Another discontinuous epitope on glycoprotein gp120 that is important in human immunodeficiency virus type 1 neutralization is identified by a monoclonal antibody.

Ho, David D.; Fung, Michael; Cao, Yunzhen; Li, Xi Ling; Sun, Chengyu; Chang, Tse Wen; Sun, N. C.

doi:10.1073/pnas.88.20.8949

Cited by 127 publications

(124 citation statements)

References 22 publications

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“…Unlike previously described mAbs against linear epitopes in V2 (47, 60), 8.22.2 was moderately cross-reactive, recognizing all three clade B R5 rgp120s tested. Other cross-reactive mAbs directed against V2 have been described, but those are directed against conformational epitopes that depend on the disulfide-bonded structure of the domain (23,61,62). Furthermore, 8.22.2 had more potent neutralizing activity against the R5 HIV SF162 isolate than 697D, the V2-directed hu-mAb previously reported to neutralize primary virus isolates (23).…”

Section: Figurementioning

confidence: 99%

Efficient Isolation of Novel Human Monoclonal Antibodies with Neutralizing Activity Against HIV-1 from Transgenic Mice Expressing Human Ig Loci

He¹,

Honnen²,

Krachmarov³

et al. 2002

The Journal of Immunology

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Despite considerable interest in the isolation of mAbs with potent neutralization activity against primary HIV-1 isolates, both for identifying useful targets for vaccine development and for the development of therapeutically useful reagents against HIV-1 infection, a relatively limited number of such reagents have been isolated to date. Human mAbs (hu-mAbs) are preferable to rodent mAbs for treatment of humans, but isolation of hu-mAbs from HIV-infected subjects by standard methods of EBV transformation of B cells or phage display of Ig libraries is inefficient and limited by the inability to control or define the original immunogen. An alternative approach for the isolation of hu-mAbs has been provided by the development of transgenic mice that produce fully hu-mAbs. In this report, we show that immunizing the XenoMouse G2 strain with native recombinant gp120 derived from HIVSF162 resulted in robust humoral Ab responses against gp120 and allowed the efficient isolation of hybridomas producing specific hu-mAbs directed against multiple regions and epitopes of gp120. hu-mAbs possessing strong neutralizing activity against the autologous HIVSF162 strain were obtained. The epitopes recognized were located in three previously described neutralization domains, the V2-, V3- and CD4-binding domains, and in a novel neutralization domain, the highly variable C-terminal region of the V1 loop. This is the first report of neutralizing mAbs directed at targets in the V1 region. Furthermore, the V2 and V3 epitopes recognized by neutralizing hu-mAbs were distinct from those of previously described human and rodent mAbs and included an epitope requiring a full length V3 loop peptide for effective presentation. These results further our understanding of neutralization targets for primary, R5 HIV-1 viruses and demonstrate the utility of the XenoMouse system for identifying new and interesting epitopes on HIV-1.

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Section: Figurementioning

confidence: 99%

Efficient Isolation of Novel Human Monoclonal Antibodies with Neutralizing Activity Against HIV-1 from Transgenic Mice Expressing Human Ig Loci

He¹,

Honnen²,

Krachmarov³

et al. 2002

The Journal of Immunology

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“…In addition to their roles in epitope masking, the V1 and V2 domains contain neutralization epitopes (11,13,15,16,23,24,32,38). The general interest in such MAbs has been limited due to their restricted specificities and, in most cases, relatively weak neutralizing activities.…”

mentioning

confidence: 99%

Type-Specific Epitopes Targeted by Monoclonal Antibodies with Exceptionally Potent Neutralizing Activities for Selected Strains of Human Immunodeficiency Virus Type 1 Map to a Common Region of the V2 Domain of gp120 and Differ Only at Single Positions from the Clade B Consensus Sequence

Honnen

Krachmarov

Kayman³

et al. 2007

J Virol

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Only a few monoclonal antibodies (MAbs) have been isolated that recognize conserved sites in human immunodeficiency virus type 1 (HIV-1) Env proteins and possess broad neutralizing activities. Other MAbs directed against targets in various domains of Env have been described that are strongly neutralizing, but they possess limited breadth. One such MAb, 2909, possesses a uniquely potent neutralizing activity specific for a quaternary epitope on SF162 Env that requires the presence of both the V2 and the V3 domains. We now show that replacement of the SF162 V3 sequence with consensus V3 sequences of multiple subtypes led to attenuated but still potent neutralization by 2909 and that the main determinants for the type specificity of 2909 reside in the V2 domain. A substitution at position 160 completely eliminated 2909 reactivity, and mutations at position 167 either attenuated or potentiated neutralization by this antibody. Different substitutions at the same positions in V2 were previously shown to introduce epitopes recognized by MAbs 10/76b and C108g and to allow potent neutralization by these MAbs. Two substitutions at key positions in the V2 domain of JR-FL Env also allowed potent expression of the 2909 epitope, and single substitutions in YU2 V2 were sufficient for expression of the 2909, C108g, and 10/76b epitopes. These results demonstrate that the minimal epitopes for 2909, C108g, and 10/76b differed from that of the clade B consensus sequence only at single positions and suggest that all three MAbs recognize distinct variants of a relatively conserved sequence in V2 that is a particularly sensitive mediator of HIV-1 neutralization.A major factor thwarting the development of a successful human immunodeficiency virus type 1 (HIV-1) vaccine is the resistance of primary isolates to neutralization by classes of antibodies commonly induced after infection or immunization (1, 45). Sequence variability at major neutralization sites contributes to this effect, but recent evidence argues that the major factor in this resistance is conformational shielding of susceptible epitopes in the native oligomeric complex (18,28). Nlinked glycans located in various regions of Env play a general role in epitope masking (6,7,22,39), and increasing evidence documents a dominant role for the V1/V2 domain in such masking (6,12,18,28,34,44). One approach being investigated to overcome the effects of this masking is to delete the V2 domain from Env-based immunogens. Oligomeric V2-deleted forms of gp140 have been reported to possess enhanced immunogenicity over the wild-type molecule and to produce increased titers of neutralizing antibodies (8,21,33,43). However, these effects are only modest, and recent studies indicate that this approach involves the induction of type-specific neutralizing antibodies directed mostly toward highly variable epitopes in V1 that possess limited neutralizing activities for heterologous isolates (10, 42).The critical role of conformational masking in neutralization resistance poses a major conundrum fo...

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“…More broadly neutralizing antibodies recognize discontinuous, conserved epitopes in three regions of the gp120 (Figure 8). In HIV-1 infected individuals, the most abundant of these are directed against the CD4 binding site (CD4bs), and block gp120-CD4 interaction (Euler et al, 2011;Ho et al, 1991;Y. Li et al, 2011;Posner et al, 1991;Walker et al, 2009;Zhou et al, 2011).…”

Section: Point Mutations Associated With Evasion Of Antibody Mediatedmentioning

confidence: 99%

“…PG9 and PG16 bind to trimer specific glycosylated epitope on the V1/V2 and V3 region. (Corti et al, 2010;Euler et al, 2011;Ho et al, 1991;Y. Li et al, 2011;Pancera et al, 2010;Posner et al, 1991;Walker et al, 2009; Glycans 2G12…”

Section: Point Mutations Associated With Evasion Of Antibody Mediatedmentioning

confidence: 99%

Point Mutations Associated with HIV-1 Drug Resistance, Evasion of the Immune Response and AIDS Pathogenesis

Khati¹,

Millroy²

2012

Point Mutation

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Another discontinuous epitope on glycoprotein gp120 that is important in human immunodeficiency virus type 1 neutralization is identified by a monoclonal antibody.

Cited by 127 publications

References 22 publications

Efficient Isolation of Novel Human Monoclonal Antibodies with Neutralizing Activity Against HIV-1 from Transgenic Mice Expressing Human Ig Loci

Efficient Isolation of Novel Human Monoclonal Antibodies with Neutralizing Activity Against HIV-1 from Transgenic Mice Expressing Human Ig Loci

Type-Specific Epitopes Targeted by Monoclonal Antibodies with Exceptionally Potent Neutralizing Activities for Selected Strains of Human Immunodeficiency Virus Type 1 Map to a Common Region of the V2 Domain of gp120 and Differ Only at Single Positions from the Clade B Consensus Sequence

Point Mutations Associated with HIV-1 Drug Resistance, Evasion of the Immune Response and AIDS Pathogenesis

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