aging can influence the immune response and whether DR can change this.