Recapitulation of HIV-1 Env-Antibody Coevolution in Macaques Leading to Neutralization Breadth

Abstract

Neutralizing antibodies elicited by HIV-1 coevolve with viral Envs in distinctive patterns, in some cases acquiring substantial breadth. Here we show that primary HIV-1 Envs, when expressed by simian-human immunodeficiency viruses in rhesus macaques, elicited patterns of Env-antibody coevolution strikingly similar to those in humans. This included conserved immunogenetic, structural and chemical solutions to epitope recognition and precise Env-amino acid substitutions, insertions and deletions leading to virus persistence. The structure of one rhesus antibody, capable of neutralizing 49% of a 208-strain panel, revealed a V2-apex mode of recognition like that of human bNAbs PGT145/PCT64-35M. Another rhesus antibody bound the CD4-binding site by CD4 mimicry mirroring human bNAbs 8ANC131/CH235/VRC01. Virus-antibody coevolution in macaques can thus recapitulate developmental features of human bNAbs, thereby guiding HIV-1 immunogen design.One sentence summaryVirus-antibody coevolution in rhesus macaques recapitulates developmental features of human antibodies.

New SHIVs and Improved Design Strategy for Modeling HIV-1 Transmission, Immunopathogenesis, Prevention and Cure

“…These Envs were selected based on their genetic subtypes, biophysical properties, derivation from primary or T/F virus strains, and in some cases, prior development as candidate vaccine strains for human clinical trials (see Table 1 for Env features and relevant literature citations). Env subtypes included A, B, C, AE and AG, which complement subtype A, B, C and D SHIVs that we reported previously [see (35, 38); Table 1B ). All ten of the new SHIVs contained Envs from tier 2 viruses except for Q23.17 Env (39), which has been variably classified as tier 1b or 2 (40–42).…”

“…Envs T250, ZM233, WITO, Q23.17 and CAP256SU were shown previously to bind unmutated common ancestors (UCAs) of human V2 apex targeted bNAbs (52–54). Thus, the Envs selected for new SHIV constructions exhibited unique pedigrees complementary to previous SHIV designs (35, 38, 55–64) that made them desirable for downstream investigations related to HIV-1 transmission, prevention, immunopathogenesis or cure.…”

“…We also found in SHIV infected RMs that redundant HIV-1 tat1 and env gp41 sequences of 68 and 21 bp in length, respectively, that were generated as a consequence of the original cloning strategy underwent spontaneous deletion [ Figs. 1A and S1; (35, 38)]. Thus, we modified the SIVmac766 backbone vector and amplification primers to simplify the PCR amplification step and eliminate the redundant sequences ( Fig.…”

“…Importantly, these amino acid substitutions at residue 375 did not alter the tier 2 neutralization phenotype of the primary Envs nor did they appreciably alter their sensitivity to bNAbs that targeted any of the canonical bNAb recognition sites, including CD4bs, V2 apex, V3 high mannose patch or membrane proximal external region (35). Thus, it became possible, for the first time, to prospectively design SHIVs that expressed particular primary or T/F Envs, including those that elicited bNAbs in HIV-1 infected humans, and to explore parallels in the immune responses of rhesus monkeys and humans to essentially identical Env immunogens (38). This EnvΔ375 design strategy also made possible the development of SHIVs to evaluate preclinical efficacy of novel active or passive vaccination regimens against challenge by viruses bearing homologous or heterologous primary Envs (7–10).…”

A broadly neutralizing macaque monoclonal antibody against the HIV-1 V3-Glycan patch

“…Monoclonal antibody Ab1485 resembles human bNAbs in many important respects including the high levels of somatic mutation suggesting a requirement for sequential interaction between B cells and the virus to drive bNAb evolution in macaques. This process of virus and antibody co-evolution has been recently shown in macaques in a study by Roark and colleagues (preprint in bioRxiv, Roark et al, 2020 ). Their work shows that infection with SHIVs bearing the Envs of transmitted founder (T/F) HIV-1 viruses that induced bNAbs in humans, recapitulates key events of the previously reported interplay between HIV-1 and antibodies in the infected individuals.…”