Use of evolutionary limitations of HIV-1 multidrug resistance to optimize therapy

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.

Optimal control of the chemotherapy of HIV

“…This, of course, will reduce the time period over which therapy can be administered. New research suggests that combination drug treatments is preferable since there is a reduced chance of the virus mutating simultaneously to strains resistant to all of the drugs present in the 'cocktail' [6,27]. We are presently exploring these phenomena through a revised model.…”

Interactions Between Drug Resistance Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase

“…How can we reconcile the above observations with those of Chow et al (1993a)? One possibility was that the replication-defective triple mutant reported was nonviable for reasons other than the presence of the four resistance mutations.…”

“…However, Chow et al (1993a) reported that mutant virus containing substitutions conferring resistance to AZT (T215Y, K219Q) and ddI (L74V) became non-viable when an NNRTI resistance mutation (K103N) was added. This prompted speculation that so-called convergent combination therapy would not result in simultaneous resistance to AZT, ddI and an NNRTI such as nevirapine.…”

Synergistic Inhibition of Human Immunodeficiency Virus Type 1 in vitro by 6-0-butanoylcastanospermine (MDL 28574) in Combination with Inhibitors of the Virus-Encoded Reverse Transcriptase and Proteinase

“…Some groups have proposed that convergent combination therapy may be the most appropriate for the treatment of HIV infections, by virtue of the fact that multiple mutations in the same viral gene should cause the total compromise of an essential viral enzyme function. Theoretically this should prevent the development of multi-drug resistance (Chow et al, 1993). It appears, however, that multi-drug-resistant variants can still be selected during such combination therapy (Emini et al, 1993;Larder et al, 1993).…”