Recapitulation of HIV-1 Env-antibody coevolution in macaques leading to neutralization breadth

Abstract

Neutralizing antibodies elicited by HIV-1 coevolve with viral envelope proteins (Env) in distinctive patterns, in some cases acquiring substantial breadth. We report that primary HIV-1 envelope proteins—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-am ino 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/PCT64-35S. 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.

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)(41)(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)(53)(54). Thus, the Envs selected for new SHIV constructions exhibited unique pedigrees complementary to 8 previous SHIV designs (35,38,(55)(56)(57)(58)(59)(60)(61)(62)(63)(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.…”

“…These results thus corroborate and extend a substantial body of scientific literature indicating that SHIVs bearing primary (non-adapted) wildtype HIV-1 Envs rarely replicate efficiently in rhesus cells (1-3, 27-29, 35, 38, 65, 66) and that this restriction can be lifted by substituting a single amino acid at position Env375. In our combined studies [this manuscript plus (35,38)], we replaced wildtype Env375 residues in 16 primary HIV-1 Envs -15 of which could not support SHIV replication in RMs -and found in all instances that this substitution alone led to efficient SHIV replication in rhesus animals.…”

“…and env gp41 sequences (68 and 21 bp, respectively) were spontaneously deleted following prolonged in vivo replication [ Fig. S1; (35,38)]. This suggested a fitness disadvantage for viruses containing the redundant sequences, leading us to hypothesize that animals infected by an equal mixture of the viruses derived from the two designs would show preferential replication by viruses lacking the redundant sequences.…”