Identification of a CD4-Binding-Site Antibody to HIV that Evolved Near-Pan Neutralization Breadth

Abstract

SUMMARY Detailed studies of the broadly neutralizing antibodies (bNAbs) that underlie the best available examples of the humoral immune response to HIV are providing important information for the development of therapies and prophylaxis for HIV-1 infection. Here, we report a CD4-binding site (CD4bs) antibody, named N6, that potently neutralized 98% of HIV-1 isolates, including 16 of 20 that were resistant to other members of its class. N6 evolved a mode of recognition such that its binding was not impacted by the loss of individual contacts across the immunoglobulin heavy chain. In addition, structural analysis revealed that the orientation of N6 permitted it to avoid steric clashes with glycans, which is a common mechanism of resistance. Thus, an HIV-1-specific bNAb can achieve potent, near-pan neutralization of HIV-1, making it an attractive candidate for use in therapy and prophylaxis.

The human naive B cell repertoire contains distinct subclasses for a germline-targeting HIV-1 vaccine immunogen

“…N6 is a potent VRC01-class bnAb that can neutralize 98% of HIV-1 isolates, making it the VRC01-class bnAb with the greatest breadth of any CD4bs-directed Ab (22). N6-subclass (Vκ1-33 + VRC01-class, with other bnAb subclass members including 12A21, 12A12, and VRC-CH31) naive human B cells are a highly desirable starting point for potential bnAb development, both because of the potency and breadth of N6 and the nature of the development pathway of an N6-like bnAb in comparison to VRC01.…”

“…It is likely that VRC01-subclass (Vκ3-20 + ) naive B cells would require deletions in L-CDR1 to acquire bnAb attributes in a human HIV-1 vaccine regimen. In contrast, N6-subclass bnAb maturation can occur via Vκ1-33 CDR1 glycine mutations to enable flexibility to accommodate HIV Env N276 (21, 22, 24). Six N6-subclass naive B cells were identified during B cell repertoire screening (Figure 2A, Table S1, Figure S1F).…”

Virological Control by the CD4-Binding Site Antibody N6 in Simian-Human Immunodeficiency Virus-Infected Rhesus Monkeys

“…The D/E279 mutation in the D loop found in the rebound virus was not present in any of the 18 pre-bnAb Env sequences but was present in 29/30 of the week 2 (first viral rebound time point) Env sequences, suggesting that the mutation developed rapidly during therapy. This residue has been shown to be critical for resistance to N6 and has been seen in the few viruses that were resistant within a panel of 181 tested pseudoviruses, as well as in the original patient's sequence in which N6 was identified (15). Sensitivity of these viruses to N6 neutralization was only recovered by reverting 279 to D. While we cannot exclude the possibility that this mutation had developed at low frequency during natural infection and was selected upon N6-LS treatment, our data highlight how rapidly virological escape can occur following single-bnAb treatment.…”

“…Animal MGI, which failed to fully suppress viremia, initially showed a robust viral decline of 1.45 log 10 RNA copies/ml until 7 days after receiving N6-LS. While the pre-MAb virus did not harbor known viral escape mutations, a fixed mutation in position D/E279 in the D loop, which has been associated with N6 resistance (15), was present on day 14, when the animal developed viral rebound. In contrast, animal DEKM, which only fully suppressed viremia after 42 days following PGT121 administration, demonstrated 2 mutations in the V3 region, P/T309 and F/I316, at baseline while these mutations were not found in any of the other PGT121-monotreated animals.…”

“…potent and has substantially more breadth than VRC01 (15), which is currently under evaluation in phase 2b clinical studies (NCT02840474 and NCT02664415). N6 is also more potent than VRC01 against SHIV-SF162P3, comparable to the CD4bs antibody VRC07-523, but less potent than certain V3-glycan MAbs, including PGT121 (Table 1).…”