Use of evolutionary limitations of HIV-1 multidrug resistance to optimize therapy
- 18 February 1993
- journal article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 361 (6413), 650-654
- https://doi.org/10.1038/361650a0
Abstract
Wild-type reverse transcriptase has evolved for the survival of human immunodeficiency virus type 1 (HIV-1) by natural selection. In contrast, therapy relying on inhibitors of reverse transcriptase by nucleosides like zidovudine (AZT) or dideoxyinosine (ddI), and by non-nucleosides like pyridinones or nevirapine, may exert different selection pressures on this enzyme. Therefore the acquisition of resistance to reverse transcriptase inhibitors by selection of mutations in the pol gene may require compromises in enzyme function that affect viral replication. As single mutations are unlikely to confer broad resistance when combinations of reverse transcriptase inhibitors are used, multiple mutations may occur that result in further compromises. Certain drug combinations may prevent the co-existence of adequate reverse transcription function and multi-drug resistance (MDR). Unlike bacterial or eukaryotic drug resistance, retroviral drug resistance is conferred only by mutations in its own genome and is limited by genome size. Combining drugs directed against the same essential viral protein may thus prevent HIV-1 MDR, whereas the conventional approach of targeting different HIV-1 proteins for combination therapy may not, because genomes with resistance mutations in different HIV-1 genes might recombine to develop MDR. Here we show that several mutations in the HIV-1 reverse transcriptase gene that confer resistance to inhibitors of this enzyme can attenuate viral replication. We tested whether combinations of mutations giving rise to single-agent resistance might further compromise or even abolish viral replication, and if multidrug-resistant viruses could be constructed. Certain combinations of mutations conferring resistance to AZT, ddI and pyridinone are incompatible with viral replication. These results indicate that evolutionary limitations exist to restrict development of MDR. Furthermore, a therapeutic strategy exploiting these limitations by using selected multidrug regimens directed against the same target may prevent development of MDR. This approach, which we call convergent combination therapy, eliminated HIV-1 replication and virus breakthrough in vitro, and may be applicable to other viral targets. Moreover, elimination of reverse transcription by convergent combination therapy may also limit MDR.Keywords
This publication has 30 references indexed in Scilit:
- Human immunodeficiency virus type 1 pol gene mutations which cause decreased susceptibility to 2',3'-dideoxycytidineAntimicrobial Agents and Chemotherapy, 1992
- Ordered Appearance of Zidovudine Resistance Mutations during Treatment of 18 Human Immunodeficiency Virus-Positive SubjectsThe Journal of Infectious Diseases, 1992
- Resistance to ddI and Sensitivity to AZT Induced by a Mutation in HIV-1 Reverse TranscriptaseScience, 1991
- Inhibition of HIV-1 Replication by a Nonnucleoside Reverse Transcriptase InhibitorScience, 1990
- Retroviral Recombination and Reverse TranscriptionScience, 1990
- Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivativesNature, 1990
- Multiple Mutations in HIV-1 Reverse Transcriptase Confer High-Level Resistance to Zidovudine (AZT)Science, 1989
- Clinical Pharmacology of 3'-Azido-2',3'-Dideoxythymidine (Zidovudine) and Related DideoxynucleosidesNew England Journal of Medicine, 1989
- Cloning of HTLV-4 and its relation to simian and human immunodeficiency virusesNature, 1987
- Complete Nucleotide Sequences of Functional Clones of the AIDS VirusAIDS Research and Human Retroviruses, 1987