title: Fc gamma receptor 3A polymorphism and risk for HIV-associated cryptococcal disease.
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.
  
  
  OBJECTIVE
  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.
authors: Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine & Montefiore Medical Center, Bronx, New York, USA.
authors: Soma
authors: S
authors: Rohatgi
authors: Shruti
authors: S
authors: Gohil
authors: Mark H
authors: MH
authors: Kuniholm
authors: Hannah
authors: H
authors: Schultz
authors: Chad
authors: C
authors: Dufaud
authors: Kathryn L
authors: KL
authors: Armour
authors: Sheila
authors: S
authors: Badri
authors: Robbie B
authors: RB
authors: Mailliard
authors: Liise-anne
authors: LA
authors: Pirofski
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000235:genetics* / Q000276:immunology / Q000382:microbiology; D000328:Adult; D000920:Antibody-Dependent Cell Cytotoxicity; D018791:CD4 Lymphocyte Count; D015331:Cohort Studies; D003453:Cryptococcosis / Q000235:genetics* / Q000276:immunology / Q000382:microbiology; D003455:Cryptococcus neoformans; D005838:Genotype; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D017452:Receptors, IgG / Q000235:genetics* / Q000276:immunology; D012307:Risk Factors
chemical_list: C496124:FCGR3A protein, human; D017452:Receptors, IgG
references: PLoS One. 2010 Dec 20;5(12):e15562
references: 21187939
references: PLoS One. 2012;7(8):e42439
references: 22879986
references: Curr Biol. 2006 Nov 7;16(21):2161-5
references: 17084702
references: J Clin Microbiol. 2004 Jul;42(7):3159-63
references: 15243076
references: Nature. 2006 Feb 16;439(7078):851-5
references: 16482158
references: Nat Genet. 2007 Jun;39(6):721-3
references: 17529978
references: BMC Genet. 2009 Dec 18;10:85
references: 20021669
references: Infect Immun. 1995 Feb;63(2):573-9
references: 7822024
references: J Leukoc Biol. 2007 Mar;81(3):584-92
references: 17135573
references: Clin Infect Dis. 2008 Jan 15;46(2):e12-8
references: 18171241
references: J Infect Dis. 1999 Sep;180(3):915-9
references: 10438394
references: Cell Immunol. 2011;267(2):109-23
references: 21292246
references: Infect Immun. 1994 Jul;62(7):2857-64
references: 8005676
references: Blood. 1997 Aug 1;90(3):1109-14
references: 9242542
references: J Immunol. 2012 Dec 15;189(12):5820-30
references: 23175699
references: Clin Infect Dis. 2009 Apr 1;48(7):856-62
references: 19222372
references: mBio. 2013 Jul 02;4(4):
references: 23820392
references: Med Mycol. 2007 Sep;45(6):513-8
references: 17710620
references: J Clin Invest. 1997 Sep 1;100(5):1059-70
references: 9276722
references: Pediatrics. 2001 May;107(5):E66
references: 11331716
references: J Leukoc Biol. 2006 Nov;80(5):1156-64
references: 17056766
references: FEMS Immunol Med Microbiol. 2012 Mar;64(2):147-61
references: 22029633
references: J Neurosci. 2006 Jan 25;26(4):1098-106
references: 16436595
references: BMC Microbiol. 2009 Mar 05;9:51
references: 19265539
references: Blood. 1999 Dec 15;94(12):4220-32
references: 10590067
references: PLoS One. 2013;8(2):e56269
references: 23457543
references: Infect Immun. 2009 Jan;77(1):120-7
references: 18936186
references: Blood. 2002 Feb 1;99(3):754-8
references: 11806974
references: BMC Med Genet. 2011 Jan 05;12:2
references: 21208440
references: Infect Dis Clin North Am. 2006 Sep;20(3):507-44, v-vi
references: 16984867
references: Antimicrob Agents Chemother. 1998 Jun;42(6):1437-46
references: 9624491
references: Cancer Epidemiol Biomarkers Prev. 2005 Mar;14(3):633-7
references: 15767342
references: J Infect Dis. 2009 Jul 15;200(2):244-51
references: 19527168
references: J Immunol Methods. 2010 Mar 31;354(1-2):20-33
references: 20138184
references: Hum Mol Genet. 2010 Aug 15;19(16):3282-94
references: 20508037
references: J Immunol. 2006 Nov 15;177(10):6842-51
references: 17082598
references: EMBO J. 1989 May;8(5):1341-8
references: 2527741
references: Am J Pathol. 1987 Aug;128(2):354-61
references: 3618730
references: Clin Infect Dis. 1998 Nov;27(5):1231-7
references: 9827275
references: J Immunol. 2008 May 1;180(9):6392-401
references: 18424763
references: Infect Immun. 1999 May;67(5):2218-24
references: 10225877
references: FEMS Yeast Res. 2006 Jun;6(4):525-36
references: 16696648
references: J Immunol. 2010 May 15;184(10):5755-67
references: 20404271
references: Leukemia. 1994 Apr;8(4):652-8
references: 8152260
references: Tissue Antigens. 2003 Mar;61(3):189-202
references: 12694568
references: Am J Epidemiol. 1987 Aug;126(2):310-8
references: 3300281
references: Clin Exp Immunol. 1995 Mar;99(3):425-32
references: 7882565
references: Adv Exp Med Biol. 2012;710:1-10
references: 22127880
references: J Virol. 2011 Oct;85(20):10826-33
references: 21849458
references: Infect Immun. 2007 Mar;75(3):1424-35
references: 17220317
references: Clin Diagn Lab Immunol. 2005 Oct;12(10):1168-76
references: 16210479
references: Infect Immun. 1996 Sep;64(9):3446-50
references: 8751883
references: Nat Med. 2007 Nov;13(11):1368-74
references: 17934470
references: J Cell Biol. 1993 Jul;122(1):235-42
references: 8314844
references: J Infect Dis. 1999 Nov;180(5):1526-35
references: 10515812
references: J Exp Med. 1998 Feb 16;187(4):641-8
references: 9463414
references: Immunity. 2006 Jan;24(1):19-28
references: 16413920
references: Infect Immun. 2009 Jun;77(6):2436-46
references: 19307209
references: Blood. 2012 Oct 4;120(14):2836-42
references: 22915639
references: J Infect Dis. 1999 Feb;179(2):449-54
references: 9878030
references: Am J Epidemiol. 2009 Sep 1;170(5):537-45
references: 19602701
references: AIDS. 2009 Feb 20;23(4):525-30
references: 19182676
references: Trans Am Clin Climatol Assoc. 2013;124:61-79
references: 23874010
references: Curr Mol Med. 2005 Jun;5(4):421-33
references: 15977998
references: J Immunol. 2003 Sep 1;171(5):2366-73
references: 12928383
references: J Clin Microbiol. 2012 Dec;50(12):3853-61
references: 22993186
references: Cell Host Microbe. 2013 Apr 17;13(4):417-28
references: 23601104