HIV-1 Subtype C Tier 3 Viruses Have Increased Infectivity Compared to Tier 2 Viruses

A primary concern of an antibody-based HIV-1 therapy is the virus' ability to rapidly escape antibody responses. Therefore, we investigated the relationships between antibody neutralization sensitivity, viral phenotype, and infectivity in 13 subtype C viruses using a HeLa transfectant-based assay. We observed that the seven tier 3 viruses exhibited higher infectivity than the tier 2 viruses, suggesting that higher neutralization resistance did not have a substantial entry cost. There was no relationship between neutralization resistance and susceptibility to entry inhibitors Maraviroc, PSC RANTES, or the fusion inhibitor T20, indicating that neutralization resistance may not alter these inhibitor target sites. By analyzing glycosylation patterns in 82 subtype C viruses, we found that the presence of an N-linked glycan motif at position N413 and its absence at N332 were the most important predictors of neutralization resistance. In a set of 200 subtype C viruses, tier 3 strains were more resistant than tier 2 or 1B viruses to several broadly neutralizing monoclonal antibodies targeting three different epitopes. This suggests that it is unlikely that resistance to antibodies targeting a single epitope drives overall resistance. In the context of an antibody-based intervention, highly resistant viruses with increased infectivity, circulating in the population, could hinder HIV-1 control since entry of tier 3 viruses is not always selected against. Therefore, for any long-term antibody-based intervention to be globally relevant, it must elicit responses that limit the occurrence of resistance.