Low frequency of broadly neutralizing HIV antibodies during chronic infection even in quaternary epitope targeting antibodies containing large numbers of somatic mutations.

Neutralizingantibodies ( Abs) are thought to be a critical component of an appropriate HIV vaccineresponse. It has been proposed that Absrecognizing conformationally dependent quaternaryepitopes on the HIV envelope (Env) trimer may be necessary to neutralizediverse HIV strains. A number of recently described broadly neutralizingmonoclonal Abs(mAbs) recognize complex and quaternaryepitopes. Generally, many such Absexhibit extensive numbers of somatic mutations and unique structural characteristics. We sought to characterize the native antibody ( Ab) response against circulating HIV focusing on such conformational responses, without a prior selection based on neutralization. Using a capture system based on VLPs incorporating cleaved envelope protein, we identified a selection of B cells that produce quaternaryepitope targeting Abs(QtAbs). Similar to a number of broadly neutralizing Abs, the Abgenes encoding these QtAbs showed extensive numbers of somatic mutations. However, when expressed as recombinant molecules, these Absfailed to neutralizevirus or mediate ADCVI activity. Molecular analysis showed unusually high numbers of mutations in the Abheavy chain framework 3 region of the variable genes. The analysis suggests that large numbers of somatic mutations occur in Abgenes encoding HIV Absin chronically infected individuals in a non-directed, stochastic, manner.