Multiple effects of the M184V resistance mutation in the reverse transcriptase of human immunodeficiency virus type 1.

Abstract

The initial use of nucleoside reverse transcriptase inhibitors (NRTIs) in treatment of human immunodeficiency virus (HIV) disease, followed by highly active antiretroviral therapy, has significantly diminished HIV-related morbidity and mortality (22). However, antiretroviral therapy has also led to the emergence of drug resistance, potentially leading to virological and clinical failure. This problem is offset to some extent by the finding that drug-resistant viruses may have a measurable replication disadvantage in comparison to wild-type strains in the absence of drug pressure (26). This diminution in viral replication capacity or fitness is the result of resistance-conferring mutations in the reverse transcriptase (RT) and protease enzymes of HIV that affect their function; these mutations are amplified and/or selected by antiviral drug pressure. Therapeutic regimens containing lamivudine (3TC) have been shown to be highly effective in the treatment of HIVinfected patients, despite the fact that a single mutation at position 184 involving a transition from methionine to valine (M184V) confers a loss of susceptibility to this drug of 100- to 1,000-fold (5). Moreover, 3TC selects for this mutation rapidly compared to the development of resistance to other drugs (16, 31, 35). The M184V mutation may also be selected on occasion by abacavir and didanosine (ddI), but it confers only low-level resistance to these compounds (11, 33), and in general, the presence of an M184V mutation alone, in the absence of other mutations, does not represent an obstacle to the use of either ddI or abacavir in antiviral chemotherapy. The M184V mutation is also associated with impaired viral fitness, increased RT fidelity, and hypersensitization to several other NRTIs (23). In this review, we discuss the various effects of the M184V mutation on viral fitness, delay of appearance of other mutations, and potential immunological consequences in HIV-infected individuals.