At later time points in subject 185F, the flexibility of the Env structure provided alternative mutational pathways to resist neutralization. Escape pathways in 185F oscillated between changes localized to the gp120 outer domain (V3V5), and conformational masking strategies that required interaction between spatially separated Env subregions ( Fig. 7A and B) . V5 or V3V5 was the major determinant at 5-, 14-, and 17-months, and also in one of the 28-month Nab resistant Envs (see Fig. S4 for neutralization curves). However, in Envs from two other time points (11-and 23-months), V3V5 did not independently confer resistance, but appeared to require contributions from V1V2. In Nab resistant Envs from three time points (20-, 26-, and 28months), the gp120 V1V5 region and the gp41 ectodomain were both required for resistance. Further mapping for one of these Envs demonstrated that the V1V2 domain contributed in large part to this phenotype, but the V3V5 domain in this context did not. Interestingly, some of the V1V2 domains in subject 185F contained changes in the predicted glycosylation pattern relative to the 0-month Env, while others had sequence changes that would not alter the original glycosylation pattern (Fig. 7A : 5-PB1.1, 11-PL5.1, 23-PL5.1, and 28-PL5.1).