HIV-1 induced immunosuppression has been attributed to a loss of CD4+ cells, but suppression of cell mediated immune (CMI) responses is present prior to significant loss of CD4+ cells. Two phenotypes of CD4+ cells have been characterized. TH1 cells produce IL2 and IFN(gamma), are thought to promote CMI, and are critical for resistance to agents that cause secondary infections in AIDS patients. TH2 cells produce IL4, IL5, IL6, and IL10 and are thought to promote humoral immunity. Recent evidence suggests that HIV-1 infected individuals produce TH2 rather than TH1 cytokines in response to antigens such as influenza virus, suggesting a TH1 to TH2 switch and increased susceptibility to secondary infections. Critical to an understanding of the immunologic defects that lead to secondary infections in AIDS patients is an animal model in which the components of the immune system can be phenotypically and functionally evaluated in response to both the immunodeficiency-inducing virus and the secondary infection. Studies in our and other laboratories indicate that FIV infection in cats is an excellent model to study the immunopathogenesis of HIV-1 infection. We now have evidence that FIV- infected cats are extremely susceptible to infection with Toxoplasma gondii, which is normally effectively controlled by a CMI (TH1) response. Challenge of FIV-infected cats leads to generalized toxoplasmosis that correlates with a deficiency in TNF-alpha and IL2 production. The overall objective of this proposal is to test the hypothesis that FIV causes an immunological dysfunction that precludes initiation of a protective TH1 immune response to primary challenge by pathogens such as T. gondii.
The specific aims will focus on identifying potential cytokine dysregulation in cats that may help identify virus-induced cellular and molecular lesions in the immune response to pathogens. Phase I studies will focus on establishing baseline lymphocyte phenotype and cytokine profiles in the immune tissues of normal cats, cats with primary T. gondii infection, and cats with primary FIV infection. Using RT-PCR for mRNA and bioassays for cytokine function, cytokine (TNF-alpha, IFN-gamma, IL2, IL4, IL6, IL10) profiles and kinetics will be established for resting and mitogen stimulated lymphoid tissue (PBMC, lymph nodes, spleen) from these cats. Cytokine responses will be correlated with lymphocyte alterations in lymph nodes and blood using flow analysis. Using the data generated from Phase I, Phase II studies will be designed, using RT-PCR and cytokine bioassays, to determine if failure of the FIV- infected host to contain a secondary T. gondii challenge is due to a non- protective TH2 response predominating over a protective TH1 response.
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