Humans cytomegalovirus (HCMV) causes opportunistic infections in immunocompromised individuals, including AIDS patients, persons immunosuppressed by chemotherapeutic agents, and newborn infants. New therapies for treating HCMV disease are warranted because of the toxicities associated with currently approved drugs (ganciclovir and foscarnet) and because of the emergence of drug-resistant viruses in the clinic. the long-term goal of this project is to discover new therapies for treating HCMV disease in immunocompromised patients. The main hypothesis to be tested is whether certain nucleotide analogs related to ganciclovir and benzothiophene analogs already found active in cell culture against HCMV and murine cytomegalovirus (MCMV) will be effective against MCMV in immunocompetent and immunosuppressed animal models. Other hypotheses to be tested concern the effectiveness of these compounds against a foscarnet- resistant virus infection in mice and when used in combination to combat MCMV disease. MCMV has been chosen as a model for HCMV because the human virus will not infect rodents. To test these hypotheses, we are providing two mouse models of MCMV infection using normal BALB/c mice and severe combined immunodeficient (SCID) mice. Compounds active in vitro (in other projects of the overall proposal) will be evaluated in normal mice to establish in vivo antiviral activity. Two of the most active agents will be tested further in detailed antiviral studies in normal and SCID mice. These studies will assess disease parameters (death, mean survival time, tissue virus titers), immune parameters (natural killer cell activity, T- cell and B-cell blastogenesis), toxicity, and analysis for latency by using polymerase chain reaction methodology. The antiviral activity of the two compounds will also be assessed against a foscarnet-resistant form of MCMV in SCID mice. A combination chemotherapy experiment will be performed the third year in SCID mice by using an active nucleotide analog or benzothiophene analog combined with a clinically approved antiviral drug (ganciclovir or foscarnet). These studies will determine the suitability of the new agents for consideration for clinical development.
| Smee, D F; Reist, E J (1996) Potent anti-murine cytomegalovirus activity and reduced nephrotoxicity of ganciclovir cyclic phosphonate. Antimicrob Agents Chemother 40:1964-6 |
| Smee, D F; Barnett, B B; Sidwell, R W et al. (1995) Antiviral activities of nucleosides and nucleotides against wild-type and drug-resistant strains of murine cytomegalovirus. Antiviral Res 26:1-9 |
| Smee, D F; Sugiyama, S T; Reist, E J (1994) Nucleotide analogs related to acyclovir and ganciclovir are effective against murine cytomegalovirus infections in BALB/c and severe combined immunodeficient mice. Antimicrob Agents Chemother 38:2165-8 |
