Fc receptor-mediated antiviral antibodies

Department of Medicine, Division of Infectious Diseases, University of California, Irvine School of Medicine, Irvine, California, USA.
Current opinion in HIV and AIDS (Impact Factor: 4.68). 09/2009; 4(5):388-93. DOI: 10.1097/COH.0b013e32832f0a89
Source: PubMed


We summarize current information on Fc receptor-mediated antiviral activities of antibodies. These activities include Fcgamma receptor-mediated inhibition and neutralization of HIV on antigen-presenting cells, antibody-dependent cellular cytotoxicity, and antibody-dependent cell-mediated virus inhibition (ADCVI).
An Fcgamma receptor-mediated mechanism that results in augmented neutralization and may render nonneutralizing antibodies inhibitory has been demonstrated in antigen-presenting cell. Antibody-dependent cellular cytotoxicity antibody activity correlates inversely with HIV disease progression in humans, and higher vaccine-induced antibody-dependent cellular cytotoxicity antibody responses are associated with lower acute simian immunodeficiency virus viremia levels in macaques. Following vaccination with rgp120, ADCVI antibody levels are higher among those with a lower rate of sexually acquired HIV infection. Nonneutralizing simian immunodeficiency virus immune serum that prevents infection of newborn macaques after oral challenge has potent ADCVI antibody activity. Abrogating the ability of the Fc segment of the broadly neutralizing mAb b12 to bind to Fcgamma receptors and to mediate ADCVI substantially reduces b12's protective effect in a simian/human immunodeficiency virus vaginal challenge model.
Fc-FcgammaR interactions play a critical role in the biological function of antibody and are likely to be instrumental in preventing or modulating lentiviral infection. Exploiting antibody responses that depend on Fc-FcgammaR interactions may help widen the breadth and increase the potency of vaccine-induced antibody. Although the importance of generating optimal Fab-antigen interactions cannot be overestimated, improving Fc-FcgammaR interactions through adjuvants or other strategies provides another option for improving HIV vaccines and immunotherapies.

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    • "This ADCC mechanism also involves FcRs (93, 101), mainly FcRIII (CD16). Cross linking of Abs that recognize an infected target cell via its Fab domain and the FcR on the effector cell via its Fc domain leads to lysis of the infected target cell subsequent to effector cell degranulation (101–105). Various immune cells such as NK cells, monocytes, macrophages, or neutrophils can induce ADCC (106). It has been suggested that ADCC participated in the 31% reduced risk of HIV infection in the RV144 trial (26). "
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    ABSTRACT: HIV antibody (Ab) functions capable of preventing mucosal cell-free or cell-to-cell HIV transmission are critical for the development of effective prophylactic and therapeutic vaccines. In addition to CD4(+) T cells, other potential HIV-target cell types including antigen-presenting cells (APCs) (dendritic cells, macrophages) residing at mucosal sites are infected. Moreover, the interactions between APCs and HIV lead to HIV cell-to-cell transmission. Recently discovered broadly neutralizing antibodies (NAbs) are able to neutralize a broad spectrum of HIV strains, inhibit cell-to-cell transfer, and efficiently protect from infection in the experimentally challenged macaque model. However, the 31% protection observed in the RV144 vaccine trial in the absence of detectable NAbs in blood samples pointed to the possible role of additional Ab inhibitory functions. Increasing evidence suggests that IgG Fcγ receptor (FcγR)-mediated inhibition of Abs present at the mucosal site may play a role in protection against HIV mucosal transmission. Moreover, mucosal IgA Abs may be determinant in protection against HIV sexual transmission. Therefore, defining Ab inhibitory functions that could lead to protection is critical for further HIV vaccine design. Here, we review different inhibitory properties of HIV-specific Abs and discuss their potential role in protection against HIV sexual transmission.
    Full-text · Article · Jun 2014 · Frontiers in Immunology
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    • "Previous studies reported that transient depletion of CD8+ cells during chronic infection leads to a significant increase of transient plasma vRNA levels in animals vaccinated with live-attenuated SIV, even though detection of SIV specific CD8+ T cell responses were low except in lymphoid organs [10,29,44-46]. However, recent developments in the vaccine protection experiments suggest a role for other mechanisms in vivo such as ADCC, which is mediated by CD8αα+ natural killer cells [47,48]. Similar to other LASIV vaccinations, animals infected with Rev-Ind Nef¯SIV for over 1 year clearly had developed various levels of humoral and cell mediated responses, yet these response were generally modest compared in response to wild type SIV [45] [41]. "
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    ABSTRACT: Rhesus macaques (RMs) inoculated with live-attenuated Rev-Independent Nef¯ simian immunodeficiency virus (Rev-Ind Nef¯SIV) as adults or neonates controlled viremia to undetectable levels and showed no signs of immunodeficiency over 6-8 years of follow-up. We tested the capacity of this live-attenuated virus to protect RMs against pathogenic, heterologous SIVsmE660 challenges. Three groups of four RM were inoculated with Rev-Ind Nef¯SIV and compared. Group 1 was inoculated 8 years prior and again 15 months before low dose intrarectal challenges with SIVsmE660. Group 2 animals were inoculated with Rev-Ind Nef¯SIV at 15 months and Group 3 at 2 weeks prior to the SIVsmE660 challenges, respectively. Group 4 served as unvaccinated controls. All RMs underwent repeated weekly low-dose intrarectal challenges with SIVsmE660. Surprisingly, all RMs with acute live-attenuated virus infection (Group 3) became superinfected with the challenge virus, in contrast to the two other vaccine groups (Groups 1 and 2) (P=0.006 for each) and controls (Group 4) (P=0.022). Gene expression analysis showed significant upregulation of innate immune response-related chemokines and their receptors, most notably CCR5 in Group 3 animals during acute infection with Rev-Ind Nef¯SIV. We conclude that although Rev-Ind Nef¯SIV remained apathogenic, acute replication of the vaccine strain was not protective but associated with increased acquisition of heterologous mucosal SIVsmE660 challenges.
    Full-text · Article · Sep 2013 · PLoS ONE
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    • "In the case of homozygous individuals for FcgRIIIa-V allotype (VV), infected tumor cells are probably killed efficiently by these “strong binding” receptor variants, possibly before the virus has even had time to replicate effectively. This may result in fierce anti-viral ADCVI (antibody-dependent cell-mediated virus inhibition) [9] against oncolytic adenoviruses partially inhibiting its efficacy. "
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    ABSTRACT: Oncolytic viruses have shown potential as cancer therapeutics, but not all patients seem to benefit from therapy. Polymorphisms in Fc gamma receptors (FcgRs) lead to altered binding affinity of IgG between the receptor allotypes and therefore contribute to differences in immune defense mechanisms. Associations have been identified between FcgR polymorphisms and responsiveness to different immunotherapies. Taken together with the increasing understanding that immunological factors might determine the efficacy of oncolytic virotherapy we studied whether FcgR polymorphisms would have prognostic and/or predictive significance in the context of oncolytic adenovirus treatments. 235 patients with advanced solid tumors were genotyped for two FcgR polymorphisms, FcgRIIa-H131R (rs1801274) and FcgRIIIa-V158F (rs396991), using TaqMan based qPCR. The genotypes were correlated with patient survival and tumor imaging data. In patients treated with oncolytic adenoviruses, overall survival was significantly shorter if the patient had an FcgRIIIa-VV/ FcgRIIa-HR (VVHR) genotype combination (P = 0,032). In contrast, patients with FFHR and FFRR genotypes had significantly longer overall survival (P = 0,004 and P = 0,006, respectively) if they were treated with GM-CSF-armed adenovirus in comparison to other viruses. Treatment of these patients with unarmed virus correlated with shorter survival (P < 0,0005 and P = 0,016, respectively). Treating FFHH individuals with CD40L-armed virus resulted in longer survival than treatment with other viruses (P = 0,047). Our data are compatible with the hypothesis that individual differences in effector cell functions, such as NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and tumor antigen presentation by APCs caused by polymorphisms in FcgRs could play role in the effectiveness of oncolytic virotherapies. If confirmed in larger populations, FcgR polymorphisms could have potential as prognostic and predictive biomarkers for oncolytic adenovirus therapies to enable better selection of patients for clinical trials. Also, putative associations between genotypes, different viruses and survival implicate potentially important mechanistic issues.
    Full-text · Article · Aug 2013 · Journal of Translational Medicine
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