Feline Leukemia Virus Infection: A Model of Effective Retroviral Immunity

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The immediate goal of the candidate, Andrea N. Torres, DVM, is to complete a mentored program investigating retrovirus immunoregulation and pathogenesis, culminating in the PhD degree and additional postdoctoral research experience. Dr. Torres' long-term goal is to become a principal investigator conducting research on immunomodulatory strategies against viral diseases of animals and humans. The research training program will be centered in the laboratory of sponsor Dr. Edward A. Hoover at Colorado State University. The environment has a strong record of extramural funding and medical scientist training. The candidate's training plan involves laboratory and didactic instruction in contemporary cellular and molecular virology research methods applied to an animal model of retroviral immunodeficiency. The proposed research examines the early cellular and humoral immune responses which distinguish effective vs. ineffective containment of retroviral infection by using the feline leukemia virus (FeLV) infection, a naturally occurring model of diametric host:retrovirus relationships. We will address two specific aims: (1) first, to determine the relationship of early cytokine balance to regression vs. progression of FeLV infection in vivo; and (2) second, to determine whether early manipulation of the type 1 and type 2 cytokine balance can induce regression or progression of FeLV infection. In Aim 1, we will examine early viral infection and immune response kinetics in FeLV-naTve and FeLV-vaccinated cats challenged oral-nasally with FeLV-61E. We will perform serial analysis of blood and lymphoid tissue cells for viral DNA, RNA, protein, and infectivity by quantitative real-time DNA and RNA PCR, p27 Gag capture, and virus isolation. We will assess possible early immune correlates of protection by quantitative real-time RNA PCR for circulating and lymphoid tissue type 1 and type 2 cytokine transcripts, virus neutralizing antibody, FeLV-specific T cytolytic and helper cell activity, in Aim 2, we will determine whether manipulation of the initial immune response toward a type 1 or type 2 response will correlate with more vs. less effective retroviral containment via administration of exogenous feline interleukin-12 or interleukin-10, delivered mucosally via adenovirus vectors at or near the time of mucosal FeLV challenge. The host:virus relationship in IL-12-, IL-10-, and sham vector-treated animals will then be analyzed using methodologies applied in Aim 1. The results of these studies should provide insight into the early effective vs. ineffective host control of retrovirus infections.