Effects of reverse-transcriptase mutations M184V and E89G on simian immunodeficiency virus in Rhesus monkeys.

Mutations in human immunodeficiency virus type 1 reverse-transcriptase codons 89 and 184 confer inhibitor resistance and alter the mutation spectrum of the enzyme. Six macaques were inoculated with wild-type or mutated derivatives (E89G or E89G and M184V) of simian immunodeficiency virus macaque (SIVmac) 239. Five of the infected monkeys maintained high virus loads; the sixth, which was infected with the E89G mutant strain, maintained viremia at a level below the limit of detection. Sequence analysis demonstrated substantial reversion of the E89G mutation in the animals with progressive infection and preservation of this mutation in the animal with controlled infection. A P272S mutation occurred at high frequency in the viruses containing M184V, which did not revert. These results demonstrate that the E89G mutation has a significant negative impact on SIVmac fitness, whereas SIVmac bearing M184V achieved high, sustained virus loads, perhaps with a compensatory effect of the P272S mutation. Although combination antiretroviral therapy can dramatically alter the clinical course of human immunodeficiency virus (HIV) infection, the emergence of drug-resistant viruses is a major concern. Although many HIV-1 reverse-transcriptase (RT) mutants have decreased virus fitness in cell culture [1‐4], these viruses can be transmitted to new hosts and cause immunodeficiency [4‐7]. The introduction of RT mutations into simian immunodeficiency virus macaque (SIVmac) allows determination of the virulence of viruses bearing drug-resistant mutations, their relative fitness (compared with wild-type virus), the extent to which the mutations revert to wild type, and the accumulation of other, potentially compensatory, mutations. The E89 and M184 RT residues are highly conserved among primate lentiviruses and are located near the active site in structural models of HIV-1 RT [8]. M184 is part of the YMDD motif, which is present in the RT protein of most retroviruses. The M184V mutation is found in clinical HIV isolates and confers high-level resistance to lamivudine (3TC) [9]. The E89G mutation was isolated during an in vitro screen for 2,3-dideoxyguanosine resistance [10] and also confers resistance to multiple nucleoside and nonnucleoside inhibitors and to foscarnet [10‐12]. However,