The impact of the M184V substitution in HIV-1 reverse transcriptase on treatment response

The M184V mutation in the HIV-1 reverse transcriptase gene is primarily associated with rapid, high-level lamivudine (3TC) resistance. It has also been observed to arise under selective pressure by abacavir, to which it confers low-level resistance. Although the development of viral drug resistance remains a major concern in antiretroviral therapy, it is known that some immunological and clinical benefit can still be derived from highly active antiretroviral therapy (HAART) regimens despite resistance-associated virological failure. This residual benefit on a failing regimen is commonly attributed to the preservation of fitness-reducing protease inhibitor (PI) resistance mutations under continued drug pressure. However, fitness-reducing nucleoside reverse transcriptase inhibitor (NRTI) mutations may also contribute to the effect. M184V is both common in the treated population and fitness-reducing. A number of studies, both of dual nucleoside therapy and HAART, have noted a residual treatment effect for 3TC despite the assumed or observed presence of M184V and high-level phenotypic resistance. The speed and consistency with which this mutation is selected by 3TC under suboptimal viral suppression therefore makes M184V a particularly interesting model for further clinical studies on the association of drug resistance with ongoing treatment benefit. While fitness considerations are likely to be a major contributor to the clinical observations noted, there are a number of other potential mechanisms that may contribute to a continuing response to 3TC in the presence of M184V. These include the delay and reversal of zidovudine (ZDV) resistance, hypersensitization to other NRTIs, reduced reverse transcriptase (RT) processivity and a possible reduction in RT pyrophosphorolysis. The full impact of M184V on therapeutic prospects will require further elucidation; ideally, the risk/benefit of preserving this substitution would be investigated in randomized trials. However, existing data suggest that the presence of this mutation may preserve some benefit in spite of the loss of 3TC susceptibility which, with further study, may prove valuable.