Role of CMV- and HIV-specific cTFH response in HIV infection

T follicular helper cells (TFH) are CD4 T helper cells that are present in the germinal centers that help initiate and maintain humoral immune response. Specifically, TFH cells induce B cells to produce antibodies with better avidity and instruct B cells to produce multiple isotypes by eliciting specific cytokine production. TFH cells are also important in eliciting survival programs in memory and plasma B cells leading to long-term survival in vaccination or infection. Large body of evidence suggests that these cells can traffic to the periphery and can become functional peripheral memory TFH (cTFH) cells. Our major objective in this research work is to identify a marker for antigen-specific cTFH cells and determine whether these cells are defective during HIV infection. We hypothesize that varying antigen-specific responses of cTFH cells could predict humoral response in HIV infection. Therefore, we sought to identify new markers to monitor antigen-specific cTFH cells and determine their function in chronic HIV infection. We found that CMAF, a transcription factor that is expressed in CD4+ T cells represents a good marker for cTFH cells. Using this marker, we have shown that antigen-specific cTFH cells are more functional in a group of HIV infected individuals called elite controllers (EC) when compared to non-controller's HIV-infected individuals (ST). Specifically, we have found that among ECs stimulated by HIV peptides, multiplex in situ hybridization results have shown that CMAF mRNA expression was significantly higher compared to STs(p<0.0079). In addition, to CMAF, we also evaluated the expression of CD40L as a marker of cTFH cells. Looking at HIV- specific response among EC and ST patients, CD40L expression was significantly higher among EC's that also showed significant cytokine production(p<0.0023). Interestingly, antigen -specific proliferation showed comparable EC and ST antigen-specific CD40L activation, but CMAF expression levels in HIV- specific response were higher among the EC's as compared to ST's. Thus, CMAF seems to be a strong marker for antigen-specific cTFH cells than CD40L expression. Overall, we have identified a candidate molecule that could potentially define antigen specific response among cTFH populations. This then will help us to understand if antigen specific cTFH responses are good correlates for immune protection in elite controllers and candidates for future vaccines.