Sensitivity to Broadly Neutralizing Antibodies of Recently Transmitted HIV-1 Clade CRF02_AG Viruses with a Focus on Evolution over Time.

Broadly neutralizing antibodies (bnAbs) are promising agents for prevention and/or treatment of HIV-1 infection. However, the diversity among HIV-1 envelope (Env) glycoproteins impacts bnAb potency and breadth. Neutralization data on the CRF02_AG clade are scarce although it is highly prevalent in West Africa and Europe. We assessed the sensitivity to bnAbs of a panel of 33 early transmitted CRF02_AG viruses over a 15-year period of the French epidemic (1997 to 2012). Env pseudotyped CRF02_AG viruses were best neutralized by the CD4 binding site (CD4bs)-directed bnAbs (VRC01, 3BNC117, NIH45-46, and N6) and the gp41 membrane-proximal external region (MPER)-directed bnAb 10E8 in terms of both potency and breadth. We observed a higher resistance to bnAbs targeting the V1V2-glycan region (PG9 and PGT145) and the V3-glycan region (PGT121 and 10-1074). Combinations were required to achieve full coverage across this subtype. We observed increased resistance to bnAbs targeting the CD4bs linked to the diversification of CRF02_AG Env over the course of the epidemic, a phenomenon which was previously described for subtypes B and C. These data on the sensitivity to bnAbs of CRF02_AG viruses, including only recently transmitted viruses, will inform future passive immunization studies. Considering the drift of the HIV-1 species toward higher resistance to neutralizing antibodies, it appears necessary to keep updating existing panels for evaluation of future vaccine and passive immunization studies. Major progress occurred during the last decade leading to the isolation of human monoclonal antibodies, termed broadly neutralizing antibodies (bnAbs) due to their capacity to neutralize various strains of HIV-1. Several clinical trials are under way in order to evaluate their efficacy in preventive or therapeutic strategies. However, no single bnAb is active against 100% of strains. It is important to gather data on the sensitivity to neutralizing antibodies of all genotypes, especially those more widespread in regions where the prevalence of HIV-1 infection is high. Here, we assembled a large panel of clade CRF02_AG viruses, the most frequent genotype circulating in West Africa and the second most frequent found in several European countries. We evaluated their sensitivities to bnAbs, including those most advanced in clinical trials, and looked for the best combinations. In addition, we observed a trend toward increased resistance to bnAbs over the course of the epidemic.