A novel preventive strategy against HIV-1 infection: combinatorial use of inhibitors targeting the nucleocapsid and fusion proteins.

The strategy of simultaneously attacking multiple targets is worthy of exploration in the field of microbicide development to combat HIV-1 sequence diversity and minimize the transmission of resistant variants. A combination of S-acyl-2-mercaptobenzamide thioester-10 (SAMT10), an inhibitor of the HIV-1 nucleocapsid protein (NCp7), and the fusion inhibitor sifuvirtide (SFT) may exert synergistic effects, since SFT can block viral fusion at an early stage of the viral cycle and SAMT10 can disrupt viral particles at a later stage. In this study, we investigated the effect of the combination of SAMT10 and SFT on HIV-1 infection using in vitro cell culture and ex vivo mucosal explant models. A range of doses for each compound was tested at 10-fold serial dilutions based on their 50% effective concentrations (EC). We observed a synergistic effect of SAMT10 and SFT in vitro against both the laboratory-adapted HIV-1 strain HIV-1 (subtype B, X4) and three pseudotyped viruses prevalent in Chinese sexually transmitted populations (SVPB16 (subtype B, R5), SVPC12 (subtype C, R5) and SH1.81 (CRF01_AE, R5)). In the ex vivo study, the EC values of the inhibitor combinations were reduced 1.5- to 2-fold in colorectal mucosal explants compared to treatment with SAMT10 or SFT alone by using with HIV-1. These results may provide a novel strategy for microbicide development against HIV-1 sexual transmission.