The reverse transcriptase of HIV-1: role of the domain connection and RNase H in anti-retroviral resistors

Twenty-five years after the beginning of HIV antiretroviral therapy, reverse transcriptase inhibitors (RTIs) remain the backbone of HAART. Unfortunately, the emergence of drug resistance can undermine the benefits of this potent treatment. As regards RTIs resistance, the vast majority of well-described resistance-associated mutations are clustered in the N-terminal polymerase domain of HIV-1 reverse transcriptase. However, this enzyme is not limited to a single domain and mutations observed at considerable distance from this location can likewise affect drug susceptibility by themselves or in association with "classical" mutations. Some authors suggest that mutations in the C-terminal, connection and RNase H, domains are associated with antiretroviral therapy. The potential clinical significance of these mutations is presented in this review. In the second part, we report the plausible biochemical mechanisms explaining how these mutations can contribute to affect drug susceptibility and viral replication capacity. Overall, sequencing the entire reverse transcriptase in order to understand resistance should be useful due to the presence of these mutations outside of the polymerase domain, but further investigations are still warranted to determine their impact in clinical practice.