HIV entry into target cells is a highly sequential and time-sensitive process. In recent years， potent HIV Env-targeting antibodies， such as VRC01， have been identified. However， antibodies bind only to a single epitope， and mutations that confer resistance to antibody-mediated inhibition of HIV entry have been detected. In contrast， HIV cannot escape from binding to soluble CD4 (sCD4) without a fitness disadvantage. sCD4 has the unique ability to induce conformational changes within the HIV envelope glycoproteins (Env) that allow fusion inhibitors to bind. We have previously linked sCD4 to the fusion inhibitor FI (sCD4-FI) and examined delivery of the bifunctional entry inhibitor via gene therapy. ... More
HIV entry into target cells is a highly sequential and time-sensitive process. In recent years， potent HIV Env-targeting antibodies， such as VRC01， have been identified. However， antibodies bind only to a single epitope， and mutations that confer resistance to antibody-mediated inhibition of HIV entry have been detected. In contrast， HIV cannot escape from binding to soluble CD4 (sCD4) without a fitness disadvantage. sCD4 has the unique ability to induce conformational changes within the HIV envelope glycoproteins (Env) that allow fusion inhibitors to bind. We have previously linked sCD4 to the fusion inhibitor FI (sCD4-FI) and examined delivery of the bifunctional entry inhibitor via gene therapy. Here， we extend our studies and analyze the ability of sCD4-FI to inhibit HIV Env-mediated cell fusion and HIV entry of several primary isolates. sCD4-FI inhibited both cell fusion and HIV entry with remarkable antiviral activity. The mean 50% inhibitory concentrations (IC) for sCD4-FI were <0.2 μg/mL in both assays. Importantly， inhibition by sCD4-FI was more potent than by VRC01， sCD4， or the previously described bifunctional protein sCD4-scFv. In contrast to sCD4， sCD4-FI as well as VRC01 and sCD4-scFv did not mediate cell fusion between HIV Env and CD4CCR5 cells. The results presented here provide further evidence for the testing of sCD4-FI and development of bifunctional proteins based on the sCD4-fusion inhibitor architecture.
