Fc gamma receptor 3A polymorphism and risk for HIV-associated cryptococcal disease

mBio. 2013 Aug 27;4(5):e00573-13. doi: 10.1128/mBio.00573-13.

Abstract

Cryptococcus neoformans is one of the most common causes of fungal disease in HIV-infected persons, but not all of those who are infected develop cryptococcal disease (CD). Although CD4(+) T cell deficiency is a risk factor for HIV-associated CD, polymorphisms of phagocytic Fc gamma receptors (FCGRs) have been linked to CD risk in HIV-uninfected persons. To investigate associations between FCGR2A 131 H/R and FCGR3A 158 F/V polymorphisms and CD risk in HIV-infected persons, we performed PCR-based genotyping on banked samples from 164 men enrolled in the Multicenter AIDS Cohort Study (MACS): 55 who were HIV infected and developed CD and a matched control group of 54 who were HIV infected and 55 who were HIV uninfected. Using additive and allelic statistical models for analysis, the high-affinity FCGR3A 158V allele was significantly associated with CD status after adjusting for race/ethnicity (odds ratio [OR], 2.1; P = 0.005), as was the FCGR3A 158 VV homozygous genotype after adjusting for race/ethnicity, rate of CD4(+) T cell decline, and nadir CD4(+) T cell count (OR, 21; P = 0.005). No associations between CD and FCGR2A 131 H/R polymorphism were identified. In binding studies, human IgG (hIgG)-C. neoformans complexes exhibited more binding to CHO-K1 cells expressing FCGR3A 158V than to those expressing FCGR3A 158F, and in cytotoxicity assays, natural killer (NK) cells expressing FCGR3A 158V induced more C. neoformans-infected monocyte cytotoxicity than those expressing FCGR3A 158F. Together, these results show an association between the FCGR3A 158V allele and risk for HIV-associated CD and suggest that this polymorphism could promote C. neoformans pathogenesis via increased binding of C. neoformans immune complexes, resulting in increased phagocyte cargo and/or immune activation.

Importance: HIV-associated CD4(+) T cell deficiency is a sine qua non for HIV-associated cryptococcal disease (CD), but not all patients with CD4(+) T cell deficiency develop CD despite serological evidence of previous infection. At present, there are no biomarkers that predict HIV-associated CD risk. The goal of our study was to understand whether Fc gamma receptor (FCGR) polymorphisms that have been shown to portend CD risk in HIV-uninfected people are associated with CD risk in HIV-infected people. Such biomarkers could identify those who would benefit most from targeted prophylaxis and/or earlier treatment, particularly in sub-Saharan Africa, where there are nearly a million cases of HIV-associated CD annually. A biomarker of risk could also identify potential candidates for immunization, should there be a vaccine for Cryptococcus neoformans.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • AIDS-Related Opportunistic Infections / genetics*
  • AIDS-Related Opportunistic Infections / immunology
  • AIDS-Related Opportunistic Infections / microbiology
  • Adult
  • Antibody-Dependent Cell Cytotoxicity
  • CD4 Lymphocyte Count
  • Cohort Studies
  • Cryptococcosis / genetics*
  • Cryptococcosis / immunology
  • Cryptococcosis / microbiology
  • Cryptococcus neoformans
  • Genotype
  • Humans
  • Killer Cells, Natural / immunology
  • Male
  • Middle Aged
  • Mutation, Missense
  • Polymorphism, Genetic*
  • Receptors, IgG / genetics*
  • Receptors, IgG / immunology
  • Risk Factors

Substances

  • FCGR3A protein, human
  • Receptors, IgG