1. McGill University AIDS Centre, Jewish General Hospital, 3755 Chemin Côte Ste-Catherine, Montreal, Quebec, Canada, H3T 1E2

Treatment of HIV-infected patients with either nucleoside (NRTI) or non-nucleoside reverse transcriptase (RT) inhibitors (NNRTI) commonly selects for viral mutants that display resistance against these compounds. Resistance is due to a series of mutations in the viral RT itself, and studies with recombinant enzymes that contain relevant amino acid substitutions have generally confirmed the presence of a drug-resistant phenotype in assays performed with nucleoside trisphosphate compounds of NNRTIs.

At least several nucleoside compounds that block the RT of HIV-1 can also interfere with the polymerase activity of hepatitis B virus. Both nucleoside triphosphate antagonists of HIV-RT and NNRTI's can specifically interfere with synthesis of (+) strand viral DNA as well as (-) DNA. In addition, drug resistance conferring mutations in RT may have a number of other effects, including altered RT processivity, fidelity and patterns of pausing, In the case of a recombinant enzyme that combines both the Ml84V and E89G substitutions, the latter mutation is dominant in regard to these considerations.

A new series of 4'-thio-heterosubstituted nucleoside analogues possesses important anti-HIV activity. Moreover, resistance against these drugs seems to be selected very slowly, and, in some cases, no mutation site in RT has been associated with diminished sensitivity to these drugs. In addition, the pro-drugs of certain well-established compounds may be worth examining in regard to anti-HIV activity, due to the fact that these may have longer half-lives and different patterns of metabolism than derivative compounds that have sometimes been used in the clinic. An excellent example is that of Phosphazid, a prodrug of AZT, but against which selection for resistance in tissue culture occurs much slower than against AZT.

Finally, 9-(2-phosphonomethoxypropyl) adenine (PMPA) is an acyelic nucleoside phosphonate analogue that is active against HIV, SIV and several of the herpes virus family. As in the case of Phosphazid and the 4'-thio-heterosubstituted nucleoside analogues, resistance in tissue culture against PMPA develops very slowly and to very low levels. Although sequencing of the viral RT and site-directed mutagenesis have shown that the K65R mutation in RT can confer low-level resistance to PMPA, it is equally interesting that the M184V mutation, associated with resistance to 3TC, may marginally enhance HIV sensitivity to PMPA, thereby establishing rationale for the use of PMPA in people who possess the M184V mutation on for the use of PMPA and 3TC in combination. The activity of PMPA is also enhanced in the presence of hydroxyurea (HU), an inhibitor of the cellular enzyme ribonucleotide reductase.

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