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The Chimpanzee SIV Envelope Trimer: Structure and Deployment as an HIV Vaccine Template.

ABSTRACT: Epitope-targeted HIV vaccine design seeks to focus antibody responses to broadly neutralizing antibody (bnAb) sites by sequential immunization. A chimpanzee simian immunodeficiency virus (SIV) envelope (Env) shares a single bnAb site, the variable loop 2 (V2)-apex, with HIV, suggesting its possible utility in an HIV immunization strategy. Here, we generate a chimpanzee SIV Env trimer, MT145K, which displays selective binding to HIV V2-apex bnAbs and precursor versions, but no binding to other HIV specificities. We determine the structure of the MT145K trimer by cryo-EM and show that its architecture is remarkably similar to HIV Env. Immunization of an HIV V2-apex bnAb precursor Ab-expressing knockin mouse with the chimpanzee MT145K trimer induces HIV V2-specific neutralizing responses. Subsequent boosting with an HIV trimer cocktail induces responses that exhibit some virus cross-neutralization. Overall, the chimpanzee MT145K trimer behaves as expected from design both in vitro and in vivo and is an attractive potential component of a sequential immunization regimen to induce V2-apex bnAbs.

SUBMITTER: Andrabi R

PROVIDER: S-EPMC6533203 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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The Chimpanzee SIV Envelope Trimer: Structure and Deployment as an HIV Vaccine Template.

Andrabi Raiees R Pallesen Jesper J Allen Joel D JD Song Ge G Zhang Jinsong J de Val Natalia N Gegg Gavin G Porter Katelyn K Su Ching-Yao CY Pauthner Matthias M Newman Amanda A Bouton-Verville Hilary H Garces Fernando F Wilson Ian A IA Crispin Max M Hahn Beatrice H BH Haynes Barton F BF Verkoczy Laurent L Ward Andrew B AB Burton Dennis R DR

Cell reports 20190501 8

Epitope-targeted HIV vaccine design seeks to focus antibody responses to broadly neutralizing antibody (bnAb) sites by sequential immunization. A chimpanzee simian immunodeficiency virus (SIV) envelope (Env) shares a single bnAb site, the variable loop 2 (V2)-apex, with HIV, suggesting its possible utility in an HIV immunization strategy. Here, we generate a chimpanzee SIV Env trimer, MT145K, which displays selective binding to HIV V2-apex bnAbs and precursor versions, but no binding to other HI ...[more]

PMID: 31116986

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Project description:IntroductionThe development of a human immunodeficiency virus 1 (HIV-1) vaccine remains a formidable challenge. An effective vaccine likely requires the induction of broadly neutralizing antibodies (bNAbs), which likely involves the use of native-like HIV-1 envelope (Env) trimers at some or all stages of vaccination. Development of such trimers has been very difficult, but much progress has been made in the past decade, starting with the BG505 SOSIP trimer, elucidation of its atomic structure and implementing subsequent design iterations. This progress facilitated understanding the weaknesses of the Env trimer, fuelled structure-guided HIV-1 vaccine design and assisted in the development of new vaccine designs. This review summarizes the relevant literature focusing on studies using structural biology to reveal and define HIV-1 Env sites of vulnerability; to improve Env trimers, by creating more stable versions; understanding antibody responses in preclinical vaccination studies at the atomic level; understanding the glycan shield; and to improve "on-target" antibody responses versus "off-target" responses.MethodsThe authors conducted a narrative review of recently published articles that made a major contribution to HIV-1 structural biology and vaccine design efforts between the years 2000 and 2021.DiscussionThe field of structural biology is evolving at an unprecedented pace, where cryo-electron microscopy (cryo-EM) and X-ray crystallography provide complementary information. Resolving protein structures is necessary for defining which Env surfaces are accessible for the immune system and can be targeted by neutralizing antibodies. Recently developed techniques, such as electron microscopy-based polyclonal epitope mapping (EMPEM) are revolutionizing the way we are analysing immune responses and shed light on the immunodominant targets on new vaccine immunogens. Such information accelerates iterative vaccine design; for example, by reducing undesirable off-target responses, while improving immunogens to drive the more desirable on-target responses.ConclusionsResolving high-resolution structures of the HIV-1 Env trimer was instrumental in understanding and improving recombinant HIV-1 Env trimers that mimic the structure of viral HIV-1 Env spikes. Newly emerging techniques in structural biology are aiding vaccine design efforts and improving immunogens. The role of structural biology in HIV-1 vaccine design has indeed become very prominent and is unlikely to diminish any time soon.

Project description:HIV-1 envelope (Env) glycoprotein gp160 exists as a trimer of heterodimers on the viral surface. In most structures of the soluble ectodomain of trimeric HIV-1 envelope glycoprotein, the regions from 512 to 517 of the fusion peptide and from 547 to 568 of the N-heptad repeat are disordered. We used aspartate scanning mutagenesis of subtype B strain JRFL Env as an alternate method to probe residue burial in the context of cleaved, cell surface-expressed Env, as buried residues should be intolerant to substitution with Asp. The data are inconsistent with a fully disordered 547 to 568 stretch, as residues 548, 549, 550, 555, 556, 559, 562, and 566 to 569 are all sensitive to Asp substitution. In the fusion peptide region, residues 513 and 515 were also sensitive to Asp substitution, suggesting that the fusion peptide may not be fully exposed in native Env. gp41 is metastable in the context of native trimer. Introduction of Asp at residues that are exposed in the prefusion state but buried in the postfusion state is expected to destabilize the postfusion state and any intermediate states where the residue is buried. We therefore performed soluble CD4 (sCD4)-induced gp120 shedding experiments to identify Asp mutants at residues 551, 554 to 559, 561 to 567, and 569 that could prevent gp120 shedding. We also observed similar mutational effects on shedding for equivalent mutants in the context of clade C Env from isolate 4-2J.41. These substitutions can potentially be used to stabilize native-like trimer derivatives that are used as HIV-1 vaccine immunogens.IMPORTANCE In most crystal structures of the soluble ectodomain of the HIV-1 Env trimer, some residues in the fusion and N-heptad repeat regions are disordered. Whether this is true in the context of native, functional Env on the virion surface is not known. This knowledge may be useful for stabilizing Env in its prefusion conformation and will also help to improve understanding of the viral entry process. Burial of the charged residue Asp in a protein structure is highly destabilizing. We therefore used Asp scanning mutagenesis to probe the burial of apparently disordered residues in native Env and to examine the effect of mutations in these regions on Env stability and conformation as probed by antibody binding to cell surface-expressed Env, CD4-induced shedding of HIV-1 gp120, and viral infectivity studies. Mutations that prevent shedding can potentially be used to stabilize native-like Env constructs for use as vaccine immunogens.

Dataset Information

The Chimpanzee SIV Envelope Trimer: Structure and Deployment as an HIV Vaccine Template.

Publications

The Chimpanzee SIV Envelope Trimer: Structure and Deployment as an HIV Vaccine Template.

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