Infection of HIV+ individuals by organisms such as P. carinii and T. gondii has been attributed to gradual erosion of the T/H1 dependent cell mediated immune system. Most studies have focused on erosion of the """"""""memory"""""""" immune response to these organisms, but little is known of the primary immune response to an antigen in HIV infection. As the primary response is mechanistically similar to a memory response, yet greater in magnitude, we predict that the primary response to a pathogen is a more sensitive and rapid indicator of lentivirus-induced immune deficiency. Study of the primary immune response would provide a means to analyze the cellular and molecular events leading to HIV-associated immunodeficiency in a more sensitive and rapid system than a memory response. Critical to such a study, which is not feasible in HIV, is an animal model in which specific components of the immune system can be phenotypically and functionally evaluated in response to both the immunodeficiency-inducing virus and to secondary infections. Existing data indicate that FIV infection of cats provides such a model. We have evidence that FIV causes deficiencies in the feline immune system that interfere with the ability of the cat to mount a protective primary immune response when challenged with T. gondii. We also have evidence that memory response is compromised in FIV infection. We propose to use the FIV-T. gondii co-infection model to examine the underlying immunologic defects in lentivirus infections that lead to the loss of both the primary and the memory immune responses. We will do this by studying both the generation phase (blood, lymph nodes, spleen) and the effector phase (alveolar macrophage, lung) of the immune response in cats infected with FIV-only, T. ,gondii-only, FIV followed by T. gondii, and T. gondii followed by FIV. Using bioassays for function and RT-qcPCR for mRNA, we will determine the cytokine profiles in lymphoid and lung tissue from these cats. Cytokine responses will be correlated with lymphocyte changes and alterations in virus expression in lymphoid and lung tissue using FACS analysis, immunohistochemistry, in situ hybridization, and virus infectivity assays. Comparison of the phenotype and functional profiles of these four groups of cats will help determine where in the T/H1 immune response the defect(s) occurs (APC function, clonal deletion, T/H1 to T/H2 switch). It will also determine whether the study of the primary immune response can be used as a sensitive, rapid mechanism to study HIV-induced immunodeficiency.
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