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IgE-FcRI Interactions Determine HIV Coreceptor Usage and Susceptibility to Infection during Ontogeny of Mast Cells¹

J. Bruce Sundstrom^2,*, Gregory A. Hair^*, Aftab A. Ansari^*, W. Evan Secor, Alasdair M. Gilfillan, Dean D. Metcalfe and Arnold S. Kirshenbaum

^* Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322; Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30341; and Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

Progenitor mast cells (prMCs), derived from CD34⁺ precursors are CD4⁺/CCR5⁺/CXCR4⁺ and susceptible to CCR5(R5)-tropic virus but only marginally susceptible to CXCR4(X4)-tropic HIV. As infected prMCs mature within extravascular compartments, they become both latently infected and HIV-infection resistant, and thus capable of establishing an inducible reservoir of CCR5-tropic infectious clones. In this report we provide the first evidence that IgE-FcRI interactions, occurring during a unique period of mast cell (MC) ontogeny, enhance prMC susceptibility to X4 and R5X4 virus. IgE-FcRI interactions significantly increased expression of CXCR4 mRNA (400- to 1800-fold), enhanced prMC susceptibility to X4 and R5X4 virus (3000- to 16,000-fold), but had no significant effect on CD4, CCR3, or CCR5 expression, susceptibility to R5 virus, or degranulation. Enhanced susceptibility to infection with X4 virus occurred during the first 3–5 wk of MC ontogeny and was completely inhibited by CXCR4-specific peptide antagonists and omalizumab, a drug that inhibits IgE-FcRI interactions. IgE-FcRI coaggregation mediated by HIVgp120 or Schistosoma mansoni soluble egg Ag accelerated maximal CXCR4 expression and susceptibility to X4 virus by prMCs. Our findings suggest that for HIV-positive individuals with atopic or helminthic diseases, elevated IgE levels could potentially influence the composition of CXCR4-tropic and R5X4-tropic variants archived within the long-lived tissue MC reservoir created during infection.

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 in part by Grant R01AI062383 from the National Institutes of Health (to J.B.S.), in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases/National Institutes of Health, and in part by base Grant RR-00165 from the Animal Resources Program of the National Institutes of Health awarded to the Yerkes National Primate Research Center at Emory University.

² Address correspondence and reprint requests to Dr. J. Bruce Sundstrom, Scientific Review Program, Division of Extramural Activities, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-7616. E-mail address: sundstromj{at}niaid.nih.gov

³ Abbreviations used in this paper: prMC, progenitor mast cell; MC, mast cell; SS, strong stop; β-hex, β-hexosaminidase; SmEA, Schistosoma mansoni egg Ag; DC, dendritic cell; HAART, highly active antiretroviral therapy.

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The JI 2009 182: 5887-5888. [Full Text]