To confer potent and broad neutralization, it is expected that an epitope will need to possess at least four properties: (i) exposure on the virion-associated native Env trimer, (ii) conservation across diverse HIV-1 variants, (iii) immunogenicity, and (iv) lack of autoreactivity. To date, there are no epitopes that meet these criteria. However, our knowledge of the epitopes that are recognized by Nab during natural infection with diverse HIV-1 is somewhat limited. It is not known which or how many epitopes are targeted by the initial autologous Nab response, what proportion of these epitopes is strain-specific or shared, how antigenicity differs between patients or viral subtypes, or what the predominant escape mechanisms are. Furthermore, there is mounting evidence that at least some of these parameters differ between HIV-1 subtypes (reviewed in [20] ). We, and others, have characterized the autologous Nab response as it first develops, and have observed high titers of autologous Nab activity against the infecting strain in most (but not all) patients [13, 14, 15, 16, 17, 18, 19] . In addition we have reported higher Nab titers in subtype C infected patients compared to subtype B infected patients that were evaluated in parallel, prompting our group and others to propose that there are differences in antigenicity between subtype B and C Envs [15, 20, 21, 22] . Recent studies honed in on regions that could be involved in early subtype C autologous Nab responses, and these included the V1V2 hyper-variable domain and the C3 to V4 subregion of gp120 [23] . However, these regions could not account for all of the Nab activity present in patient plasma, suggesting the involvement of additional determinants. Furthermore, we have demonstrated that both V1V2-dependent and -independent pathways are utilized for escape from Nab during chronic subtype C infection [24] . In addition, we have shown a strong association between mutations in the a2 helix region of C3 and neutralization resistance, although these mutations did not directly alter neutralization sensitivity when transferred between sensitive and resistant Envs from linked transmission partners [25] .