The worldwide AIDS epidemic is most devastating in developing countries where more than 40 million people are infected. The development of an HIV-1 vaccine for populations in southern Africa and other developing countries is the highest priority. The majority of inhabitants in developing countries are also infected with parasitic helminthes which drive Th2-biasing and immune suppression. Helminth infection suppresses immune responses to Th1-type vaccines, and the expansion of viral antigen specific CD4+ and CD8+ T cell responses. Th1-type and cytotoxic CD8+ T cell responses are the goal of the majority of HIV-1 candidate vaccines in development or in clinical trials. Thus, how helminth infection will impact not only the induction of robust T cell responses to candidate HIV-1 vaccines but also the durability of these T cell responses is an important question. DNA/Adenoviral vector vaccines have shown great success in driving systemic and or mucosal vaccine-specific antibody, CD4+ and CD8+ T cell responses to HIV-1, as well as other pathogens. Thus the first goal of this application is to determine if DNA/Adenoviral vector HIV-1 vaccines will induce strong vaccine specific T cell responses following elimination of helminth parasites. To mimic the scenario in developing countries, we next ask if these vaccine specific T cell responses are maintained in mice that become re-infected with helminth parasites. In this same regard we will determine how re-infection during the vaccination regimen impacts the induction of vaccine specific T cell responses. We will also determine whether F4/80+,Gr1+ suppressor macrophages and/or CD4+,CD25+ T regulatory cells play prominent roles in suppression of HIV-1 vaccine specific T cell responses in helminth mice. Lastly, because the majority of HIV-1 transmission in developing countries is via mucosal sites, we ask if helminth infection differentially impacts systemic vs mucosal HIV-1 vaccine specific T cell responses in helminth infected mice.
The specific aims of this proposal are: 1) Will eradication of schistosome infection and restoration of normal immune bias allow for successful vaccination with HIV-1 candidate vaccines in mice? 2) Will established immune responses to HIV-1 vaccines remain durable or be altered by subsequent infection with immunomodulatory helminthes? 3) Does helminth infection differentially impact systemic vs mucosal HIV-1 vaccine specific T cell responses?
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