Immune responses to M. tuberculosis (MTB) are dependent on the recognition of protective MTB epitopes in the context of the MHC background of the individual at risk. Thus, putative MTB epitopes for a synthetic vaccine against MTB must be tested using T cells from populations at risk for tuberculosis. Tuberculosis is one of the primary manifestation of HIV in The Gambia, a country that bisects Senegal on the West Coast of Africa. Between 80-90 percent of HIV seropositive patients seen at the MRC Fajara Clinic are co-infected with MTB and as many as 20 percent have active tuberculosis. The distribution of MHC alleles in Africa is strikingly different from the distribution of alleles in Caucasian populations. This laboratory group has developed a novel computer-driven algorithm that identifies peptides from MTB protein sequences that contain high densities of MHC binding motifs. Preliminary studies demonstrate that the computer-driven algorithm is both more efficient and more accurate than standard methods of MTB epitope identification. However, many of the evaluations of MTB epitopes have been performed using T cells from predominantly Caucasion donors in developed countries, where tuberculosis is no longer endemic. In this application, novel MTB epitopes will be synthesized that have been predicted by the algorithm and these peptides will be tested in assays to be performed in The Gambia, where tuberculosis is endemic. MHC typing and investigations of the correlation between the MHC type of individuals who respond to the peptides and the motifs contained within the peptide will be performed.
The specific aims are: 1. To identify """"""""protective"""""""" MTB epitopes that are recognized by individuals in a tuberculosis endemic area; 2. To evaluate the predictive power of the computer-driven algoritym for non-Caucasian T cell epitopes; and 3. To evaluate correlations between the MHC motifs included in the predicted peptide and the MHC type of responders. If these novel MHC binding motif-rich epitopes are recognized by MTB-immune individuals in The Gambia, they may be important candidates for inclusion in a synthetic tuberculosis vaccine targeting HIV seropositive individuals in sub Saharan Africa.
