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.