Gaiha: Multi-networked T cell epitope vaccine for global HIV prevention and therapy
Recent findings indicate that successful in vivo control of clade B HIV is achieved by directing functional CD8
+ T cell responses towards epitopes derived from topologically important regions of the viral proteome. Highly
networked epitopes, which are a subset of sequence-conserved epitopes, could serve as a valuable set of
mutation-resistant epitopes for inclusion in a T cell-based vaccine for HIV. CD8+ T cell targeting of highly
networked epitopes may distinguish individuals who naturally control HIV, even in the absence of protective
HLA alleles. This investment will be used to optimize a T cell-based prophylactic and therapeutic vaccine for
HIV that incorporates CD8+ T cell epitopes identified by a structure-based network analysis algorithm. This
method utilizes network theory and protein structure data to identify amino acid residues and T cell epitopes
of topological importance (and with broad representation in the global population). Epitopes identified using
this approach will first be evaluated to determine whether they are preferentially targeted by controllers in a
sub-Saharan African cohort. Specifically, the protective nature of highly networked epitopes will be studied in
HIV clade C-infected individuals. The design of HLA class I-restricted and HLA-E-restricted CD8+ T cell
vaccine candidates composed of highly networked epitopes will then be optimized with the goal of testing
immunogenicity in an improved human leukocyte antigen (HLA)-expressing mouse model. These studies will
provide critical pre-clinical evidence in support of advancing multi-networked T cell epitope vaccine
candidates towards clinical safety and efficacy testing in humans.
The specific goals of this investment are:
1) Confirm the protective nature of highly networked epitopes in a cohort of HIV clade C-infected individuals from sub-Saharan Africa.
2) Optimize the development of a multi-networked T cell epitope vaccine candidate.
3) Evaluate the immunogenicity of a multi-networked T cell epitope vaccine candidate in HLAexpressing mice.