This project (TMA2020CDF-3183) is part of the EDCTP2 programme supported by the European Union. The project is also co-funded by Bill and Melinda Gates Foundation and the South African Medical Research Foundation (NRF). The purpose of this study is to evaluate the sensitivity of HIV-1 subtype C transmitted/ founder viruses to a panel of nine broadly neutralizing antibodies that target various regions of the HIV envelope. The first step was the amplification and cloning of HIV-1 Env from acute subtype C infected participants. This was followed by determining genetic characteristics of transmitted/founder env sequences by Sanger sequencing and the production of Env-pseudotyped viruses in human embryonic kidney 293 T cells. Subsequently, we measured the sensitivity of transmitted/ founder viruses to broadly neutralizing antibodies using the TZM-bl neutralization assay.

We amplified 48 HIV-1 env transmitted/founder clones from 38 participants from HIV-1 infected women from the Females Rising through Education, Support and Health (FRESH) cohort in Durban, South Africa. HIV Env-pseudotyped viruses were generated by co-transfecting full HIV-1 Env clones with HIV-1 Env-backbone with a defective envelope. Neutralization sensitivity of 45 pseudoviruses were assessed against a panel of nine broadly neutralizing antibodies that target the CD4 binding site, V2 apex, V3 glycan supersite, membrane proximal external region (MPER) of gp41 and gp120-gp41 interface . We also analysed HIV-1 env sequences to identify amino acid signatures that are associated with sensitivity or resistance to bNAbs. We used bioinformatics tools to identify combination of broadly neutralizing antibodies that could be effective in preventing HIV-1 subtype C infection. Indeed, we identified a combination of three broadly neutralizing antibodies that have the highest neutralization coverage and potency against HIV-1 subtype C cohort. This was followed by the design of the Gilead phase I human clinical trial in Durban, South Africa. The data generated from this project may contribute in HIV vaccine development efforts.