Distinct conformational states of HIV-1 gp41 are recognized by neutralizing and non-neutralizing antibodies

Frey, Gary; Chen, Jia; Rits-Volloch, Sophia; Freeman, Michael; Zolla‐Pazner, Susan; Chen, Bing

doi:10.1038/nsmb.1950

Cited by 82 publications

(101 citation statements)

References 59 publications

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“…6b). This observation was in line with the finding that the gp41 MPER is most accessible in a fusion intermediate state after attachment of gp120 to its cellular receptors [65,66]. Thus, at least antisera with MPER specificity seemed to be able to react with native Env as mandatory for virus neutralisation.…”

Section: Binding Of Induced Antibodies To Infected Cellssupporting

confidence: 77%

Immunisation with foamy virus Bet fusion proteins as novel strategy for HIV-1 epitope delivery

et al. 2013

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The induction of 2F5-and 4E10-like antibodies broadly neutralising HIV-1 and targeting the membrane external proximal region (MPER) of the transmembrane envelope protein gp41 would be a major advancement for the development of a preventive HIV-1 vaccine but successful attempts remain rare. Recent studies demonstrated that broadly reactive antibodies develop relatively late during infection and after intensive affinity maturation. Therefore, a prolonged antigen delivery might be beneficial to induce them. Replicating foamy viruses which are characterised by apathogenic but persistent infection could represent suitable carrier viruses for this purpose. In order to develop such a system, we modified the accessory foamy virus Bet protein to contain the MPER of gp41, or the MPER linked to the stabilising fusion peptide proximal region (FPPR) of gp41 and analysed here the antigenic and immunogenic properties of such hybrid proteins. The antigens, expressed and purified to homogeneity, were recognised by the monoclonal antibodies 2F5 and 4E10 with nanomolar affinities and induced high levels of antibodies specific for gp41 after immunisation of rats. The antisera also bound to virus particles attached to infected cells and peptide-based epitope mapping showed that they recognised the 2F5 epitope. Although no HIV-1 neutralising activity was observed, the presented data demonstrate that using the foamy virus Bet for HIV-1 epitope delivery is successfully applicable. Together with the attractive potential for sustained antigen expression after transfer to replicating virus, these results should therefore provide a first basis for the development of chimeric foamy viruses as novel HIV-1 vaccine vectors.

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Section: Binding Of Induced Antibodies To Infected Cellssupporting

confidence: 77%

Immunisation with foamy virus Bet fusion proteins as novel strategy for HIV-1 epitope delivery

et al. 2013

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“…1B). Consistent with this hypothesis, these mAbs have the highest affinity to the prehairpin gp41 intermediate (30,31). If the trimeric Soc-gp41M-Fd and Socgp41ectoM-Fd have a prehairpin structure, they should bind to 2F5 and 4E10 mAbs at high affinity and inhibit their ability to neutralize HIV-1 infection.…”

Section: Neutralizing Mper Epitopes Are Well Exposed In Gp41supporting

confidence: 53%

“…Consistent with this prediction, a 34-aa HR2 peptide bound to the gp41 trimers, and the oligomerization pattern was identical with or without the peptide. The gp41 trimers did not bind to NC-1 mAb that is specific to hexahelical bundle structure but bound strongly to bnAbs 2F5 and 4E10 that have the highest affinity to the prehairpin structure (30,31). The trimers potently inhibited 2F5 and 4E10 virus neutralization even at an equimolar ratio of gp41 to mAb and in the presence of excess virus, suggesting that the MPER epitopes are well exposed, as would be expected in a prehairpin intermediate (30,31).…”

Section: Discussionmentioning

confidence: 88%

“…Mutations-Introduction of mutations that disrupt intramolecular HR1-HR2 interactions should disfavor the formation of hexa-helical bundle and stabilize gp41 in a prehairpin intermediate structure, where the chains would be held by intermolecular HR1-HR1 interactions and the MPER epitopes would be better exposed (30,31).…”

Section: Resultsmentioning

confidence: 99%

“…The prehairpin intermediate is one such target because it is relatively stable with a half-life on the order of several minutes (19) and its ectodomain most extended and the conserved neutralization epitopes most exposed (Fig. 1B) (30,31,62,63). Indeed, Enfuvirtide, a potent 20-aa entry inhibitor approved for clinical use (64), and a series of bnAbs, such as 2F5 and 4E10, arrest virus entry by binding to this intermediate.…”

Section: Discussionmentioning

confidence: 99%

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Designing a Soluble Near Full-length HIV-1 gp41 Trimer

Gao

Wieczorek

Peachman

et al. 2013

Journal of Biological Chemistry

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Background:The envelope glycoprotein gp41 is a key component of HIV-1 virus entry into host cells. Results: Structure-based mutagenesis and biochemical approaches lead to the design of soluble gp41 trimers. Conclusion: Trimers are in a prehairpin structure, similar to that observed during virus entry. Significance: The new gp41 recombinants could lead to the development of novel diagnostics, therapeutics, and vaccines.

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Preclinical development of a molecular clamp‐stabilised subunit vaccine for severe acute respiratory syndrome coronavirus 2

et al. 2021

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Objectives Efforts to develop and deploy effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) continue at pace. Here, we describe rational antigen design through to manufacturability and vaccine efficacy of a prefusion‐stabilised spike (S) protein, Sclamp, in combination with the licensed adjuvant MF59 ‘MF59C.1’ (Seqirus, Parkville, Australia). Methods A panel recombinant Sclamp proteins were produced in Chinese hamster ovary and screened in vitro to select a lead vaccine candidate. The structure of this antigen was determined by cryo‐electron microscopy and assessed in mouse immunogenicity studies, hamster challenge studies and safety and toxicology studies in rat. Results In mice, the Sclamp vaccine elicits high levels of neutralising antibodies, as well as broadly reactive and polyfunctional S‐specific CD4 + and cytotoxic CD8 + T cells in vivo . In the Syrian hamster challenge model ( n = 70), vaccination results in reduced viral load within the lung, protection from pulmonary disease and decreased viral shedding in daily throat swabs which correlated strongly with the neutralising antibody level. Conclusion The SARS‐CoV‐2 Sclamp vaccine candidate is compatible with large‐scale commercial manufacture, stable at 2–8°C. When formulated with MF59 adjuvant, it elicits neutralising antibodies and T‐cell responses and provides protection in animal challenge models.

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Distinct conformational states of HIV-1 gp41 are recognized by neutralizing and non-neutralizing antibodies

Cited by 82 publications

References 59 publications

Immunisation with foamy virus Bet fusion proteins as novel strategy for HIV-1 epitope delivery

Immunisation with foamy virus Bet fusion proteins as novel strategy for HIV-1 epitope delivery

Designing a Soluble Near Full-length HIV-1 gp41 Trimer

Preclinical development of a molecular clamp‐stabilised subunit vaccine for severe acute respiratory syndrome coronavirus 2

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