HEMATOLOGIC AND VIROLOGICAL EFFECTS OF LINEAGE-SPECIFIC AND NON-LINEAGE-SPECIFIC RECOMBINANT HUMAN AND RHESUS CYTOKINES IN A COHORT OF SIVMAC239-INFECTED MACAQUES

The hematologic abnormalities of SIV and HIV are well described, altho ugh the mechanisms that lead to hematopoietic dysfunction are yet to b e fully defined, A number of growth factors and cytokines have been us ed to induce the differentiation, maturation, and proliferation of app ropriate lineages, with the aim that such therapy will lead to functio nal hematopoietic reconstitution, Within this context, some cytokines have been shown to influence HIV and SIV replication in vitro and, in selected cases, in vivo. However, few studies detail the effects of he matopoietic cytokines such as IL-3, Flt-3 ligand, G-CSF, Tpo, and Epo or correlate the effects on virus replication. In an effort to address this issue, we infected 12 rhesus macaques with 500 TCID50 of SIVmac2 39 and intensively evaluated hematologic, virologic, and immunologic p arameters during administration of cytokines, When all animals had lym phadenopathy, hepatosplenomegaly, and CD4(+) cell counts greater than or equal to 1000/mu l, subgroups of three rhesus macaques were adminis tered either rhFlt-3; rrIL-3a; combination of rhG-CSF, rhTpo, and rhEp o (rhGET); or rrIL-12. Fourteen days of rhFlt-3 administration induced expansion of the bone marrow CD34(+) cells and granulocyte-macrophage colony-forming units (GM-CFUs) and increased absolute peripheral bloo d CD34(+) cells and total CFUs, Following rrIL-3 and rhGET administrat ion absolute peripheral blood CD34(+) cells and total CFUs increased. rhGET also increased granulocyte, platelet, and reticulocyte counts by day 14 of administration. Branched DNA and coculture assays did not d emonstrate any significant change in viral load with any of the cytoki nes administered, These data suggest that SIV-infected rhesus macaques have the hematopoietic capability to expand and mobilize CD34(+) and GM-CFU progenitors and formed elements at 6-8 months postinfection in response to various cytokines, without increasing viral load.