Journal of virology 2017 07 12() pii 10.1128/JVI.00811-17
Strategies are needed to improve the immunogenicity of HIV-1 envelope (Env) antigens for more long lived, efficacious HIV-1 vaccine induced B-cell responses. HIV-1 Env gp140 (native or un-cleaved molecules) or gp120 monomeric proteins elicit relatively poor B-cell responses which are short-lived. We hypothesized that Env engagement of the CD4 receptor on T-helper cells may result in anergic effects on T-cell recruitment and consequently a lack of strong robust and durable B-memory responses. To test this hypothesis we occluded the CD4 binding site (CD4bs) of gp140 by stable cross-linking with a 3kD CD4 miniprotein mimetic serving to block ligation of gp140 on CD4+T-cells while preserving CD4 inducible (CDi) neutralizing and epitopes targeted by antibody dependent cellular cytotoxic (ADCC) effector responses. Importantly immunization of rhesus macaques consistently gave superior B-cell (p<0.001) response kinetics and superior ADCC (p<0.014) in a group receiving the CD4bs-occluded vaccine compared to those animals immunized with gp140. Of the cytokines examined, Ag-specific IL-4 T-helper ELISpots in the CD4bs-occluded group increased earlier (p=0.025) during the inductive phase. Importantly CD4bs-occluded gp140 antigen not only induced superior B-cell and ADCC responses, the elevated B-cell responses proved to be remarkably durable lasting more than 60 weeks post-immunization.IMPORTANCE Attempts to develop HIV vaccines capable of inducing potent and durable B-cell responses have until now been unsuccessful. Antigen specific B-cell development and affinity maturation occurs in germinal centers in lymphoid follicles through a critical interaction between B-cells and T follicular helper cells. The HIV envelope binds the CD4 receptor on T-cells as soluble shed antigen or as antigen antibody complexes causing impairment in the activation of these specialized CD4 positive T-cells. We proposed that CD4-binding impairment may in part be responsible for the relatively poor B-cell responses to HIV envelope based vaccines. To test this hypothesis we blocked the CD4 binding site of the envelope antigen and compared it to currently used unblocked envelope protein. We found superior and durable B-cell responses in macaques vaccinated with an occluded CD4 binding site on the HIV envelope antigen, demonstrating a potentially important new direction in future design of new HIV vaccines.