Modulating cathepsin cleavage sites in HIV gp120 envelope protein alters the cellular immune response. (VAC7P.989)

A major goal in HIV vaccine development is to identify antigens that can elicit long-term, protective antibody and cellular responses. Limited success with native recombinant HIV gp120 proteins suggested altering antigen processing as an approach to improve the immunogenicity of the HIV gp120 protein. Cathepsins S and D are important proteases which play critical roles in antigen processing. Here, we have utilized recombinant HIV gp120 proteins with mutations at the cathepsin S site (T322T323) and D cleavage site (L181Y182) within HIV gp120 to investigate the effects of these mutations on MHC class I/II presentation to CD8+/4+ T cells. We have found that altering the cathepsin S site in the minimal epitope, IGPGRAFYTT from T322T323 to V322V323 might improve CD8+ T cell recognition to this epitope in the V3 domain. We are investigating the mechanisms by which this mutation might enhance the CD8 response. It is possible this mutation can increase the binding affinity by changing the anchor residue with the MHC I molecule, or it can prevent degradation of the minimal epitope, or both. In a mouse model, we found that gp120 elicited antigen-specific CD4+ T cell responses against the V1V2 domain. Currently, we are investigating whether the altered cathepsin sites in gp120 affect antigen-specific CD4+T cell responses to the V1V2 regions. As antigen processing plays an important role in immunogenicity, we speculate that HIV may exploit this process to escape recognition.