Lineage-specific expression of human immunodeficiency virus (HIV) receptor/coreceptors in differentiating hematopoietic precursors: Correlation with susceptibility to T- and M-tropic HIV and chemokine-mediated HIV resistance

Human immunodeficiency virus (HIV) entry is mediated not only by the CD4 re ceptor, but also by interaction with closely related molecules that act as membrane coreceptors. We have analyzed mRNA expression and/or cell membrane exposition of the coreceptors most widely used by diverse HIV-1 strains (C XCR4, CCR5, and CCR3) on purified hematopoietic progenitor cells (HPCs) ind uced in liquid suspension culture to unilineage differentiation/maturation through the erythroid (E), granulocytic (G), megakaryocytic (Mk), and monoc ytic (Mo) lineages. Reverse transcriptase-polymerase chain reaction (RT-PCR ) and cytofluorimetric analysis showed the presence of both CXCR4 and CCR5 in quiescent HPCs, but failed to detect CCR3-specific transcripts. Chemokin e expression in HPC progenies showed that CXCR4 receptor is detected on the majority of MKs from early to late stages of maturation, whereas it is mod erately decreased in the Mo lineage. In the G pathway, two distinct cell po pulations, CXCR4(+) and CXCR4(-), were observed: morphological analysis of the sorted populations showed that the CXCR4(+) cells were largely eosinoph ils and the CXCR4- were granulocytes of the neutrophilic series. Furthermor e, in the E pathway, CXCR4 was almost completely absent. CCR5 expression is restricted to Mo cultures, ie, approximate to 30% to 80% cells throughout all monocytopoietic differentiation/maturation stages. Finally, CCR3 mRNA i s always absent in all the unilineage cultures. Evaluation of CD4 expressio n by flow cytometry on both quiescent HPCs and differentiating unilineage p recursors showed that the CD4 receptor is present on approximate to 15% of the starting CD34(+) HPC population, highly expressed in the Mo lineage up to 80% at terminal maturation, present on 20% to 30% of maturing Mks, and n ot detectable in either the E or G lineage. Expression of CD4 receptor toge ther with CXCR4 and/or CCR5 coreceptor in the four lineages correlates with hematopoietic precursor susceptibility to T-lymphotropic and macrophage (M )-tropic HIV strains infection: (1) CD4(-) G and E cells were resistant to both M-tropic and T-lymphotropic strains; (2) HPC derived Mks were suscepti ble to T tropic, but resistant to M-tropic, infection; (3) Mo differentiati ng cells efficiently replicate both HIV strains. Furthermore, we showed tha t the CXCR4 and CCR5 ligands (stromal-derived factor 1 and macrophage-infla mmatory protein-1 alpha [MIP-1 alpha], MIP-1 beta and RANTES, respectively) inhibit HIV replication in both maturing Mo and Mk cells. Taken together, our data show a lineage-specific modulation of chemokine receptor/corecepto r during hematopoietic cell differentiation and extend previous observation s on the relationship between the expression of HIV receptor/ coreceptors, susceptibility, and chemokine mediated resistance to HIV infection. (C) 199 9 by The American Society of Hematology.