Effects of Mutations in the Connection and RNase H Domains of HIV-1 Reverse Transcriptase on Drug Susceptibility

Despite the success in the development of antiretroviral therapy, the emergence of drug resistanceremains an important factor that can undermine the benefits of treatment. The vast majority of welldescribedresistance-associated mutations are clustered around the binding site for a given inhibitor.However, mutations that are observed at considerable distance from this location can likewise affectdrug susceptibility. Treatment-associated mutations in the C-terminal region of HIV-1 reverse transcriptaseprovide a recently surfaced example in this regard. In this review, we discuss the potentialclinical significance of these mutations and underlying molecular mechanisms. Routine resistancetesting does not usually include the C-terminal region of HIV-1 reverse transcriptase. However, previousstudies have shown that mutations in this region can reduce susceptibility to both nucleoside andnonnucleoside reverse transcriptase inhibitors. The prevalence of some of these mutations can be ashigh as reported for several classic resistance mutations in HIV-1 reverse transcriptase. Biochemicalstudies provided plausible mechanisms that help to explain how certain C-terminal mutations cancontribute to alterations in drug susceptibility and viral replication capacity. Overall, the available datawarrant further investigation on the impact of C-terminal mutations in combination with classic resistance-associated mutations, on changes in viral load, and response to treatment with different classesof reverse transcriptase inhibitors.