A significant obstacle to developing an HIV vaccine is the potential for the virus to escape from the immune response induced by immunization. We previously showed that subjects in a Zambian cohort developed potent neutralizing antibody responses shortly after becoming infected by subtype C HIV-1, and here we have extended those findings to demonstrate that cycles of viral escape occurred in two of these subjects despite a potent immune response. We investigated the determinants of immune escape, and found that a single common mutational pathway was not sufficient to facilitate viral escape. Instead, we demonstrate that multiple strategies, including potential changes in glycosylation pattern, direct alteration of an epitope sequence, and cooperative envelope interactions, were used independently or together to evade neutralization. We also recovered individual monoclonal antibodies from one of the subjects and found that a single mutation can confer escape from different neutralizing antibody specificities. The studies demonstrate the remarkable flexibility of subtype C HIV-1, and suggest that the envelope glycoproteins are uniquely equipped to adjust to the specific properties of the immune response in each newly infected host. this point forward [38] . Samples from five subsequent time points over the first two years of infection were evaluated. A subset of Envs was chosen to represent the diversity of the circulating quasispecies at each time point (see arrows in Fig. S1A and B) , and was evaluated for sensitivity to neutralization by each contemporaneous (simultaneously collected) plasma sample using the JC53-BL (Tzm-bl) pseudovirus assay [15, 24, 25] . The IC50 Nab titer for each plasma-Env combination was calculated from each virus infectivity curve using a growth function. Fig. 1 shows that the median IC50 titer of the 0-month Envs (designated according to the first seropositive time point; see Table 1 ) was higher than the contemporaneous Envs at each time point, indicating repeating cycles of neutralization resistance. This difference in median IC50 titer was statistically significant at all time points for 185F. However, for 205F, the median IC50 titer differed significantly at only two time points, probably due to the wide range of Nab sensitivities observed for the contemporaneous Envs of this subject (Fig. 1B) . Nevertheless, Nab-resistant variants were present at each time point and these were neutralized by subsequent plasma samples, indicating continued induction of a de novo Nab response (data not shown).