The hematologic effects of SIV and HIV are well described, but the pathogenesis is poorly understood. Postulated mechanisms include abnormal regulation of CD34+ progenitor cell growth, dysregulation of hematopoietic cytokines, or the presence of an inhibitor of hematopoiesis. Regardless of mechanism, hematopoietic cytokines can be used to improve peripheral blood counts though their effect on viral replication and burden has not been adequately addressed. To study potential mechanisms and effect on viral regulation, a cohort of 27 rhesus macaques was infected with 500 TCID50 SIVmac239 with the intent of administering cytokines at approximately 6 months (""""""""early"""""""" infection; n=12) and when symptomatic with disease (""""""""late"""""""" infection; n=12). In each group of 12 animals, 4 subgroups are assigned (n=3 each subgroup) to receive either rh-flt-3 ligand (a stem cell compartment specific cytokine), rr-IL-3 (a committed progenitor cell compartment cytokine), combination rh-G-CSF/EPO/ TPO (active on maturing cell lineages), or rr-IL-12 (as an immunomodulatory cytokine). One subgroup has received rh-flt-3 ligand and one subgroup rr-IL-3 (early) with G-CSF/EPO/TPO and IL-12 (early) subgroups to commence presently. Following rh-flt-3 ligand, the CD34+ progenitor cell bone marrow compartment did not significantly expand (1.03 +/-0.19%, day 0 vs 1.48 +/- 0.8%, day 15), though release of CD34+ cells into the peripheral blood led to a maximum of 22.9 x 103/ml on day 8. (This is in comparison to our SIV- monkeys where BM CD34+ cells were 0.75 +/- 0.22, day 0 and 2.11 +/- 1.14% day 11 [p < .05], and day 15 CD34+ cells reached 96.2 x 103/ml ). CFU-GM expansion and viral burden studies by quantitative PCR are underway. PCR of CD34+ cells enriched by flow cytometric sorting did not amplify SIV genomic elements. Parallel experiments of non-adherent peripheral blood MNC from this cohort (with and without stimulation with 5 ug PHA) and with increasing doses of cytokines dem onstrated an increase in p27 of > 2x over control by rr-IL-3 but not rh-flt -3 or EPO. Full characterization of the 12 animals that received cytokines """"""""early"""""""", including CD34+ cells and subsets, CD3, 4, 8, 19, 16/56, CFU-GM, BFU-E, viral coculture, and viral burden by PCR is underway.
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