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...

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Autores principales:	Soma Rohatgi, Shruti Gohil, Mark H. Kuniholm, Hannah Schultz, Chad Dufaud, Kathryn L. Armour, Sheila Badri, Robbie B. Mailliard, Liise-anne Pirofski
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Lenguaje:	EN
Publicado:	American Society for Microbiology 2013
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/6602f27835e947148982552475dbe6fe
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spelling	oai:doaj.org-article:6602f27835e947148982552475dbe6fe2021-11-15T15:42:47ZFc Gamma Receptor 3A Polymorphism and Risk for HIV-Associated Cryptococcal Disease10.1128/mBio.00573-132150-7511https://doaj.org/article/6602f27835e947148982552475dbe6fe2013-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00573-13https://doaj.org/toc/2150-7511ABSTRACT 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.Soma RohatgiShruti GohilMark H. KuniholmHannah SchultzChad DufaudKathryn L. ArmourSheila BadriRobbie B. MailliardLiise-anne PirofskiAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 4, Iss 5 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Soma Rohatgi Shruti Gohil Mark H. Kuniholm Hannah Schultz Chad Dufaud Kathryn L. Armour Sheila Badri Robbie B. Mailliard Liise-anne Pirofski Fc Gamma Receptor 3A Polymorphism and Risk for HIV-Associated Cryptococcal Disease
description	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.
format	article
author	Soma Rohatgi Shruti Gohil Mark H. Kuniholm Hannah Schultz Chad Dufaud Kathryn L. Armour Sheila Badri Robbie B. Mailliard Liise-anne Pirofski
author_facet	Soma Rohatgi Shruti Gohil Mark H. Kuniholm Hannah Schultz Chad Dufaud Kathryn L. Armour Sheila Badri Robbie B. Mailliard Liise-anne Pirofski
author_sort	Soma Rohatgi
title	Fc Gamma Receptor 3A Polymorphism and Risk for HIV-Associated Cryptococcal Disease
title_short	Fc Gamma Receptor 3A Polymorphism and Risk for HIV-Associated Cryptococcal Disease
title_full	Fc Gamma Receptor 3A Polymorphism and Risk for HIV-Associated Cryptococcal Disease
title_fullStr	Fc Gamma Receptor 3A Polymorphism and Risk for HIV-Associated Cryptococcal Disease
title_full_unstemmed	Fc Gamma Receptor 3A Polymorphism and Risk for HIV-Associated Cryptococcal Disease
title_sort	fc gamma receptor 3a polymorphism and risk for hiv-associated cryptococcal disease
publisher	American Society for Microbiology
publishDate	2013
url	https://doaj.org/article/6602f27835e947148982552475dbe6fe
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Fc Gamma Receptor 3A Polymorphism and Risk for HIV-Associated Cryptococcal Disease

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