Mechanisms of Resistance To Reverse Transcriptase Inhibitors
While NRTIs and NNRTIs alike are effective at terminating DNA synthesis and HIV replication, HIV can and eventually does develop mechanisms that confer the virus resistance to the drugs. HIV-1 RT does not have proof-reading activity, this combined with selective pressure from the drug leads to mutations in reverse transcriptase that make the virus less susceptible to NRTIs and NNRTIs. Aspartate residues 110, 185, and 186 in the reverse transcriptase polymerase domain are important in the binding and incorporation of nucleotides. The side chains of residues K65, R72, and Q151 interact with the next incoming nucleotide. Also important is L74, which interacts with the template strand to position it for base pairing with the nucleotide. Mutation of these key amino acids results in reduced incorporation of the analogs.
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