Role of HTLV Rex in Viral Replication &Transformation

Ohio State University, Columbus OH

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Abstract

DESCRIPTION (provided by applicant): It is estimated that between 15 and 25 million people worldwide are infected with human T-cell leukemia virus type 1 (HTLV-1) or type 2 (HTLV-2). HTLV infection is associated primarily with leukemia and neurological disease in a small percentage of infected patients. Although infected patients develop antibody and cytotoxic T-lymphocyte (CTL) response to many of the viral proteins, the virus manages to persist throughout life. One of the viral regulatory proteins, Rex, is critical for viral replication and has been implicated in the transition from early to late phase of HTLV gene expression. Rex is a nuclear phosphoprotein and acts post-transcriptionally to facilitate accumulation of full-length gag/pol and singly spliced env viral RNAs in the cytoplasm of HTLV-infected cells. We have reported that phosphorylation of HTLV-2 Rex (Rex-2) is required for the efficient binding of Rex to HTLV target RNAs in vitro. Several outstanding questions regarding Rex function and HTLV biology are: 1) how does phosphorylation regulate Rex function, 2) does control of the Rex regulatory switch of early-to-late viral gene expression contribute to viral latency and persistence and, 3) does Rex contribute directly to the cellular transformation process? Our recent rex mutational analysis resulted in the identification of a novel domain at the carboxy terminus that is phosporylated in vivo positively regulating Rex function. Phosphomimetic amino acid substitutions in this domain results in a fully functional constitutively active Rex. In this application, we focus on this unique phosphorylation domain taking advantage of a key set of mutants to determine how Rex regulates viral gene expression and contributes to the overall biology of the HTLV. Our Specific Aims are (1) to define the biochemical properties of Rex-2 mutants required for function, (2) to determine the role of Rex-2 phosphorylation on viral replication and cellular transformation, (3) to determine the effects of Rex on viral persistence in HTLV infected rabbits (4) to develop an HTLV that replicates independent of Rex to directly assess the role of Rex in cellular transformation.