The impact of the M184V substitution on drug resistance and viral fitness.


Treatment of HIV/AIDS with antiretroviral therapy can result in HIV-1 drug resistance, limiting its use. Resistance mutations arise prior to therapy due to errors in HIV-1 replication, and are also spread by sexual and other modes of transmission. However, it is also generally believed that resistance is due to multiple drug mutations to any single or combination of antiretroviral agents selected during viral replication in the presence of incompletely suppressive drug regimens. In the case of protease inhibitors and most nucleoside analog reverse transcriptase inhibitors, drug resistance is due to the accumulation of mutations in the HIV-1 protease and reverse transcriptase genes respectively. However, in the case of non-nucleoside reverse transcriptase inhibitors, a single primary drug mutation is usually sufficient to abrogate antiviral activity. This is also true of certain specific mutations, such as M184V in the reverse transcriptase enzyme, resulting in resistance to the nucleoside analog, lamivudine (Epivir, GlaxoSmithKline). However, it is thought that lamivudine may still contribute to the effectiveness of antiretroviral therapy, even after the appearance of the M184V mutation. M184V may affect sensitivity to other drugs, such as zidovudine (Retrovir, GlaxoSmithKline), in HIV-1 variants that already contain resistance mutations to zidovudine, during concomitant treatment with lamivudine. M184V also has a positive effect on HIV-1 RT fidelity, reducing spontaneous HIV mutagenesis. Processivity of the reverse transcriptase enzyme may be affected by mutations such as M184V, and this may be a major determinant of viral replication fitness.




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