Am. J. Respir. Cell Mol. Biol., Volume 20, Number 5, May, 1999 864-871

CD4 Receptor-Dependent Entry of Human Immunodeficiency Virus Type-1 env-Pseudotypes into CCR5-, CCR3-, and CXCR4-Expressing Human Alveolar Macrophages Is Preferentially Mediated by the CCR5 Coreceptor

In-Woo Park, Henry Koziel, William Hatch, Xiuhong Li, Bin Du, and Jerome E. Groopman

Divisions of Experimental Medicine, Hematology/Oncology, and Pulmonary and Critical Care Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts

Alveolar macrophages (AM) are important host-defense cells and targets of human immunodeficiency virus type 1 (HIV-1) infection. However, the receptors mediating HIV-1 entry into AM are not completely characterized. We observed that, in addition to CD4 receptors, AM from healthy adults expressed low levels of CCR5, CCR3, and CXCR4 chemokine receptors by flow cytometry, and specific messenger RNA was detected for all three receptors by reverse transcriptase/polymerase chain reaction. The macrophage monocytotropic (M-tropic; YU2) and dual-tropic (89.6) HIV-1 env-pseudotypes entered AM efficiently, as expected given CCR3 and CCR5 expression. However, the T-lymphocytotropic (T-tropic; HXB2) pseudotype did not enter AM despite expression of the appropriate chemokine coreceptor CXCR4. Incubation of AM with regulated on activation, normal T cells expressed and secreted (RANTES) significantly impaired entry of the M-tropic (YU2) HIV-1 pseudotype, whereas SDF-1 or eotaxin did not impair entry. The entry of simian immunodeficiency virus (SIV) pbj1.9 env-pseudotype into AM was not blocked by RANTES, SDF-1, or eotaxin. The competence of these chemokine receptors for virus entry was confirmed in Cf2Th canine thymocytes cotransfected with the human CD4 and chemokine receptors. Entry of the M-tropic (YU2) HIV-1 pseudotype was shown to be mediated by either CCR3 or CCR5, the T-tropic (HXB2) HIV-1 pseudotype by CXCR4, and the dual-tropic (89.6) HIV-1 or the SIVpbj1.9 pseudotype by CCR5, CCR3, or CXCR4. Our data indicate that the mechanisms for HIV-1 entry are both receptor-specific and cell type-specific, and that chemokine receptor expression on AM does not fully explain cell susceptibility to different virus isolates.

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