Requirement of diverse T-helper responses elicited by HIV vaccines: induction of highly targeted humoral and CTL responses

Abstract

With the continued spread of the HIV/AIDS epidemic at alarming proportions there is a sense of urgency for an effective prophylactic HIV vaccine. However, in addition to the social, geopolitical and public health problems, the scientific challenges often seem insurmountable. Empirical approaches to develop an HIV/AIDS vaccine have been unsuccessful and this, coupled with the recent failure of the first Phase III clinical trials, calls for a strong rational approach based on a deeper scientific understanding of the correlates of immunity observed in both preclinical and clinical settings. While the field has been polarized between those who have been proponents of vaccines that induce strong cytotoxic T-cell responses, and those who advocate inducing neutralizing antibody responses, we have maintained middle ground. Based on our early preclinical observations in rigorous nonhuman primate vaccine efficacy studies, we have focused on vaccine strategies that induce potent T-helper immune responses capable of driving both cytotoxic, as well as broad highly effective neutralizing antibodies. The critical issue remains in the selection of the specific vaccine antigens. To date, our approach has been to utilize multiple structural as well as regulatory HIV antigens containing highly conserved epitopes. The current challenge faced is to design novel antigens based on mimicking envelope structures capable of inducing broad neutralizing antibodies. Our aim is to combine these with immunization strategies capable of eliciting potent cellular as well as humoral immune responses with the ultimate goal of providing mucosal barriers to HIV entry.