Although these studies were conducted on a small number of subjects, it is still beneficial to work toward developing a mechanistic model that can explain the underlying complexity of escape pathways between and within subjects. The results presented here provide the basis for such an endeavor. First, the escape pathways observed here appear to define Nab resistance through a combination of direct and indirect mechanisms. Direct epitope changes may be sufficient in the setting of limited antibody specificities, such as during the early phase of infection, while indirect 'masking' or cooperative mechanisms may be required later when multiple antibody specificities are circulating. However, it will be important to expand and confirm these studies by characterizing Nab escape in additional subjects. The frequency, timing, and underlying basis for convergent escape pathways within a subject will require further investigation, as will the significance of regions of subtype C Env that appear to be under positive selection but do not contribute directly to escape from plasma Nab. Lastly, it will be important to determine if different escape pathways share any common conformational basis or point to specific regions of the Env that should be incorporated into or excluded from vaccine immunogens.