Polymorphism of Fc receptor IIa for IgG in infants is associated with susceptibility to perinatal HIV-1 infection

Brouwer, Kimberly C.; Lal, Renu B.; Mirel, Lisa B.; Yang, Chunfu; Eijk, Anna Maria van; Ayisi, John; Otieno, Juliana A.; Nahlen, Bernard L.; Steketee, Richard W.; Lal, Altaf A.; Shi, Ya Ping

doi:10.1097/00002030-200405210-00012

Cited by 57 publications

(60 citation statements)

References 28 publications

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“…Highaffinity polymorphisms of Fc␥R3a, while protective in monoclonal antibody therapy of cancer, have been associated with HIV progression (43). Similarly, the allele of Fc␥R2a with improved recognition of IgG2 subclass antibodies has been found to be a risk factor in neonatal HIV transmission (22), whereas it has been associated with protection from progression in adults (21). Yet passive-transfer studies of both neutralizing monoclonal and vaccine-induced nonneutralizing antibodies have implicated antibody effector functions in protection (9,44,45).…”

Section: Discussionmentioning

confidence: 99%

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Enhanced Phagocytic Activity of HIV-Specific Antibodies Correlates with Natural Production of Immunoglobulins with Skewed Affinity for FcγR2a and FcγR2b

Ackerman

Dugast

McAndrew

et al. 2013

J Virol

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While development of an HIV vaccine that can induce neutralizing antibodies remains a priority, decades of research have proven that this is a daunting task. However, accumulating evidence suggests that antibodies with the capacity to harness innate immunity may provide some protection. While significant research has focused on the cytolytic properties of antibodies in acquisition and control, less is known about the role of additional effector functions. In this study, we investigated antibody-dependent phagocytosis of HIV immune complexes, and we observed significant differences in the ability of antibodies from infected subjects to mediate this critical effector function. We observed both quantitative differences in the capacity of antibodies to drive phagocytosis and qualitative differences in their Fc␥R usage profile. We demonstrate that antibodies from controllers and untreated progressors exhibit increased phagocytic activity, altered Fc domain glycosylation, and skewed interactions with Fc␥R2a and Fc␥R2b in both bulk plasma and HIV-specific IgG. While increased phagocytic activity may directly influence immune activation via clearance of inflammatory immune complexes, it is also plausible that Fc receptor usage patterns may regulate the immune response by modulating downstream signals following phagocytosis-driving passive degradation of internalized virus, release of immune modulating cytokines and chemokines, or priming of a more effective adaptive immune response.

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Section: Discussionmentioning

confidence: 99%

“…Several lines of evidence support the importance of phagocytosis in HIV infection. First, Fc␥R2a polymorphisms have been found to correlate with disease progression (21) and susceptibility (22). Second, IgG2 subclass antibodies, in combination with the Fc␥R2a allele capable of interacting with IgG2, are associated with delayed progression (23).…”

mentioning

confidence: 99%

Enhanced Phagocytic Activity of HIV-Specific Antibodies Correlates with Natural Production of Immunoglobulins with Skewed Affinity for FcγR2a and FcγR2b

Ackerman

Dugast

McAndrew

et al. 2013

J Virol

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“…Otherwise, we might expect the high-affinity genotypes (VVs and HHs) to be associated with a lower risk of infection at any given level of serum ADCVI activity because the higher affinity genotypes mediate better ADCC activity (40,41). In contrast, high-affinity genotypes may enhance the risk of infection through an Ab-dependent mechanism, as suggested by the finding that infants homozygous for Fc␥RIIa H have at least a 2.2-fold increased risk of perinatal HIV infection compared with infants having one or no H allele (42). We propose that our results reflect opposing Ab functions: ADCVI on the one hand and virus enhancement or blocking of beneficial functions in contrast.…”

Section: Discussionmentioning

confidence: 99%

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

Gilbert

Landucci

et al. 2007

The Journal of Immunology

163

159

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Nonneutralizing Abs may play a role in protecting animals and humans from lentiviral infections. We explored the Ab-dependent, cell-mediated virus inhibition (ADCVI) Ab response to recombinant gp120 (rgp120) vaccination in sera from 530 participants in the Vax 004 trial. Serum ADCVI activity was measured against a clinical R5 strain of HIV-1 using peripheral blood mononuclear effector cells from healthy donors. The level of vaccine-induced ADCVI activity correlated inversely with the rate of acquiring HIV infection following vaccination, such that for every 10% increase in ADCVI activity, there was a 6.3% decrease in the hazard rate of infection (p = 0.019). Some vaccinated individuals also mounted an ADCVI response against two other clinical R5 strains of HIV-1. However, ADCVI activity correlated poorly with neutralizing or CD4-gp120-blocking Ab activity measured against laboratory strains. Finally, the degree to which the ADCVI Ab response predicted the rate of infection was influenced by polymorphisms at the FcγRIIa and FcγRIIIa gene loci. These data indicate that rgp120 vaccination can elicit Abs with antiviral activity against clinical strains of HIV-1. However, such activity requires the presence of FcR-bearing effector cells. Our results provide further evidence that ADCVI may play a role in preventing HIV infection.

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“…The high affinity HH genotype may be disadvantageous where immune-complexed pathogens establish infection within phagocytes or where IgG2 Abs block beneficial Fc␥R-triggered events. With respect to HIV, Brouwer et al reported a 2-fold increased risk of perinatal infection in HH infants compared with RR infants (35). They suggested that maternal Ab bound to virus may have facilitated infection of macrophages or dendritic cells bearing the higher affinity HH receptor.…”

Section: Discussionmentioning

confidence: 99%

FcγRIIa Genotype Predicts Progression of HIV Infection

Forthal

Landucci

Bream

et al. 2007

The Journal of Immunology

119

129

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Polymorphisms in FcγR genes are associated with susceptibility to or severity of a number of autoimmune and infectious diseases. We found that HIV-infected men in the Multicenter AIDS Cohort Study with the FcγRIIa RR genotype progressed to a CD4+ cell count of <200/mm3 at a faster rate than individuals with the RH or HH genotypes (relative hazard = 1.6; p = 0.0001). However, progression to AIDS (using the broad definition of either a CD4+ cell count <200/mm3 or development of an AIDS-defining illness) was less impacted by FcγRIIa genotype, largely because HH homozygotes had an increased risk of Pneumocystis jiroveci pneumonia as an AIDS-defining illness. We also showed that chronically infected subjects develop a substantial anti-gp120-specific IgG2 response. Moreover, HIV-1 immune complexes are more efficiently internalized by monocytes from HH subjects compared with RR subjects, likely because of the presence of IgG2 in the complexes. Finally, the FcγRIIIa F/V gene polymorphism was not associated with progression of HIV infection, but, as demonstrated previously, did predict the risk of Kaposi’s sarcoma. These results demonstrate the importance of FcγRs in AIDS pathogenesis and point toward a critical role for interactions between FcγRs and immune complexes in disease progression.

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Polymorphism of Fc receptor IIa for IgG in infants is associated with susceptibility to perinatal HIV-1 infection

Abstract: This study provides the first evidence that the infant Fc gamma RIIa His/His131 genotype is associated with susceptibility to perinatal HIV-1 transmission and further suggests that there is a dose-response relationship for the effect of the Fc gamma RIIa His131 gene on transmission.

Cited by 57 publications

References 28 publications

Enhanced Phagocytic Activity of HIV-Specific Antibodies Correlates with Natural Production of Immunoglobulins with Skewed Affinity for FcγR2a and FcγR2b

Enhanced Phagocytic Activity of HIV-Specific Antibodies Correlates with Natural Production of Immunoglobulins with Skewed Affinity for FcγR2a and FcγR2b

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

FcγRIIa Genotype Predicts Progression of HIV Infection

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