Recombinant gp120 Vaccine-Induced Antibodies Inhibit Clinical Strains of HIV-1 in the Presence of Fc Receptor-Bearing Effector Cells and Correlate Inversely with HIV Infection Rate

Forthal, Donald N.; Gilbert, Peter B.; Landucci, Gary; Phan, Tran B.

doi:10.4049/jimmunol.178.10.6596

Cited by 163 publications

(166 citation statements)

References 47 publications

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“…In the second study, ADCC activity of breast milk IgG correlated with decreased maternal-child transmission of HIV-1 (24). Taken together with an earlier study showing an inverse relationship between ADCVI and HIV-1 acquisition in a subset of Vax-004 subjects (22), substantial data in humans now indicate that Fc-mediated effector functions play a role in reducing HIV-1 acquisition. Our studies shed light on the range of epitopes that are potential targets of potent Fc-mediated effector responses and should aid in further refinements of HIV-1 vaccine candidates.…”

Section: Discussionsupporting

confidence: 51%

“…First, studies in HIV-1-infected people (8)(9)(10)(11)(12)(13)(14) and in macaques infected with simian immunodeficiency virus (15,16) consistently show an inverse correlation between Fc-mediated effector functions, including antibody-dependent cell-mediated cytotoxicity (ADCC) (8,9) or antibody-dependent cell-mediated viral inhibition (ADCVI), and viral loads or decreased disease progression (17). Second, vaccine-elicited protection both in nonhuman primates (18)(19)(20)(21) and in a subset of human subjects in the Vax-004 trial (22) correlates with Fc-mediated effector function often observed in the absence of detectable neutralizing antibodies (18)(19)(20)(21). Similarly, there was an inverse relationship between acquisition of HIV-1 and ADCC in the RV144 trial for a subset of subjects who had low to moderate IgA anti-gp120 titers (23).…”

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confidence: 99%

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Diverse specificity and effector function among human antibodies to HIV-1 envelope glycoprotein epitopes exposed by CD4 binding

Guan

Pazgier

Sajadi

et al. 2012

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

139

341

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The HIV-1 envelope glycoprotein (Env) undergoes conformational transitions consequent to CD4 binding and coreceptor engagement during viral entry. The physical steps in this process are becoming defined, but less is known about their significance as targets of antibodies potentially protective against HIV-1 infection. Here we probe the functional significance of transitional epitope exposure by characterizing 41 human mAbs specific for epitopes exposed on trimeric Env after CD4 engagement. These mAbs recognize three epitope clusters: cluster A, the gp120 face occluded by gp41 in trimeric Env; cluster B, a region proximal to the coreceptor-binding site (CoRBS) and involving the V1/V2 domain; and cluster C, the coreceptor-binding site. The mAbs were evaluated functionally by antibody-dependent, cell-mediated cytotoxicity (ADCC) and for neutralization of Tiers 1 and 2 pseudoviruses. All three clusters included mAbs mediating ADCC. However, there was a strong potency bias for cluster A, which harbors at least three potent ADCC epitopes whose cognate mAbs have electropositive paratopes. Cluster A epitopes are functional ADCC targets during viral entry in an assay format using virionsensitized target cells. In contrast, only cluster C contained epitopes that were recognized by neutralizing mAbs. There was significant diversity in breadth and potency that correlated with epitope fine specificity. In contrast, ADCC potency had no relationship with neutralization potency or breadth for any epitope cluster. Thus, Fcmediated effector function and neutralization coselect with specificity in anti-Env antibody responses, but the nature of selection is distinct for these two antiviral activities.

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Section: Discussionsupporting

confidence: 51%

mentioning

confidence: 99%

Diverse specificity and effector function among human antibodies to HIV-1 envelope glycoprotein epitopes exposed by CD4 binding

Guan

Pazgier

Sajadi

et al. 2012

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

139

341

View full text Add to dashboard Cite

show abstract

“…Also in macaques, reduction of SHIV viremia correlated with the Ab-dependent cellular cytotoxicity (ADCC) activity of Abs elicited by an adenovirus-based vaccine (2). In humans, vaccination with recombinant gp120 resulted in an ADCVI response for which magnitude correlated with a reduced rate of sexually acquired HIV infection during the Vax004 trial (3). Thus, an effective HIV vaccine, as well as effective immunotherapy, may depend not only on interactions between Ab and Ag, but also on interactions between FcgRs and their Fc ligands.…”

mentioning

confidence: 96%

Fc-Glycosylation Influences Fcγ Receptor Binding and Cell-Mediated Anti-HIV Activity of Monoclonal Antibody 2G12

Forthal

Gach

Landucci

et al. 2010

The Journal of Immunology

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131

111

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Interactions between the Fc segment of IgG and FcγRs on a variety of cells are likely to play an important role in the anti-HIV activity of Abs. Because the nature of the glycan structure on the Fc domain is a critical determinant of Fc–FcγR binding, proper Fc glycosylation may contribute to Ab-mediated protection. We have generated five different glycoforms of the broadly HIV-1–neutralizing mAb 2G12 in wild-type and glycoengineered plants and Chinese hamster ovary cells. Plant-derived 2G12 exhibited highly homogeneous glycosylation profiles with a single dominant N-glycan species. Using flow cytometry with FcγR-expressing cell lines, all 2G12 glycoforms demonstrated similar binding to FcγRI, FcγRIIa, and FcγRIIb. In contrast, two glycoforms derived from glycoengineered plants that lack plant-specific xylose and core α1,3-fucose, and instead carry human-like glycosylation with great uniformity, showed significantly enhanced binding to FcγRIIIa compared with Chinese hamster ovary or wild-type plant-derived 2G12. Using surface plasmon resonance, we show that binding of 2G12 to FcγRIIIa is markedly affected by core fucose, irrespective of its plant-specific α1,3 or mammalian-type α1,6 linkage. Consistent with this finding, 2G12 glycoforms lacking core fucose (and xylose) mediated higher antiviral activity against HIV-1 or simian immunodeficiency virus as measured by Ab-dependent cell-mediated virus inhibition. This is, to our knowledge, the first demonstration that specific alterations of Fc glycosylation can improve antiviral activity. Such alterations may result in better immunotherapeutic reagents. Moreover, biasing vaccine-induced immune responses toward optimal Fc glycosylation patterns could result in improved vaccine efficacy.

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“…This assay was used to show that ADCC Abs correlate with protection of monkeys from SIV challenge (12). Forthal and colleagues have recently used convincing assays of in vitro viral replication inhibition to illustrate the effectiveness of HIVand SIV-specific ADCC responses (4,(13)(14)(15).…”

mentioning

confidence: 99%

Rapid Degranulation of NK Cells following Activation by HIV-Specific Antibodies

Chung

Rollman

Kent

et al. 2009

The Journal of Immunology

125

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Ab-dependent cellular cytotoxicity (ADCC) Abs stimulate NK cell effector functions and play a role in protecting from and controlling viral infections. We characterized ADCC Abs in a cross-sectional cohort of 80 HIV-infected subjects not on antiretroviral therapy. We analyzed ADCC response by killing fluorescently labeled target cells, as well as expression of IFN-γ and the degranulation marker CD107a from activated NK cells as measured by a novel intracellular cytokine assay. HIV-specific ADCC directed toward Envelope proteins were present in the majority of 80 untreated HIV-infected individuals measured by killing function. Similarly, most subjects had HIV-specific Abs that mediated degranulation or cytokine expression by NK cells. Interestingly, there was a poor correlation between ADCC-mediated killing of fluorescently labeled whole Envelope protein-pulsed cell lines and Ab-mediated expression of IFN-γ by NK cells. However, in contrast to healthy donor NK cells, autologous patient NK cells more effectively degranulated granzyme B in response to ADCC activation. Activation of NK cells in response to stimulation by HIV-specific Abs occurs at least as rapidly as activation of Gag-specific CTLs. Our studies highlight the complexity of ab-mediated NK cell activation in HIV infection, and suggest new avenues toward studying the utility of ADCC in controlling HIV infection.

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Recombinant gp120 Vaccine-Induced Antibodies Inhibit Clinical Strains of HIV-1 in the Presence of Fc Receptor-Bearing Effector Cells and Correlate Inversely with HIV Infection Rate

Cited by 163 publications

References 47 publications

Diverse specificity and effector function among human antibodies to HIV-1 envelope glycoprotein epitopes exposed by CD4 binding

Diverse specificity and effector function among human antibodies to HIV-1 envelope glycoprotein epitopes exposed by CD4 binding

Fc-Glycosylation Influences Fcγ Receptor Binding and Cell-Mediated Anti-HIV Activity of Monoclonal Antibody 2G12

Rapid Degranulation of NK Cells following Activation by HIV-Specific Antibodies

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