Structural determinants and molecular mechanisms for the resistance of HIV-1 RT to nucleoside analogues

The reverse transcriptase (RT) of human immunodeficiency virus type-1 (HIV-1) is all RNA- and DNA-dependent DNA polymerase capable of copying the viral genome before it gets integrated into the human host DNA. Hence, HIV-1 RT plays a major role in viral replication and represents a key target for anti-AIDS treatments. Amongst the eleven licensed drugs that inhibit RT. eight are chain-terminating nucleoside analogues (NRT1s) that compete with their natural counterparts during the DNA polymerization process. Unfortunately, under therapeutic pressure, the HIV-1 inevitably develops resistance to these inhibitors by accumulating mutations in the viral pot gene encoding RT. Mechanisms for this resistance can be sorted in two categories, depending oil the nature of the drug and the selected mutations. The first category includes mutations involving a specific alteration of the discrimination between natural nucleotides and NRT1s. The second category includes mutations able to promote the removal of the incorporated NRT1 and thus repair the nascent DNA chain. This review summarizes the modes of inhibition of HIV-1 RT with NRT1s, and describes the mechanisms of resistance to these drugs, based oil enzymatic data correlated to crystal structures and molecular models involving HIV-1 RT. We also give insights into different aspects of resistance such as antagonistic mutations, replication capacity and the implications for a rational, structure-based drug design.