ANTISENSE INHIBITION OF HIV INFECTION

THE GOAL OF THIS RESEARCH IS TO USE SPECIFIC ANTISENSE SEQUENCES TO INHIBIT, IN VITRO, ACUTE INFECTION OF LYMPHOID CELLS BY HIV. PHASE IEEFFORTS WILL INCLUDE: (1) EXAMINATIONOF THE PROCESS OF DNA REPLICATION AND INTEGRATION DURING HIV INFECTION OF LYMPHOID CELL LINES USING IN SITU HYBRIDIZATION AND IN VITRO ANALYSIS OF NUCLEAR DNA, (2) EXAMINATION OF THE EFFECTS OF KNOWN INHIBITORS OF THE EARLY PHASE OF HIV INFECTION ON THIS PROCESS, AND (3) DESIGN AND TESTING OF SPECIFIC ANTISENSE RNA CONSTRUCTS FOR INHIBITION OF ACUTE INFECTION OF LYMPHOID CELLS. BECAUSE LATENCY IS ESTABLISHED DURING ACUTE INFECTION OF CELLS BY HIV, THE ANTISENSE CONSTRUCTS DEVELOPED MAY BE USEFUL FOR PREVENTING THE ESTABLISHMENT OF LATENCY. THESE AND NEW CONSTRUCTS WILL BE USED TO PREVENT THE ACTIVATION OFHIV FROM LATENTLY INFECTED CELLS. APPROPRIATE DELIVERY VECTORS CONTAINING EFFECTIVE ANTISENSE CONSTRUCTS WILL THEN BE DEVELOPED. THE RESEARCH PROGRAM HAS SIGNIFICANCE IN TWO AREAS: IT WILL INCREASE UNDERSTANDING OF THE VIROLOGY AND PATHOLOGY OF HIV,AND IT WILL HAVE AN IMPACT ON EFFORTS DESIGNED TO CONTROL THE INFECTIOUS PROCESS AND THE DISEASE. ANTISENSE CONSTRUCTS AND ANTISENSE MANIPULATION OF BLOOD STEM CELLS OF AIDS PATIENTS EVENTUALLY MAY BE USED TO CONTROL THE EXPRESSION OF HIV IN CHRONICALLY INFECTED CELLS; TO PREVENT THE ACTIVATION OF HIV FROM THE CHRONICALLY INFECTED CELLS; AND TO PREVENT THE INFECTION OF NEWLY GENERATED, OR INTRODUCED, PREVIOUSLY UNINFECTED CELLS.