In a previous study, we demonstrated that subtype C infected seroconvertors mount robust Nab responses against their autologous viruses during the early stages of infection [15] . Here we have extended those findings to demonstrate that cycles of viral escape occur despite potent Nab and that these cycles involve multiple mechanisms and regions of Env. In subject 185F, early Nab escape required amino acid substitutions in V5 that were independent of glycosylation. It is possible that these changes directly altered an epitope in V5, as this region may be accessible to Nab on the Env trimer. However, attempts to remove Nab activity with a V5 peptide were unsuccessful, and Env chimeras in which unrelated Envs were engineered to carry the 185F 0-month V5 sequence lacked biological activity (data not shown). Thus neither of these approaches allowed definitive identification of a V5 epitope, and the latter suggested that the V5 domain itself, or the proximal region of gp120, likely evolved in concert with adjacent regions of the protein. Another possibility is that the early changes in V5 created conformational changes that protected a distinct target. The N-terminal region of V5 has been shown to contain contact sites for both CD4 and Mab b12 [39] , and the escape mutations could therefore have influenced exposure of epitopes such as the CD4 binding site. These two alternatives, epitope mutation or masking, are not mutually exclusive, and it is conceivable that V5 changes could protect from more than one antibody specificity. This is clearly the case for 205F, where a single amino acid change in V2 creating a potential glycan addition site resulted in resistance against two distinct Mabs.