Megakaryocyte precursors, megakaryocytes and platelets express the HIV co-receptor CXCR4 on their surface: determination of response to stromal-derived factor-1 by megakaryocytes and platelets

Thrombocytopenia is a late complication of human immunodeficiency Virus (HI V) infection. The chemokine receptor CXCR4 has been shown to be a co-recept or for lymphocyte-tropic HIV-1 strains. CXCR4 is also a natural receptor fo r the chemokine SDF-1. We have previously shown that CXCR1 and CXCR2 are pr esent on megakaryocytes and platelets. Although interleukin-8 (IL-8) and ot her chemokines that bind to these two receptors do not activate platelets, they are able to inhibit megakaryocytopoiesis, presumably through these rec eptors. We therefore examined whether CXCR4 is present on developing and ma ture megakaryocytes and on platelets. Reverse transcription-polymerase chai n reaction (RT-PCR) demonstrated the presence of CXCR4 message. Immature an d mature alpha IIb alpha 3(+) megakaryocytes, and platelets were also posit ive for CXCR4 by flow cytometric studies using a CXCR4-specific antibody. W e then tested whether SDF-1 can affect the biology of these cells. CD34(+) cells and immature alpha IIb beta 3(+) cells responded to SDF-1 as indicate d by Ca2+ mobilization and chemotaxis, However, mature megakaryocytes faile d to demonstrate either of these responses, in spite of their continued abi lity to bind I-125-SDF-1. Further, SDF-1 failed to inhibit megakaryocyte co lony growth. platelets bound I-125-SDF-1 with a K-D similar to the affinity seen for CXCR4 on other cells, yet SDF-1 did not aggregate washed platelet s nor augment aggregation by low-dose ADP or thrombin. SDF-1 also failed to stimulate Ca2+ mobilization, granular release or expression of P-selectin in platelets. Accordingly, although our studies demonstrate that CD34(+) pr ecursors, megakaryocytes and platelets all express CXCR4 and bind SDF-1, bi ological effects were only demonstrable of SDF-1 on CD34(+) precursors. The potential biological implications of CXCR4 expression on maturing megakary ocytes and platelets in normal individuals and following HIV infection are discussed.