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To stop the spread of the HIV epidemic and contribute to the development of a vaccine.

Frank Plummer has been the Canada Research Chair in Resistance and Susceptability to Infections at the University of Manitoba since January 1, 2001. Based on his experience examining individuals that exhibit a natural resistance to HIV, Plummer currently investigates the possibility of a genetic cause for HIV immunity and hopes the results of his work will foster the development of a vaccine against AIDS in the near future. Presently directs the National Microbiology Laboratory in Winnipeg.

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Dr. Plummer and colleagues will expand on past research that has identified groups of commercial sex workers in Kenya who do not become infected with HIV despite repeated sex without condoms. While the phenomenon is well documented, it is not well understood. The project will undertake a comprehensive analysis of these women’s immune systems and genetics. Understanding what makes them apparently immune to the virus could guide HIV vaccine and drug development.

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Research Plan

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Bill and Melinda Gates Foundation

With more than 42 million people living with AIDS in the world today and an estimated 27 million people dead of AIDS, the development of HIV-1 vaccines is an ever more urgent goal. Most vaccines for infectious diseases of humans have been developed from an understanding, however imperfect, of what constitutes natural immunity. There is mounting evidence that some individuals are protected against HIV-1 infection.

In this cohort, HIV-1 resistance correlates with T helper cell recognition of HIV-1 antigens, CTL to HIV-1, neutralizing HIV-1 specific mucosal IgA and HLA alleles, suggesting that resistance may be mediated by immune mechanisms. The potential role of the mucosal immune response to HIV-1 in protection against infection has been poorly studied. In this submission, we propose to expand our studies of resistance to further characterize mucosal immune mechanisms potentially mediating HIV-1 resistance with the goal of understanding the correlates of protection against HIV. Towards this goal, we will determine the frequency and correlates of HIV-1 specific IgA in the genital tract of resistant women.

To map HIV neutralizing mucosal antibody, we will produce recombinant HIV neutralizing IgA monoclonal antibodies from the genital tract of resistant women and identify their epitopes using antibody excision and mass spectrometry. CTL directed against env are the best immunologic correlates of HIV-1 resistance, thus we will determined the frequency and epitope specificity of env specific cytotoxic T cells (CTL) to HIV-1 in the genital tract of resistant women. As T helper cell responses are critical in determining what type of immune effectors develop, we will characterize the T helper cell response to HIV-1 and other antigens in the genital tract of HIV-1 resistant women using intracellular cytokine staining. To further understand why HIV-1 resistant women from this cohort develop the immunologic responses that are associated with resistance, we will characterize the immunologic microenvironment in the genital tract of HIV resistant women using a mass spectrometry proteomics approach.

Finally, we will correlate HIV-1 specific immune responses in the genital tract with genetic factors and epidemiologic, reproductive and behavioural variables. Studies of this cohort and other HIV-1 exposed uninfected individuals has already made significant contributions to HIV-1 vaccine development. The continuation of this work is expected to make further contributions to understanding the types of immune responses that are necessary for protection and to identify potential targets for HIV-1 vaccines.

Most evidence suggests that these women are naturally immune to HIV. Although they don’t have antibody to HIV in their blood, their white blood cells are able to recognize and kill HIV infected cells. They also have HIV-1 antibody in their genital tract that is able to neutralize a broad range of HIV viruses.

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Scientists from the University of Manitoba Biology of Sexually Transmitted Infection CIHR Research Group have been studying the basis for resistance to infection with the AIDS virus (HIV) for the past 10 years. Working with a group of prostitutes who practice their sex trade in a slum in Nairobi, Kenya, they have identified a group of 120 women who remain HIV uninfected despite many years of exposure

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Vaccination strategies that induce strong mucosal as well as systemic responses show promise in macaque models of HIV pathogenesis. Indeed, HIV specific effector immune responses at the mucosal surface are detectable in a high proportion of individuals who are resistant to HIV despite repeated exposure. HIV specific IFN-? secreting CD8+ T cells have been detected in approximately half of HIV resistant women from a highly exposed population of sex workers in Nairobi, Kenya.

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The majority of heterosexual transmission of HIV-1 occurs at the site of the genital tract. This is the first site of exposure to HIV in the majority of instances and immune responses at mucosal surfaces are likely to be critical in mediating protection against infection. HIV specific IgA capable of neutralizing a broad range of HIV isolates, and capable of inhibiting HIV transcytosis across epithelial surfaces has been detected in 70% of HIV resistance sex workers.

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MRSI has been collaborating with institutions based at Oxford University, the University of Ghent and Université de Montréal. The Kenya program has given birth to collaborations in India, where Manitoba scientists are applying their hard-won expertise in projects financed by the Canadian International Development Agency and the Bill and Melissa Gates Foundation.

For more information check out the collaborators page and the publications page