Convergent combination therapy can select viable multidrug-resistant HIV-1 in vitro

Abstract

THE reverse transcriptase enzyme of human immunodeficiency virus type 1 (HIV-1) is the target for many inhibitors¹. Amino-acid substitutions in functional regions of the enzyme that abolish reverse transcriptase activity also prevent HIV-1 replication^2,3. But selection pressure by drugs such as AZT (3'-azido-3'-deoxythymid-ine, zidovudine)^4–6, ddl (2',3'-dideoxyinosine)^7,8 and non-nucleoside reverse transcriptase inhibitors (NNRTIs)^9–14 causes outgrowth of resistant variants due to non-lethal mutations in the enzyme^7,9–16. Reports of synergy^17–19 and lack of cross-resistance between reverse transcriptase inhibitors (refs 7, 9, 10, 12–14, 17, 18, 20, 21), plus the reversal of AZT resistance by mutations induced by ddl7 and NNRTIs¹⁴, have indicated that specific drug combinations directed at reverse transcriptase might curtail resistance. Chow et al.²² extended this concept in a report that specific multiple combinations of resistance mutations in the reverse transcriptase can significantly impair HIV-1 replication. They concluded that evolutionary limitations may exist to prevent the emergence of multidrug resistance to inhibitors of reverse transcriptase²². We report here that HIV-1 co-resistant to AZT, ddl and the NNRTI nevirapine²³ can be readily selected in cell culture starting with dual AZT- and ddl-resistant virus. We found no evidence for 'replication incompatible' combinations of resistance mutations, although a mutation (M184→V) conferring oxathiolane-cytosine nucleoside resistance in reverse transcriptase^24,25 completely sup-pressed AZT resistance in a triple-resistant background. These in vitro observations suggest that triple drug combination therapy might ultimately result in co-resistant HIV-1, although they do not preclude assessment of such combinations for treatment of HIV-1 disease.