The timing and mechanisms that underlie the development of thymic dysfunction during HIV infection are largely unknown and difficult to study in humans. Feline immunodeficiency virus (FIV) infection of cats leads to significant pathological changes in the thymus with many similar effects on immune function as seen in HIV-1 infections. We have extensive experience using the FIV/cat model to document thymic pathogenesis and to map temporal changes in thymus integrity and function following FIV infection. Among the these changes is the surprising observation that thymectomy (ThX) of adult cats subsequently infected with FIV led to a rapid loss of virus-specific cytolytic T cell function. The cause of this loss is unknown and may result from a lack of replenishment, CD4+ T-cell functional deficiency, loss of cytokine/thymic hormonal support, failure of CD8+ T-cell maturation, or suppression by T regulatory (T-reg) cells. The overall objective of the proposed studies is to identify the mechanism causing the loss of CTL function and to understand better the broad implications of lentivirus-mediated thymic involution leading to irreversible loss of thymic function. Based on our current understanding of the role of the thymus in maintaining a robust antivirus T-cell response, we offer the overall hypothesis that in adults, sustained cytolytic T-cell responses to HIV-1 require a functional thymus that influences the peripheral T-cell compartment through direct resupply HIV-1 specific T-cell clones, or indirectly through endocrine-like thymic hormones that promote T-cell maturation and effector cell function. We also hypothesize that thymic influence is necessary at the time of initial antigen exposure to augment the immune response either by supplying a burst of naive T-cells or indirectly through endocrine-like thymic hormone that enhance the primary immune response. To test these hypotheses, we propose three Specific Aims.
Aim #1 will identify the mechanism(s) that causing the loss of cytolytic CD8+ function in thymectomized, FIV-infected cats.
Aim #2 will evaluate the effect of post-infection ThX on maintenance of immune competency.
Aim #3 will evaluate the role of the thymus in maintaining recall antigen responses where antigen is given chronically or intermittantly. Using this novel FIV/ThX model, we can monitor immune function in the dynamic context of active lentivirus infection also explore the underlying mechanism by which the thymus participates in maintaining peripheral T-cell homeostasis.
