I.
GATES PROGRAM SUMMARY
Introduction: 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:
1.1
Determine the functional phenotype/specificity of HIV specific CD4 and CD8 T
cells,
1.2
Characterise the frequency, specificity, neutralisation capacity and ability to
inhibit transcytosis of HIV specific IgA and IgG,
1.3
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:
2.1
Conducting a non-biased genome wide SNP screen to map genes associated with
resistance in both the SW and Kindred cohorts,
2.2
Determine if associations exist between resistance and polymorphisms in
previously identified genes important in susceptibility to HIV-1,
2.3
Determine by gene expression analysis if there are genes differentially expressed
in resistant women and their families,
2.4
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.
3.1
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.
4.1
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.