The study of retroviruses have resulted in important discoveries and has lead to insights into basic cellbiology including mechanisms of cell signaling, transcriptional and post transcriptional control of geneexpression, and ultimately cellular transformation and cancer. Project 2 focuses on the human T-cellleukemia virus (HTLV) which is associated primarily with leukemia and highly valuable model of retrovirusinduced cancer. The long-term objective of this highly interactive project is to understand virus-hostinteractions that regulate viral replication post-transcriptionally. We have shown that the post-transcriptionalpositive HTLV regulatory protein, Rex, the focus of the previous application, does not directly contribute tocellular transformation in vitro. We extended our work through collaboration to identify and characterize anovel function of HTLV-1 and HTLV-2 related accessory gene products that act post-transcriptionally asnegative regulators of both Tax and Rex. Our exciting new function assigned to p28 and p30 as posttranscriptionalcontrol regulators provide the basis for the current proposal. We hypothesize that p28-mediated reduction of viral replication in T-lymphocytes and/or the proliferation of T-lymphocytes may permitsurvival of these cells by allowing escape from immune recognition, which would be consistent with thecritical role of HTLV accessory proteins in viral persistence in vivo. We seek to define the post-transcriptionalmechanisms of p28 repressive activity by 1) identifying and characterizing functional domains andbiochemical properties of p28, 2) determining the primary sequence and structure/function of the p28 mRNAtarget, and 3) determining the contribution of p28 in viral replication, lymphocyte activation/transformation,and persistence of the virus and in vivo. Understanding the exact mechanism of action of post-transcriptionalcontrol of p28/p30 ultimately will provide a means for therapeutic targeting of these proteins to eradicateHTLV persistence in the host. Important to this PPG, our findings will contribute to understand how HTLValters T-cell physiology and thus gain insight into the mechanisms of regulating viral replication and the earlyphases of lymphocyte activation and cellular transformation.
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