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?

Public Health Relevance

The HIV-1 pandemic remains one of the greatest global disease threats we face. The majority of infected individuals as well as the """"""""at-risk"""""""" populations reside in sub-saharan Africa and other developing countries. Tremendous effort has been put forth to develop HIV-vaccines for these populations and many are currently in trial. Most of the individuals in sub-saharan Africa and other developing countries are also infected with immune suppressive helminth parasites which have been shown to negatively impact vaccination with BCG and tetanus toxin. No one has examined the impact of earlier helminth infection on HIV-1 vaccination, nor what happens to HIV-1 vaccine induced immune responses following reinfection with immune suppressive helminthes. This study is designed to answer both of these questions.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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HIV/AIDS Vaccines Study Section (VACC)
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Mehra, Vijay L
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Harvard University
Schools of Public Health
United States
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