The objective of this proposal is to develop a new strategy that the investigator calls lethal mutagenesis for treatment of HIV infection. The AIDS virus mutates at an exceptionally high rate. As a result, the virus is able to evade the immunologic defenses of the host and to develop mutants resistant to chemotherapeutic agents. The applicants propose an approach to chemotherapy for HIV that is not defeated by viral mutagenesis, but rather exploits the unusually high mutation rate of HIV, and is intended for individuals who have failed currently available treatment protocols. They propose to identify nucleotide analogs that are efficiently incorporated by HIV reverse transcriptase, that are resistant to repair, and that form non-complementary base pairs with exceptionally high frequency. Their studies indicate that once-incorporated into an RNA-DNA hybrid, the first intermediate in viral replication, these mutagenic analogs are indeed resistant to repair by the host cell DNA repair systems. As a result, mutations are fixed and would progressively accumulate during repetitive viral replication cycles in the presence of the analog until the virus is unable to code for proteins required for its replication and infectious viruses are no longer produced. Preliminary results indicate that culture in the presence of a nucleoside analog can induce mutations in the HIV genome and ablate viral replication without diminishing host cell viability. Their goals are to validate the concept of lethal mutagenesis with known mutagenic analogs; to evaluate lead compounds for abolition of HIV infection in vitro, and for toxicity to host cells; and to design a system for screening large numbers of nucleotide derivatives that effectively promote lethal mutagenesis of HIV.
| Smith, Robert A; Loeb, Lawrence A; Preston, Bradley D (2005) Lethal mutagenesis of HIV. Virus Res 107:215-28 |
| Kawate, Hisaya; Landis, Daniel M; Loeb, Lawrence A (2002) Distribution of mutations in human thymidylate synthase yielding resistance to 5-fluorodeoxyuridine. J Biol Chem 277:36304-11 |
| Loeb, L A; Essigmann, J M; Kazazi, F et al. (1999) Lethal mutagenesis of HIV with mutagenic nucleoside analogs. Proc Natl Acad Sci U S A 96:1492-7 |
