S021-05 OA. Broadly neutralizing anti-HIV-1 antibodies disrupt a hinge-related function of gp41 at the membrane interface
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ABSTRACT:
SUBMITTER: Song L
PROVIDER: S-EPMC2767573 | biostudies-literature | 2009 Jan
REPOSITORIES: biostudies-literature
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Project description:A vaccine capable of stimulating protective antiviral antibody responses is needed to curtail the global AIDS epidemic caused by HIV-1. Although rarely elicited during the course of natural infection or upon conventional vaccination, the membrane-proximal ectodomain region (MPER) of the HIV-1 glycoprotein of M(r) 41,000 (gp41) envelope protein subunit is the target of 3 such human broadly neutralizing antibodies (BNAbs): 4E10, 2F5, and Z13e1. How these BNAbs bind to their lipid-embedded epitopes and mediate antiviral activity is unclear, but such information might offer important insight into a worldwide health imperative. Here, EPR and NMR techniques were used to define the manner in which these BNAbs differentially recognize viral membrane-encrypted residues configured within the L-shaped helix-hinge-helix MPER segment. Two distinct modes of antibody-mediated interference of viral infection were identified. 2F5, like 4E10, induces large conformational changes in the MPER relative to the membrane. However, although 4E10 straddles the hinge and extracts residues W672 and F673, 2F5 lifts up residues N-terminal to the hinge region, exposing L669 and W670. In contrast, Z13e1 effects little change in membrane orientation or conformation, but rather immobilizes the MPER hinge through extensive rigidifying surface contacts. Thus, BNAbs disrupt HIV-1 MPER fusogenic functions critical for virus entry into human CD4 T cells and macrophages either by preventing hinge motion or by perturbing MPER orientation. HIV-1 MPER features important for targeted vaccine design have been revealed, the implications of which extend to BNAb targets on other viral fusion proteins.
| S-EPMC2690059 | biostudies-literature
Project description:The identification and epitope mapping of broadly neutralizing anti-human immunodeficiency virus type 1 (HIV-1) antibodies (Abs) is important for vaccine design, but, despite much effort, very few such Abs have been forthcoming. Only one broadly neutralizing anti-gp41 monoclonal Ab (MAb), 2F5, has been described. Here we report on two MAbs that recognize a region immediately C-terminal of the 2F5 epitope. Both MAbs were generated from HIV-1-seropositive donors, one (Z13) from an antibody phage display library, and one (4E10) as a hybridoma. Both MAbs recognize a predominantly linear and relatively conserved epitope, compete with each other for binding to synthetic peptide derived from gp41, and bind to HIV-1(MN) virions. By flow cytometry, these MAbs appear to bind relatively weakly to infected cells and this binding is not perturbed by pretreatment of the infected cells with soluble CD4. Despite the apparent linear nature of the epitopes of Z13 and 4E10, denaturation of recombinant envelope protein reduces the binding of these MAbs, suggesting some conformational requirements for full epitope expression. Most significantly, Z13 and 4E10 are able to neutralize selected primary isolates from diverse subtypes of HIV-1 (e.g., subtypes B, C, and E). The results suggest that a rather extensive region of gp41 close to the transmembrane domain is accessible to neutralizing Abs and could form a useful target for vaccine design.
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Project description:Most antibodies induced by HIV-1 are ineffective at preventing initiation or spread of infection because they are either nonneutralizing or narrowly isolate-specific. Rare, "broadly neutralizing" antibodies have been detected that recognize relatively conserved regions on the envelope glycoprotein. Using stringently characterized, homogeneous preparations of trimeric HIV-1 envelope protein in relevant conformations, we have analyzed the molecular mechanism of neutralization by two of these antibodies, 2F5 and 4E10. We find that their epitopes, in the membrane-proximal segment of the envelope protein ectodomain, are exposed only on a form designed to mimic an intermediate state during viral entry. These results help explain the rarity of 2F5- and 4E10-like antibody responses and suggest a strategy for eliciting them.
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Project description:This SuperSeries is composed of the SubSeries listed below.
2024-06-04 | GSE229123 | GEO
Project description:We generated the humoral immune repertoire of circulating memory B cells from healthy and HIV infected immune donors. These repertoires were used to predict specific HIV antibodies directed against gp120/gp41.
2024-06-04 | GSE229122 | GEO
Project description:We generated the humoral immune repertoire of circulating memory B cells from healthy and HIV infected immune donors. These repertoires were used to predict specific HIV antibodies directed against gp120/gp41.
2024-06-04 | GSE228912 | GEO
Project description:We generated the humoral immune repertoire of circulating memory B cells from healthy and HIV infected immune donors. These repertoires were used to predict specific HIV antibodies directed against gp120/gp41.
2024-06-04 | GSE229121 | GEO
Project description:Prediction of broadly neutralizing antibodies
| PRJNA952996 | ENA
Project description:A goal of HIV-1 vaccine development is to elicit broadly neutralizing Abs (BnAbs), but current immunization strategies fail to induce BnAbs, and for unknown reasons, often induce nonneutralizing Abs instead. To explore potential host genetic contributions controlling Ab responses to the HIV-1 Envelope, we have used congenic strains to identify a critical role for MHC class II restriction in modulating Ab responses to the membrane proximal external region (MPER) of gp41, a key vaccine target. Immunized H-2(d)-congenic strains had more rapid, sustained, and elevated MPER(+) Ab titers than those bearing other haplotypes, regardless of immunogen, adjuvant, or prime or boost regimen used, including formulations designed to provide T cell help. H-2(d)-restricted MPER(+) serum Ab responses depended on CD4 TH interactions with class II (as revealed in immunized intra-H-2(d/b) congenic or CD154(-/-) H-2(d) strains, and by selective abrogation of MPER restimulated, H-2(d)-restricted primed splenocytes by class II-blocking Abs), and failed to neutralize HIV-1 in the TZM-b/l neutralization assay, coinciding with lack of specificity for an aspartate residue in the neutralization core of BnAb 2F5. Unexpectedly, H-2(d)-restricted MPER(+) responses functionally mapped to a core TH epitope partially overlapping the 2F5/z13/4E10 BnAb epitopes as well as nonneutralizing B cell-Ab binding residues. We propose that class II restriction contributes to the general heterogeneity of nonneutralizing gp41 responses induced by Envelope. Moreover, the proximity of TH and B cell epitopes in this restriction may have to be considered in redesigning minimal MPER immunogens aimed at exclusively binding BnAb epitopes and triggering MPER(+) BnAbs.
| S-EPMC3936991 | biostudies-literature
Project description:HIV-1 vaccine research has obtained an enormous boost since the discovery of many broadly neutralizing antibodies (bnAbs) targeting all accessible sites on the HIV-1 envelope glycoprotein (Env). This in turn facilitated high-resolution structures of the Env glycoprotein in complex with bnAbs. Here we focus on gp41, its highly conserved heptad repeat region 1 (HR1), the fusion peptide (FP) and the membrane-proximal external region (MPER). Notably, the broadest neutralizing antibodies target MPER. Both gp41 HR1 and MPER are only fully accessible once receptor-induced conformational changes have taken place, although some studies suggest access to MPER in the close to native Env conformation. We summarize the data on the structure and function of neutralizing antibodies targeting gp41 HR1, FP and MPER and we review their access to Env and their complex formation with gp41 HR1, MPER peptides and FP within native Env. We further discuss MPER bnAb binding to lipids and the role of somatic mutations in recognizing a bipartite epitope composed of the conserved MPER sequence and membrane components. The problematic of gp41 HR1 access and MPER bnAb auto- and polyreactivity is developed in the light of inducing such antibodies by vaccination.
| S-EPMC7690876 | biostudies-literature