Research Article

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

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Science  08 Jan 2021:
Vol. 371, Issue 6525, eabd2638
DOI: 10.1126/science.abd2638

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Convergent HIV evolution across species

Human immunodeficiency virus (HIV) has a highly diverse envelope protein that it uses to target human cells, and the complexity of the viral envelope has stymied vaccine development. Roark et al. report that the immediate and short-term evolutionary potential of the HIV envelope is constrained because of a number of essential functions, including antibody escape. Consequently, when introduced into humans as HIV or into rhesus macaque monkeys as chimeric simian-human immunodeficiency virus, homologous envelope glycoproteins appear to exhibit conserved patterns of sequence evolution, in some cases eliciting broadly neutralizing antibodies in both hosts. Conserved patterns of envelope variation and homologous B cell responses in humans and monkeys represent examples of convergent evolution that may serve to guide HIV vaccine development.

Science, this issue p. eabd2638

Structured Abstract

INTRODUCTION

It is widely believed that the development of an effective neutralizing antibody–based HIV-1 vaccine will require consistent activation of multiple germline precursor B cells that express immunoglobulin receptors specific for one or more of the canonical broadly neutralizing antibody (bNAb) epitope clusters, followed by efficient antigen-driven selection for antibody affinity maturation. How to accomplish this feat by immunization has proven to be a daunting scientific challenge. One roadblock to rational HIV-1 vaccine design is the lack of a suitable outbred primate model in which bNAbs can be commonly induced, thereby enabling the molecular, biological, and immunological mechanisms responsible for such responses to be studied in a reproducible and iterative fashion.

RATIONALE

Given that most HIV-1 bNAbs identified to date have come from humans chronically infected by HIV-1, we hypothesized that one means to elicit such antibodies in primates might be by infecting rhesus macaques (RMs) with simian-human immunodeficiency virus (SHIV) strains that bear primary HIV-1 envelope proteins (Envs), including those that induced bNAbs in humans. SHIV-infected RMs could then be used to assess the potential of particular HIV-1 Envs to elicit bNAbs and to characterize the coevolutionary pathways of bNAb lineages and the cognate Env intermediates that elicited them, thus serving as a molecular guide for rational vaccine design. Recent innovations in SHIV design make this experimental strategy testable.

RESULTS

Neutralizing antibodies elicited by HIV-1 in naturally infected humans coevolve with viral Envs in distinctive molecular patterns, in some cases acquiring substantial breadth. We constructed SHIVs bearing primary transmitted/founder Envs from three HIV–1 infected humans who developed bNAbs and used these SHIVs to infect 22 RMs. Seven monkeys developed bNAbs that exhibited a wide range of breadth and potency. Unexpectedly, SHIV infections elicited molecular patterns of Env-antibody coevolution in monkeys that mirrored what was seen in humans infected by HIV-1 strains bearing homologous Envs. Similarities included conserved immunogenetic, structural, and chemical solutions to epitope recognition and precise Env–amino acid substitutions, insertions, and deletions leading to virus persistence. One rhesus antibody, capable of neutralizing 49% of a 208-strain global virus panel, contained a 24–amino acid heavy chain complementarity-determining region 3 (HCDR3) with a sulfated tyrosine at its tip; this rhesus bNAb exhibited a V2 apex mode of recognition similar to human bNAbs PGT145 and PCT64-35S, with critical interactions involving lysine or arginine residues at Env positions 121, 166, and 169 and an N-linked glycan at position 160. Another rhesus antibody bound the CD4 binding site by CD4 mimicry mirroring human bNAbs 8ANC131, CH235, and VRC01. In other SHIV-infected animals, bNAb responses targeted a canonical V3 high mannose patch epitope cluster that included Env residues 324GDIR327 and N332. Molecular patterns of epitope evolution enabling virus escape, and at the same time promoting bNAb affinity maturation, were similar in SHIV-infected RMs and HIV-1–infected humans.

CONCLUSION

SHIV infection of RMs is the only model system other than naturally infected humans where the immunogen (Env) coevolves with neutralizing antibodies. The high mutability and dynamic replication of HIV-1 and SHIV in vivo result in a constantly evolving virus quasispecies, which means that Envs with binding affinities sufficient to drive bNAb lineage affinity maturation are continuously being generated. SHIV-infected macaques may thus provide insights for vaccine design by enabling the identification of Env intermediates that can guide the evolution of precursor B cells through stages of affinity maturation leading to breadth and potency.

Envelope-antibody coevolution in monkey and human.

Env-antibody coevolution in SHIV-infected rhesus macaques mirrors that in HIV-1–infected humans, including the elicitation of broadly neutralizing antibodies. The illustration depicts a mirror with images, left to right, of organism, longitudinal changes in viral Env sequence, Env trimer recognition by virus-elicited broadly neutralizing antibodies, and atomic-level details of paratope–epitope interactions.

IMAGE: J. GORMAN, NIH

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 very similar to those in humans, including 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 broadly neutralizing antibodies (bNAbs) PGT145 and PCT64-35S. Another rhesus antibody bound the CD4 binding site by CD4 mimicry, mirroring human bNAbs 8ANC131, CH235, and VRC01. Virus-antibody coevolution in macaques can thus recapitulate developmental features of human bNAbs, thereby guiding HIV-1 immunogen design.

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