DEVELOPMENT OF A NOVEL ANTI-HIV-1 AGENT FROM WITHIN - EFFECT OF CHIMERIC VPR-CONTAINING PROTEASE CLEAVAGE SITE RESIDUES ON VIRUS-REPLICATION

Effective antiviral agents will he of great value in controlling virus replication and delaying the onset of HIV-1-related disease symptoms, Current therapy involves the use of antiviral agents that target the enzymatic functions of the virus, resulting In the emergence of resist ant viruses to these agents, thus lowering their effectiveness. To ove rcome this problem, we have considered the idea of developing novel ag ents from within HIV-1 as inhibitors of virus replication, The specifi city of the Vpr protein fur the HIV-I virus particle makes it an attra ctive molecule for the development of antiviral agents targeting the e vents associated with virus maturation. We have generated chimeric Vpr proteins containing HIV-l-specific sequences added to the C terminus of Vpr, These sequences correspond ttl nine cleavage sites of the Gag and Gag-Pol precursors of HIV-1. The chimeric Vpr constructs were intr oduced into HIV-1 proviral DNA to assess their effect on virus infecti vity using single- and multiple-round replication assays, The virus pa rticles generated exhibited a variable replication pattern depending o n the protease cleavage site used as a fusion partner, Interestingly, the chimeric Vpr containing the cleavage sequences from the junction o f p24 and p2, 24/2, completely abolished virus infectivity, These resu lts show that chimeric proteins generated fi om within HIV-1 have the ability to suppress HIV-I replication and make ideal agents for gene t herapy or intracellular immunization to treat HIV-1 infection.