Antibody-Dependent Cell-Mediated Viral Inhibition Emerges after Simian Immunodeficiency Virus SIVmac251 Infection of Rhesus Monkeys Coincident with gp140-Binding Antibodies and Is Effective against Neutralization-Resistant Viruses

Asmal, Mohammed; Sun, Yue; Lane, Sophie; Yeh, Wendy W.; Schmidt, Stephen D.; Mascola, John R.; Letvin, Norman L.

doi:10.1128/jvi.00313-11

Cited by 45 publications

(37 citation statements)

References 48 publications

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“…The flow cytometry-based assay allowed us to gate on CD3 Ϫ CD20 Ϫ CD56 ϩ cells in characterizing the function of NK cells following activation. The results of the present study show that, in contrast to neutralizing antibody activity, antibody-mediated killing of the SIV-infected cells in the presence of NK effector cells is detectable in monkeys as early as 3 weeks after SIVmac251 infection (2,21). This finding suggests that HIV-1-specific antibody may play a role in the control of viremia during acute infection.…”

Section: Discussionmentioning

confidence: 42%

Antibody-Dependent Cell-Mediated Cytotoxicity in Simian Immunodeficiency Virus-Infected Rhesus Monkeys

Sun

Asmal

Lane

et al. 2011

J Virol

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With the recent demonstration in the RV144 Thai trial that a vaccine regimen that does not elicit neutralizing antibodies or cytotoxic T lymphocytes may confer protection against human immunodeficiency virus type 1 (HIV-1) infection, attention has turned to nonneutralizing antibodies as a possible mechanism of vaccine protection. In the current study, we evaluated the kinetics of the antibody-dependent cell-mediated cytotoxicity (ADCC) response during acute and chronic SIVmac251 infection of rhesus monkeys. We first adapted a flow cytometry-based ADCC assay, evaluating the use of different target cells as well as different strategies for quantitation of activated natural killer (NK) cells. We found that the use of SIVmac251 Env gp130-coated target cells facilitates analyses of ADCC activity with a higher degree of sensitivity than the use of simian immunodeficiency virus (SIV)-infected target cells; however, the kinetics of the measured responses were the same using these different target cells. By comparing NK cell expression of CD107a with NK cell expression of other cytokines or chemokine molecules, we found that measuring CD107a expression is sufficient for evaluating the anti-SIV function of NK cells. We also showed that ADCC responses can be detected as early as 3 weeks after SIVmac251 infection and that the magnitude of this antibody response is inversely associated with plasma viral RNA levels in animals with moderate to high levels of viral replication. However, we also demonstrated an association between NK cell-mediated ADCC responses and the amount of SIVmac251 gp140 binding antibody that developed after viral infection. This final observation raises the possibility that the antibodies that mediate ADCC are a subset of the antibodies detected in a binding assay and arise within weeks of infection.

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Section: Discussionmentioning

confidence: 42%

Antibody-Dependent Cell-Mediated Cytotoxicity in Simian Immunodeficiency Virus-Infected Rhesus Monkeys

Sun

Asmal

Lane

et al. 2011

J Virol

Self Cite

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“…In both humans and macaques, ADCC activity has correlated with delayed progression to AIDS (12,13,19,20), and ADCVI has been reported in early stages of simian immunodeficiency virus (SIV) infection, coincident with the appearance of anti-gp140 antibodies. Viruses that had mutated to escape neutralization remained susceptible to ADCVI during later infection, and ADCVI was correlated with control of viral replication, showing that at least in this model, ADCVI played a substantial role in a protective immune response (21). Furthermore, in a French cohort, ADCC antibodies were detected at higher levels in nonprogressors than in viremic patients.…”

Section: Importancementioning

confidence: 84%

Divergent Antibody Subclass and Specificity Profiles but Not Protective HLA-B Alleles Are Associated with Variable Antibody Effector Function among HIV-1 Controllers

Lai

Licht

Dugast

et al. 2014

J Virol

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Understanding the coordination between humoral and cellular immune responses may be the key to developing protective vaccines, and because genetic studies of long-term HIV-1 nonprogressors have associated specific HLA-B alleles with spontaneous control of viral replication, this subject group presents an opportunity to investigate relationships between arms of the adaptive immune system. Given evidence suggesting that cellular immunity may play a role in viral suppression, we sought to determine whether and how the humoral immune response might vary among controllers. Significantly, Fc-mediated antibody effector functions have likewise been associated with durable viral control. In this study, we compared the effector function and biophysical features of HIV-specific antibodies in a cohort of controllers with and without protective HLA-B alleles in order to investigate whether there was evidence for multiple paths to HIV-1 control, or whether cellular and humoral arms of immunity might exhibit coordinated profiles. However, with the exception of IgG2 antibodies to gp41, HLA status was not associated with divergent humoral responses. This finding did not result from uniform antibody responses across subjects, as controllers could be regrouped according to strong differences in their HIV-specific antibody subclass specificity profiles. These divergent antibody profiles were further associated with significant differences in nonneutralizing antibody effector function, with levels of HIVspecific IgG1 acting as the major distinguishing factor. Thus, while HLA background among controllers was associated with minimal differences in humoral function, antibody subclass and specificity profiles were associated with divergent effector function, suggesting that these features could be used to make functional predictions. Because these nonneutralizing antibody activities have been associated with spontaneous viral control, reduced viral load, and nonprogression in infected subjects and protection in vaccinated subjects, understanding the specific features of IgGs with potentiated effector function may be critical to vaccine and therapeutic antibody development. IMPORTANCEIn this study, we investigated whether the humoral and cellular arms of adaptive immunity exhibit coordinated or compensatory activity by studying the antibody response among HIV-1 controllers with different genetic backgrounds.

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“…Beyond neutralization, antibodies are able to mediate a variety of additional effector functions through their capacity to recruit the innate immune system via Fc receptors (FcRs). Moreover, these antibodies are readily induced early in HIV infection, are enriched in long-term nonprogressors, and have been shown to provide protection in some models (3)(4)(5)(6)(7). However, the specific antibody characteristics that are associated with enhanced innate immune activity have yet to be defined.…”

Section: Introductionmentioning

confidence: 99%

Natural variation in Fc glycosylation of HIV-specific antibodies impacts antiviral activity

Ackerman

Crispin²,

Yu³

et al. 2013

J. Clin. Invest.

319

349

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While the induction of a neutralizing antibody response against HIV remains a daunting goal, data from both natural infection and vaccine-induced immune responses suggest that it may be possible to induce antibodies with enhanced Fc effector activity and improved antiviral control via vaccination. However, the specific features of naturally induced HIV-specific antibodies that allow for the potent recruitment of antiviral activity and the means by which these functions are regulated are poorly defined. Because antibody effector functions are critically dependent on antibody Fc domain glycosylation, we aimed to define the natural glycoforms associated with robust Fc-mediated antiviral activity. We demonstrate that spontaneous control of HIV and improved antiviral activity are associated with a dramatic shift in the global antibody-glycosylation profile toward agalactosylated glycoforms. HIV-specific antibodies exhibited an even greater frequency of agalactosylated, afucosylated, and asialylated glycans. These glycoforms were associated with enhanced Fc-mediated reduction of viral replication and enhanced Fc receptor binding and were consistent with transcriptional profiling of glycosyltransferases in peripheral B cells. These data suggest that B cell programs tune antibody glycosylation actively in an antigen-specific manner, potentially contributing to antiviral control during HIV infection.

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Antibody-Dependent Cell-Mediated Viral Inhibition Emerges after Simian Immunodeficiency Virus SIVmac251 Infection of Rhesus Monkeys Coincident with gp140-Binding Antibodies and Is Effective against Neutralization-Resistant Viruses

Cited by 45 publications

References 48 publications

Antibody-Dependent Cell-Mediated Cytotoxicity in Simian Immunodeficiency Virus-Infected Rhesus Monkeys

Antibody-Dependent Cell-Mediated Cytotoxicity in Simian Immunodeficiency Virus-Infected Rhesus Monkeys

Divergent Antibody Subclass and Specificity Profiles but Not Protective HLA-B Alleles Are Associated with Variable Antibody Effector Function among HIV-1 Controllers

Natural variation in Fc glycosylation of HIV-specific antibodies impacts antiviral activity

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