Structural definition of a conserved neutralization epitope on HIV-1 gp120

Zhou, Tongqing; Xu, Li; Dey, Barna; Hessell, Ann J.; Ryk, Donald Van; Xiang, Shi Hua; Yang, Xinzhen; Zhang, Meiyun; Zwick, Michael B.; Arthos, James; Burton, Dennis R.; Dimitrov, Dimiter S.; Sodroski, Joseph; Wyatt, Richard T.; Nabel, Gary J.; Kwong, Peter D.

doi:10.1038/nature05580

Cited by 708 publications

(975 citation statements)

References 47 publications

Supporting

Mentioning

937

Contrasting

Order By: Relevance

“…6C). This affinity is Ϸ2 orders of magnitude weaker than measured for the same mAb with gp120 from isolates HXB2 or YU2 (17), probably because of a sequence difference in the CD4-binding loop [P369L, HXB2 numbering, a residue that makes direct contact with b12 (17)]. In addition, the 92UG-gp140-Fd trimer does not bind two other ''nonneutralizing'' CD4-binding site antibodies, b6 and 15e, despite high affinities of these two antibod- ies for 92UG-gp120 core (Table 1 and SI Fig.…”

Section: Stable Conformations Of Hiv Envelope Glycoprotein Gp140 Trimentioning

confidence: 87%

A fusion-intermediate state of HIV-1 gp41 targeted by broadly neutralizing antibodies

Frey

Peng²,

Rits-Volloch³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

218

305

View full text Add to dashboard Cite

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. envelope glycoprotein ͉ membrane fusion H IV-1 infection generally induces a strong antibody response to the envelope glycoprotein [trimeric (gp160) 3 , cleaved to (gp120/gp41) 3 ], the sole antigen on the virion surface. Most induced antibodies are ineffective in preventing infection, however, because they are either nonneutralizing or narrowly isolate-specific, and the virus replicates so rapidly that ongoing selection of neutralization resistant mutants allows viral evolution to ''keep ahead'' of highaffinity antibody production (1). Moreover, much of the antibody response may be to rearranged or dissociated forms of gp120 and gp41, on which the dominant epitopes may be either in hypervariable loops or in positions occluded on virion-borne envelope trimer. Rare, ''broadly neutralizing'' antibodies have been detected that recognize one of three relatively conserved regions on the envelope protein: the CD4-binding site (mAb b12) (2); carbohydrates on the outer gp120 surface (mAb 2G12) (3); and a segment of the gp41 ectodomain adjacent to the viral membrane (mAbs 2F5 and 4E10) (4, 5), often called the ''membrane-proximal external region'' (MPER). We seek to understand the molecular mechanisms of neutralization by these and other antibodies.Fusion of viral and target-cell membranes initiates HIV-1 infection. Conformational changes in gp120 that accompany its binding to receptor (CD4) and coreceptor (e.g., CCR5 or CXCR4) lead to dissociation of gp120 from gp41 and a cascade of refolding events in the latter (6). In the course of these rearrangements, the N-terminal fusion peptide of gp41 translocates and inserts into the target-cell membrane. A proposed extended conformation of the gp41 ectodomain, with its fusion peptide thus inserted and the transmembrane anchor still in the viral membrane, has been called the ''prehairpin intermediate'' (7). It is the target of various fusion inhibitors, including T-20/enfuvirtide, the first approved fusioninhibiting antiviral drug (8), and the characteristics of the intermediate have been deduced from the properties of these inhibitors or mimicries by short gp41 fragments (9). Subsequent rearrangements from the intermediate to the postfusion state of gp41 involve ...

show abstract

Section: Stable Conformations Of Hiv Envelope Glycoprotein Gp140 Trimentioning

confidence: 87%

A fusion-intermediate state of HIV-1 gp41 targeted by broadly neutralizing antibodies

Frey

Peng²,

Rits-Volloch³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

218

305

View full text Add to dashboard Cite

show abstract

“…To further map the epitopes of the selected VHH, they were tested for their ability to compete with anti-CD4bs MAbs b12, 654-D, and GP68. Antibody b12 has been shown to bind to an epitope that overlaps a subset of the CD4bs (94). Human monoclonal antibodies 654-D and GP68 have been shown to compete with sCD4 for binding to recombinant gp120 but can only neutralize some T-cell-line-adapted isolates and not primary isolates (29,37,40,74).…”

Section: Fig 3 Percentage Of Hiv-1 Isolates Neutralized By the Vhh Andmentioning

confidence: 99%

“…Of these, only a handful have been found to be broadly neutralizing across HIV-1 subtypes (8), and have been the result of HIV-1 infection rather than immunization. Two of these are directed against gp120: MAb b12, which binds to an epitope that overlaps a subset of the CD4-binding site (CD4bs) of gp120 (3,10,11,68,94), and MAb 2G12, which recognizes a carbohydrate motif (9,70,72,80). Two broadly neutralizing MAbs, 4E10 and 2F5, recognize gp41 (9,56,77,96).…”

mentioning

confidence: 99%

Llama Antibody Fragments with Cross-Subtype Human Immunodeficiency Virus Type 1 (HIV-1)-Neutralizing Properties and High Affinity for HIV-1 gp120

Forsman

Beirnaert

Aasa-Chapman

et al. 2008

J Virol

111

138

View full text Add to dashboard Cite

Members of the Camelidae family produce immunoglobulins devoid of light chains. We have characterized variable domains of these heavy chain antibodies, the VHH, from llamas immunized with human immunodeficiency virus type 1 (HIV-1) envelope protein gp120 in order to identify VHH that can inhibit HIV-1 infection. To increase the chances of isolating neutralizing VHH, we employed a functional selection approach, involving panning of phage libraries expressing the VHH repertoire on recombinant gp120, followed by a competitive elution with soluble CD4. By immunizing with gp120 derived from an HIV-1 subtype B /C primary isolate, followed by panning on gp120 from HIV-1 isolates of subtypes A, B, and C, we could select for VHH with cross-subtype neutralizing activity. Three VHH able to neutralize HIV-1 primary isolates of subtypes B and C were characterized. These bound to recombinant gp120 with affinities close to the suggested affinity ceiling for in vivo-maturated antibodies and competed with soluble CD4 for this binding, indicating that their mechanism of neutralization involves interacting with the functional envelope spike prior to binding to CD4. The most potent VHH in terms of low 50% inhibitory concentration (IC 50 ) and IC 90 values and cross-subtype reactivity was A12. These results indicate that camelid VHH can be potent HIV-1 entry inhibitors. Since VHH are stable and can be produced at a relatively low cost, they may be considered for applications such as HIV-1 microbicide development. Antienvelope VHH might also prove useful in defining neutralizing and nonneutralizing epitopes on HIV-1 envelope proteins, with implications for HIV-1 vaccine design.

show abstract

“…This contrasts with the average 16 residues of CDRH3 in the antibodies elicited by other viral antigens [54,70]. The role of such long CDRH3 (18 residues) in b12, as a member of CD4 binding site antibodies, is to access a glycosylation site [71,72]. However, the CDRH3 in CD4bs BrNAbs are shorter than the glycan-related V1/V2 and V3 category.…”

Section: Bovine Cdrh3 Length Goes Beyond Expectationmentioning

confidence: 41%

Broad Neutralizing Antibodies to HIV Env and Other Complex Viral Antigens from Vaccinated Cows

Heydarchi¹,

Quiroz²,

Purcell³

2016

J Vaccines Vaccin

View full text Add to dashboard Cite

The idea of using antibodies to restrain HIV viral replication has been a growing interest since many years ago. HIV-patient serum with elite virus-neutralizing breadth has led to the preparation of broadly neutralizing antibodies (BrNAbs) with long and highly mutated CDRH3 domains that can neutralize a broad array of viral strains and prevent transmission in animal models. Recent advances have resulted in the discovery of BrNAbs that are more potent and can neutralize many HIV-1 subtypes. However, elicitation of these antibodies in infected individuals usually requires a long time of antigen exposure. Though BrNAbs are shown to be successful either therapeutically or prophylactically against HIV-1, production of these antibodies in bulk, commercial-sized batches are expensive and non-affordable particularly for poor countries. Therefore, more durable preventative or therapeutic strategies are required. Immunization of the cows with HIV Env is shown to be capable of producing 20 kg purified anti-HIV-1 BrNAbs and this amount could be sufficient for 2 million × 10 mg doses for formulation and pre-clinical testing as an HIV microbicide. In addition, bovine immunoglobulins typically have variable third heavy complementarity determining regions (CDRH3) that may potentially facilitate access to antigenic epitopes that are very difficult for other species to engage. Thus, cows could be engaged to elicit anti-HIV antibodies with the features of human BrNAbs and bovine colostrum could be a promising and cheap resource for the development of combination microbicides.

show abstract

Structural definition of a conserved neutralization epitope on HIV-1 gp120

Cited by 708 publications

References 47 publications

A fusion-intermediate state of HIV-1 gp41 targeted by broadly neutralizing antibodies

A fusion-intermediate state of HIV-1 gp41 targeted by broadly neutralizing antibodies

Llama Antibody Fragments with Cross-Subtype Human Immunodeficiency Virus Type 1 (HIV-1)-Neutralizing Properties and High Affinity for HIV-1 gp120

Broad Neutralizing Antibodies to HIV Env and Other Complex Viral Antigens from Vaccinated Cows

Contact Info

Product

Resources

About