A NOVEL STRATEGY TO INTERFERE WITH HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 PROPAGATION

Aim. investigate a unique and critical step in retroviral gene express ion not yet targeted for anti-viral therapy and to validate its potent ial as a site for anti-MN intervention with a new group of therapeutic drugs. Methods. A reporter system was designed using recombinant DNA methods to include sequence elements mediating translational frameshif ting from HIV-1 and human antizyme RNAs. A mammalian in vitro protein synthesis system was used to assess the ratio of two separate reporter products in the presence of several drugs that are known to affect ri bosomal function. Results. The strategy aimed at modulating the ratio of viral proteins by disrupting frameshifting. Of the drugs tested, cy cloheximide at 1 mu M was the most promising candidate, resulting in a 35% reduction in frameshifting efficiency at the HIV site in the repo rter system. At this concentration cycloheximide did not significantly affect frameshifting at the human antizyme site (the only known human protein to use translational frameshifting in its synthesis), nor inh ibit translational efficiency of cellular proteins in general. Conclus ions. A new group of drugs like cycloheximide that modify viral protei n ratios have the potential to add significantly to the control of HIV . Viruses may be less likely to escape control from such a drug since it is targeted to cellular components required by the virus for frames hifting rather than the viral frameshift sequence itself. The reporter system used in this study is amenable for the first stage testing of a wide range of drugs.