Abstract Administration of HIV-1 neutralizing antibodies can suppress viremia and prevent infection in vivo. However, clinical use is challenged by broad envelope sequence diversity and rapid emergence of viral escape 1–9. Here, we performed single B cell profiling of 32 top HIV-1 elite neutralizers to identify broadly neutralizing antibodies (bNAbs) with highest potency and breadth for clinical application. From 831 expressed monoclonal antibodies, we identified 04A06, a new V H 1-2-encoded CD4 binding site bNAb with remarkable breadth and potency against extended multiclade pseudovirus panels (GeoMean IC 50 = 0. 059 µg/ml, breadth = 98. 5%, 332 virus strains). Moreover, 04A06 was not susceptible to classic viral CD4bs escape variants and maintained full viral suppression in HIV-1-infected humanized mice. Structural analyses revealed that antiviral activity is mediated by an unusually long 11-amino acid heavy chain insertion. This insertion facilitates inter-protomer contacts and interactions with highly conserved residues on the adjacent gp120 protomer. Finally, 04A06 demonstrated high activity against contemporaneously circulating viruses from the Antibody Mediated Prevention (AMP) trials (GeoMean IC 50 = 0. 082 µg/ml, breadth = 98. 4%, 191 virus strains) and in silico modeling for 04A06LS predicted HIV-1 prevention efficacy of >93%. Thus, 04A06 will provide unique opportunities for effective treatment and prevention strategies of HIV-1 infection.
Gieselmann et al. (Wed,) studied this question.