The broad goals of this proposal are to characterize the mechanisms involved in lentivirus-induced marrow suppression by studying virus:host cell interactions in cats with acute feline immunodeficiency virus (FIV) infection. Experimental acute FIV infection induces severe neutropenia that is associated with a high level of plasma viremia, productively- infected marrow accessory cells, and alterations in hematopoietic progenitor frequencies, cell-cycle kinetics, and growth in autologous serum. Chronic infection causes a long- latency AIDS-like illness that is also associated with frequent peripheral blood and marrow abnormalities. This disease is, however, variably induced in experimental models and studies of hematopoiesis in community cats are confounded by opportunistic infections, nutritional deficiencies, profound immunosuppression, and, occasionally, neoplasms. As FIV and human immunodeficiency virus (HIV) are virologically and biologically similar, these studies are relevant to the effects of (HIV) on marrow hematopoietic and accessory cells. The first specific aim is to systematically study the changes in numbers and in vitro growth characteristics of marrow CFU-GM BFU-E, and earlier progenitors in cats which have been inoculated with FIV-Petaluma. The infection frequencies of peripheral blood and marrow T-lymphocytes and monocyte/macrophages will be determined and correlated with the growth- promoting or inhibitory effects of these cells, or their soluble products, on progenitors in coculture assays. The progenitor growth-inhibitory effect of sera from cats with acute infection will be characterized as to the possible role of cytokines, viral products, antibodies, or immune complexes. The effects of clinical and laboratory FIV isolates, and of recombinant FIV proteins, on hematopoietic progenitors and on the ability of marrow microenvironmental cells to support progenitor growth will be assessed in in vitro experimental models.
The second aim i s to determine the mechanisms by which a nonpathogenic coinfecting retrovirus, feline leukemia virus (FeLV- A/61E), augments FIV-associated marrow suppression in vivo and alters FIV:host cell interactions in marrow cells in vitro. As dual infection with HIV and human T-cell leukemia virus (HTLV) is well-documented and associated with a shorter survival, these studies are relevant to the role of viral copathogenesis in AIDS. The third specific aim is to characterize the genetic determinants responsible for the virulent phenotype of FIV isolates. Preliminary studies revealed that the hematopoiesis-supporting ability of a stromal cell line was significantly impaired after infection with a clinical isolate from a neutropenic cat, while infection with a clinical isolate from a second (non-neutropenic) cat had no effect. Proviral DNA from this and other isolates will be cloned and virulent (hematosuppressive) and nonvirulent variants will be characterized. Recombinant chimeric viruses will then be constructed, exchanging sequences from a nonvirulent molecular clone with sequences from a hematosuppressive variant, in order to localize the gene region(s) that correlate with adverse effects on hematopoietic cells. Together, these studies will provide insights to the viral, humoral, and host cell factors mediating hematologic disorders in AIDS.
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