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FcRIIa Genotype Predicts Progression of HIV Infection¹

Donald N. Forthal^2,*, Gary Landucci^*, Jay Bream, Lisa P. Jacobson, Tran B. Phan^* and Benjamin Montoya^*

^* Division of Infectious Diseases, Department of Medicine, University of California, Irvine School of Medicine, Irvine, CA 92697; and Disease Prevention and Control Program, Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, and Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205

Polymorphisms in FcR 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 FcRIIa 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 FcRIIa 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 FcRIIIa 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 FcRs in AIDS pathogenesis and point toward a critical role for interactions between FcRs and immune complexes in disease progression.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by funds from the California HIV/AIDS Research Program (formerly the University-wide AIDS Research Program) of the University of California, Grant ID06-I-226. The MACS is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute: UO1-AI-35042, 5-MO1-RR-00722 (GCRC), UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, and UO1-AI-35041.

² Address correspondence and reprint requests to Dr. Donald N. Forthal, 3044 Hewitt Hall, University of California, Irvine, CA 92697. E-mail address: dnfortha{at}uci.edu

³ Abbreviations used in this paper: MACS, Multicenter AIDS Cohort Study; CI, confidence interval; OR, odds ratio; IC, immune complexes; KS, Kaposi’s sarcoma.

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