Glycopeptide-specific helper T cells eliciting protective humoral immunity against HIV - Resubmission

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PROJECT SUMMARY/ABSTRACT HIV has been a major threat to human health and a protective AIDS vaccine has not as yet been developed. Designing strategies for reproducibly inducing the production of neutralizing and non-neutralizing protective antibodies through vaccination has been a high-value target for halting the spread of HIV. However, the design of the current generation of vaccines does not make use of immune system activation mechanisms to maximize stimulation of critical immune cells (i.e., helper T cells) involved in producing protective antibodies. A new perspective to HIV vaccine research is much needed. Here, we propose an innovative approach with the potential of establishing a new paradigm that the human CD4+ T cell repertoire contains a population of carbohydrate-specific T cells (i.e., Tcarbs) that recognize the N-glycan shield of gp120. The HIV-1 surface is decorated with a heavily glycosylated envelope protein called gp120, whose interaction with the CD4 molecule is the key step for the virus’s entry into CD4+ T cells. Using the discovery of such Tcarbs and their glycan epitopes, we can design and develop knowledge-based, new-generation HIV vaccines that will elicit a strong and long lasting adaptive immune response to protect from HIV. We hypothesize that recruitment of Tcarbs will not only induce T cell proliferation and memory, but will also induce production of protective, high-affinity antibodies by B cells through mechanisms such as affinity maturation and antibody class-switch. We believe our proposed studies will yield a platform to develop a new-generation of protective future HIV vaccines.