IgE-FcepsilonRI interactions determine HIV coreceptor usage and susceptibility to infection during ontogeny of mast cells.
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-FcepsilonRI interactions, occurring during a unique period of mast cell (MC) ontogeny, enhance prMC susceptibility to X4 and R5X4 virus. IgE-FcepsilonRI interactions significantly increased expression of CXCR4 mRNA ( approximately 400- to 1800-fold), enhanced prMC susceptibility to X4 and R5X4 virus ( approximately 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-FcepsilonRI interactions. IgE-FcepsilonRI 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.
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA. sundstromj@niaid.nih.gov
J Bruce
JB
Sundstrom
Gregory A
GA
Hair
Aftab A
AA
Ansari
W Evan
WE
Secor
Alasdair M
AM
Gilfillan
Dean D
DD
Metcalfe
Arnold S
AS
Kirshenbaum
D000818:Animals; D000947:Antigens, Helminth / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression; D006678:HIV / Q000276:immunology*; D015658:HIV Infections / Q000150:complications / Q000276:immunology*; D006373:Helminthiasis / Q000150:complications / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000276:immunology; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000150:complications / Q000276:immunology; D007073:Immunoglobulin E / Q000276:immunology* / Q000378:metabolism; D016130:Immunophenotyping; D008253:Macaca mulatta; D008407:Mast Cells / Q000276:immunology / Q000821:virology*; D054397:Receptors, CCR3 / Q000276:immunology / Q000378:metabolism; D019713:Receptors, CCR5 / Q000276:immunology / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000276:immunology* / Q000378:metabolism; D017455:Receptors, IgE / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000947:Antigens, Helminth; C515350:CCR3 protein, human; D015704:CD4 Antigens; C527276:CXCR4 protein, human; C502447:MS4A2 protein, human; D054397:Receptors, CCR3; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D017455:Receptors, IgE; D007073:Immunoglobulin E