Anemia, granulocytopenia, lymphopenia, and thrombocytopenia are common in HIV infection thought their pathogenesis is not well understood. Bone marrow hypoproliferation (ineffective hematopoiesis) is likely to be a main contributor to the etiology of these hematologic aberrations, and may be due to stem cell infection, or stromal cell infection with loss of a satisfactory microenvironment to support bone marrow growth. This growth is a complex process requiring primary and secondary colony stimulating factors, nutrients, and cell:cell contact. In addition, toxic, inhibitory, and immune factors must not be present if optimal hematopoiesis is expected. In studies of SIV infected rhesus macaques, we have described peripheral blood cytopenias, stage-related CFU-GM and BFU-E hypoproliferation, and absence of infection in CD34+ progenitors, partial restoration of CFU growth with high doses of IL-3 and GM-CSF, and the presence of an inhibitor of rhesus bone marrow secr eted by H IV-infected H9 cells. These data show the similarity of SIV-infected monkeys to HIV-infected humans, suggest that ineffective hematopoiesis, with cytokinetic and possibly inhibitory abnormalities, is a factor and support the use of this model for studying the effects of cytokine administration. We propose a comprehensive study of the hematologic and virologic consequences of exogenous cytokine administration in rhesus macaques experimentally infected with SIV. We will study effects of exogenously administered cytokines on hematopoietic compartment expansion, sites of cellular infection, and viral replication and burden following cytokine administration. We will utilize compartment specific cytokines, tested in monkeys infected with a lymphocyte or a monocyte predominant SIV strain. It is expected that, through these aims, the positive effects of cytokines in SIV-infected macaques can be demonstrated, any untoward effects of cytokines on viral replication can be elucidated, and a m odel can be characterized for future cytokine, bone marrow transportation, and gene therapy experiments. The studies in this project represent multidisciplinary collaboration among investigators with expertise in hematopoietic, immunologic, and virologic aspects of SIV infection and cytokine use in animal models. FUNDING NHLBI / R01HL55176-04 $277,927 8/01/95 - 7/31/99 PUBLICATIONS Brice, G.T., Riley, J.L., Villinger, F., Mayne, A., Hillyer, C.D., June, C.H. and Ansari, A.A. Development of an animal model for autotransfusion therapy in vitro characterization and analysis of anti-CD3/CD28 expanded cells. AIDS Res Human Retrovirus 19:210-20, 1998. Brice, G.T., Riley, J.R., Villinger, F., Mayne, A., June, C.H., Hillyer, C.D. and Ansari, A.A. Stimulation of costimulatory ligands induces SIV resistance and propagation of CD4+ T cells from non-human primates. AIDS (In press). Bucur, S.Z., Lackey III, D.A., Adams, J.W., Lee, M.E., Villinger, F., Mayne, A., Bray, R.A., Winton, E.F., Novembre, F., Strobert, E.A., de Rosayro, J., Dailey, P.J., Ansari, A.A. and Hillyer, C.D. Hematologic and virologic effects of lineage-specific and non-lineage-specific recombinant human and rhesus cytokines in a cohort of SIVmac239-infected macaques. AIDS Res. Hum. Retrovirus 14:651-660, 1998. Lee, M.E., Bucur, S.Z., Gillespie, T.W., Adams, J.W., Barker, A.T., Thomas, E.K., Roback, J.D. and Hillyer, C.D. Recombinant human CD40 ligand inhibits SIVmac replication A role for interleukin-16. J Med Primatol (In press). Lee, M.E., Adams, J.W., Villinger, F., Brar, S.S., Meadows, M., Bucur, S.Z., Lackey, D.A., Brice, G.T., Cruikshank, W.W., Ansari, A.A. and Hillyer, C.D. Molecular cloning and expression of rhesus macaque interleukin-16 and its inhibition of simian immunodeficiency virus infection and/or replication. AIDS Res Human Retrovirus 14:1323-8, 1998. Villinger, F., Chikkala, N.F., Brar, S.S., Bucur, S.Z., Lee, M.E., Gillespie, T.W., Adams, J.A., Bostik, P., Mayne, A.E., Dailey, P., Novembre, F.J., Ansari, A.A. and Hillyer, C.D. IL-12 responses in vivo are lost during disease progression in SIV infected macaques. J Med Primatol (In press). P51RR00165-38 1/1/1998 - 12/31/1998 Yerkes Regional Primate Research Center
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