Functional Analysis of FIV ORF-A

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DESCRIPTION (provided by applicant):Feline immunodeficiency virus (FIV), a lentivirus of cats, causes an AIDS similar to what is seen in humans with human immunodeficiency virus (HIV). The clinical course of FIV infection parallels HIV infection in humans. A few weeks after experimental infection with FIV, cats develop an acute clinical syndrome like the HIV infection, including low-grade fever and transient generalized lymph node enlargement. This is followed by a long asymptomatic period in which the CD4+:CD8+ cell ratio declines because of a gradual decrease in CD4+ cells, and an increase in CD8+ cells as well. Similar to HIV, the FIV genome contains several open reading frames (ORFs) in addition to genes encoding for the structural proteins. The ORF-A gene product transactivates FIV promoter-dependent gene expression in vitro. Infection studies with ORF-A defective FIV show that virus replication is reduced both in vitro and in vivo. In cats infected with ORF-A defective FIV the onset of reduced peripheral blood CD4:CD8 ratio is delayed. Comparison of thymocyte subpopulations demonstrated a reduced expansion of single positive CD4-CD8+ thymocytes in ORF-A defective FIV infected cats. The observation that there is a reduction in virus replication and delay of the onset of parameters that measure immunodeficiency in cats infected with an ORF-A defective mutant suggests that this protein is important in the progress of disease caused by FIV. By determining the level of viral gene expression in different primary cells in the presence and absence of ORF- A, we will define the role of ORF-A in controlling the cell tropism and cytopathology. These studies in combination with dissection of functional characterization of the ORF-A will clarify the role of ORF-A in FIV pathogenesis.