The elicitation of broadly neutralizing antibodies (bNAbs) is likely to be essential for a preventative HIV-1 vaccine, but this has not yet been achieved by immunization. In contrast some HIV-1-infected individuals naturally mount bNAb responses during chronic infection, suggesting that years of maturation are required for breadth1-6. Recent studies have shown that viral diversification precedes the emergence of bNAbs but the significance of this observation is unknown7,8. Here, we delineate the key viral events that drove neutralization breadth within the CAP256-VRC26 family of 33 monoclonal antibodies (mAbs) isolated from a superinfected individual. First, we identified minority viral variants that were distinct from both transmitted/founder (T/F) viruses and efficiently engaged the bNAb precursor, termed bNAb-initiating envelopes. Second, deep sequencing revealed a pool of diverse epitope variants (immunotypes) that were preferentially neutralized by broader members of the antibody lineage. In contrast, a “dead-end” antibody sublineage unable to neutralize these immunotypes showed limited evolution and failed to develop breadth. Thus, early viral escape at key antibody-virus contact sites selects for sublineages that can tolerate these changes, providing a new mechanism for the generation of neutralization breadth within a developing antibody lineage.

Disease-free infection in HIV-infected adults is associated with HLA-mediated suppression of viremia, whereas in the sooty mangabey and other healthy natural hosts of SIV, viral replication continues unabated. To better understand factors preventing HIV disease, we here investigated pediatric infection, where AIDS typically develops more rapidly than in adults. Among 170 non-progressing anti-retroviral therapy-naïve children aged >5yrs maintaining normal-for-age CD4 T-cell counts, immune activation levels were low despite high viremia (median 26,000 copies/ml). Potent, broadly neutralizing antibody responses in the majority of subjects and strong virus-specific T-cell activity were present but did not drive pediatric non-progression. However, reduced CCR5 expression and low HIV infection in long-lived central memory CD4 T-cells were observed in pediatric non-progressors. These children therefore express two cardinal immunological features of non-pathogenic SIV infection in sooty mangabeys - low immune activation despite high viremia and low CCR5 expression on long-lived central memory CD4 T-cells – suggesting closer similarities with non-pathogenetic mechanisms evolved over thousands of years in natural SIV hosts than those operating in HIV-infected adults.

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