2F5-like antibody clonal lineage. Wills, Saintedym R. et al (JI)

Mimicry of conserved self-antigens by HIV-1 may be a mechanism by which HIV evades the immune response. The broadly neutralizing antibody (bnAb) 2F5 targets the membrane proximal external region of HIV-1 which shares sequence identity with the human self-antigen kynureninase (KYNU). We previously reported that an HIV-1 chronically infected individual, SC44, had evidence of both autoantibodies and circulating 2F5-like antibodies in serum. Whether development of 2F5-like antibodies to a self-antigen leads to a bnAb response, or if reactivity to self-antigen is a requirement for the neutralization breadth, is unknown and challenging to investigate due to the scarcity these antibodies in HIV-1 infected individuals. In this study, we identify additional members of the m66 lineage, a mAb previously derived from SC44 by phage/yeast display that shares epitope specificity with 2F5, from SC44. The unmutated ancestor of the m66 lineage does not bind KYNU, but more mature antibodies in the constructed lineage displayed reactivity to KYNU and other self-antigens driven by VH mutations. At the same time, the accumulation of mutations VH (variable heavy chain) region in the m66 lineage resulted in decreased HIV epitope binding affinity and virus neutralization potency, consistent with the action of host mechanisms that limit antibody autoreactivity by placing constraints on affinity maturation. These results indicate that antibody affinity reversion may be a major roadblock in the development of bnAbs in humans.