Broad HIV-1 neutralization mediated by CD4-binding site antibodies

Li, Yuxing; Migueles, Stephen A.; Welcher, Brent; Svehla, Krisha; Phogat, Adhuna; Louder, Mark K.; Wu, Xueling; Shaw, George M.; Connors, Mark; Wyatt, Richard T.; Mascola, John R.

doi:10.1038/nm1624

Cited by 362 publications

(454 citation statements)

References 16 publications

(1 reference statement)

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“…The beads were then pelleted by centrifugation, and the Protein A-depleted fraction was collected. Serum adsorptions with antigen-coupled beads were performed using tosyl-activated magnetic beads, as described previously (25). A total of 1 mg of gp120 or 1 mg of TM-Pst1 was used for bead coupling.…”

Section: Methodsmentioning

confidence: 99%

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Rapid development of glycan-specific, broad, and potent anti–HIV-1 gp120 neutralizing antibodies in an R5 SIV/HIV chimeric virus infected macaque

Walker

Sok

Nishimura

et al. 2011

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

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It is widely believed that the induction of a broadly neutralizing antibody (bNAb) response will be a critical component of a successful vaccine against HIV. A significant fraction of HIV-infected individuals mount bNAb responses, providing support for the notion that such responses could be elicited through vaccination. Infection of macaques with simian immunodeficiency virus (SIV) or SIV/HIV chimeric virus (SHIV) has been widely used to model aspects of HIV infection, but to date, only limited bNAb responses have been described. Here, we screened plasma from 14 R5-tropic SHIV-infected macaques for broadly neutralizing activity and identified a macaque with highly potent cross-clade plasma NAb response. Longitudinal studies showed that the development of broad and autologous NAb responses occurred coincidentally in this animal. Serum-mapping studies, using pseudovirus point mutants and antigen adsorption assays, indicated that the plasma bNAbs are specific for epitopes that include carbohydrates and are critically dependent on the glycan at position 332 of Env gp120. The results described herein provide insight into the development and evolution of a broad response, suggest that certain bNAb specificities may be more rapidly induced by immunization than others, and provide a potential model for the facile study of the development of bNAb responses.

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Section: Methodsmentioning

confidence: 99%

“…Two rounds of adsorption were performed to ensure complete removal of antigen-specific antibodies. Functional antibodies were eluted from beads by exposing the beads to series of increasingly acidic conditions, as described (25).…”

Section: Methodsmentioning

confidence: 99%

Rapid development of glycan-specific, broad, and potent anti–HIV-1 gp120 neutralizing antibodies in an R5 SIV/HIV chimeric virus infected macaque

Walker

Sok

Nishimura

et al. 2011

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

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“…Altogether, these results indicated that CXCL4 interacts with a region of the gp120 outer domain located proximal to the CD4-BD, but not directly overlapping with this domain. To further confirm the lack of identity between the binding sites of CXCL4 and CD4 in gp120, we tested a mutated gp120 bearing the D368R substitution that abrogates interaction with CD4 (29) showing that it was coimmunoprecipitated by CXCL4 with similar efficiency as wild-type gp120 (Fig. S8).…”

Section: Cd4 + T Cells Was Not Downmodulated Upon Treatment With Cxcl4mentioning

confidence: 99%

Identification of the platelet-derived chemokine CXCL4/PF-4 as a broad-spectrum HIV-1 inhibitor

Auerbach

Yin

Miao

et al. 2012

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

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The natural history of HIV-1 infection is highly variable in different individuals, spanning from a rapidly progressive course to a longterm asymptomatic infection. A major determinant of the pace of disease progression is the in vivo level of HIV-1 replication, which is regulated by a complex network of cytokines and chemokines expressed by immune and inflammatory cells. The chemokine system is critically involved in the control of HIV-1 replication by virtue of the role played by specific chemokine receptors, most notably CCR5 and CXCR4, as cell-surface coreceptors for HIV-1 entry; hence, the chemokines that naturally bind such coreceptors act as endogenous inhibitors of HIV-1. Here, we show that the CXC chemokine CXCL4 (PF-4), the most abundant protein contained within the α-granules of platelets, is a broad-spectrum inhibitor of HIV-1 infection. Unlike other known HIV-suppressive chemokines, CXCL4 inhibits infection by the majority of primary HIV-1 isolates regardless of their coreceptor-usage phenotype or genetic subtype. Consistent with the lack of viral phenotype specificity, blockade of HIV- 1 infection occurs at the level of virus attachment and entry via a unique mechanism that involves direct interaction of CXCL4 with the major viral envelope glycoprotein, gp120. The binding site for CXCL4 was mapped to a region of the gp120 outer domain proximal to the CD4-binding site. The identification of a platelet-derived chemokine as an endogenous antiviral factor may have relevance for the pathogenesis and treatment of HIV-1 infection

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“…In certain HIV-1-infected individuals, it has been found that neutralization is exclusively or substantially mediated by CD4 binding site antibodies (42,43). Previous attempts to focus the immune response toward the b12 epitope were done in the context of whole gp120 by introducing mutations to selectively diminish non-neutralizing antibody binding and adding glycosylation sites to dampen responses to regions outside the CD4bs (14 -16).…”

Section: Discussionmentioning

confidence: 99%

Design of an Escherichia coli Expressed HIV-1 gp120 Fragment Immunogen That Binds to b12 and Induces Broad and Potent Neutralizing Antibodies

Bhattacharyya

Singh

Rathore

et al. 2013

Journal of Biological Chemistry

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Background: b12 is a broadly neutralizing human antibody that targets the conserved receptor binding site on HIV-1 gp120. Results: Designed gp120 fragment immunogens (b121a/b122a) targeting the b12 binding site were tested in rabbit immunization studies. Conclusion: Priming with b122a and boosting with gp120 elicited broadly neutralizing sera. Significance: gp120 fragment immunogens can elicit broadly neutralizing sera in small animals.

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Broad HIV-1 neutralization mediated by CD4-binding site antibodies

Cited by 362 publications

References 16 publications

Rapid development of glycan-specific, broad, and potent anti–HIV-1 gp120 neutralizing antibodies in an R5 SIV/HIV chimeric virus infected macaque

Rapid development of glycan-specific, broad, and potent anti–HIV-1 gp120 neutralizing antibodies in an R5 SIV/HIV chimeric virus infected macaque

Identification of the platelet-derived chemokine CXCL4/PF-4 as a broad-spectrum HIV-1 inhibitor

Design of an Escherichia coli Expressed HIV-1 gp120 Fragment Immunogen That Binds to b12 and Induces Broad and Potent Neutralizing Antibodies

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