Gates Grand Challenge
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.
The solution to the HIV/AIDS pandemic, the greatest health issue facing humankind, is the development of effective vaccines. Almost all vaccines were derived out of an understanding, no matter how primitive, of what results in protective immunity. Development of HIV vaccines has suffered from a lack of understanding of the correlates and causal pathways of immunity to HIV. We seek to understand the mechanisms of natural protection against HIV in women who are highly exposed to HIV yet escape infection. A subset of women in a highly HIV exposed Kenyan sex worker (SW) cohort studied since 1985 remain uninfected despite many hundreds of exposures. These women have systemic and mucosal cellular immunologic responses to HIV (both CD4 and cytotoxic T cell [CTL] responses) and mucosal CTL and neutralizing IgA antibody to HIV. While this type of data has been clear for some time in this and other groups of highly exposed, HIV uninfected individuals, an understanding of why these responses develop is limited. A partial answer may lie in genetic correlates of HIV resistance. HLA alleles correlate with protection against HIV infection, as do polymorphisms in immune response genes and HIV co-receptor molecules. Although resistance to HIV infection certainly segregates as a familial trait in genetic studies, it is unclear how these genetic associations correlate with putative protective immune responses. A key reason for slowness in the advance of knowledge on the targets of protective immune response to HIV and the reasons for their development is the small scale – both in terms of numbers of individuals studied and the parameters examined - of previous studies.
Our Specific Objective is to undertake an exhaustive analysis of immunologic and genetic factors that
mediate HIV-1 resistance with the goal of a more complete understanding what constitutes protective immunity against HIV infection.
Goal 1: To characterize correlates of protective immune responses to HIV in the systemic and mucosal compartments of resistant and
susceptible women by:
- Determine the functional phenotype/specificity of HIV specific CD4 and CD8 T cells,
- Characterise the frequency, specificity, neutralisation capacity and ability to inhibit transcytosis of HIV specific IgA and IgG,
- Determine if resistant women exhibit differential responsiveness to innate stimulation, or altered innate receptor expression such that are more likely to develop protective immune responses to HIV,
Goal 2: To identify genetic and innate factors associated with resistance in resistant
women and their families by:
- Conducting a non-biased genome wide SNP screen to map genes associated with resistance in both the SW and Kindred cohorts,
- Determine if associations exist between resistance and polymorphisms in previously identified genes important in susceptibility to HIV-1,
- Determine by gene expression analysis if there are genes differentially expressed in resistant women and their families,
- By a mass spectrometry approach identify known and unknown innate factors in serum or mucosa differentially expressed in resistant and susceptible women
Goal 3: To determine how genotypes/phenotypes identified above will determine immune responsiveness to a model antigenic challenge of a live, attenuated mucosal vaccinogen.
- The nature and specificity of immune responsiveness to the challenge vaccinogen will be determined by a combination of assays utilised above (gene expression analysis, proteomics, and T cell analysis of function and specificity),
Goal 4: To determine if genotypes/phenotypes associated with resistance, or with a favourable response to the model vaccinogen protect against HIV infection in a prospective study of HIV serocoversion in sexworker and non-sexworker cohorts.
- The presence of innate, genetic, or the development of HIV specific cellular immune responses correlate with a reduced likelihood of HIVs seroconversions in initially HIV uninfected individuals at significant risk for HIV infection.
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