How NRTIs and NtRTIs work

As nucleoside reverse transcriptase inhibitors (NRTIs) and nucleotide reverse transcriptase inhibitors (NtRTIs) have a similar mechanism of action, they are usually regarded as a single drug class.

When reverse transcription occurs in the presence of these drugs, they disrupt the construction of a new piece of proviral DNA. Instead of taking up a natural nucleotide from the supply in the cell, reverse transcriptase may use an NRTI or NtRTI triphosphate instead. Because these drugs have a slightly different structure than natural nucleotides, they cannot form the necessary chemical bonds, and natural nucleotides cannot be added on to continue the chain. Since HIV has no mechanism for correcting such mistakes, NRTIs and NtRTIs can interrupt reverse transcription and thereby halt HIV replication.

NRTIs and NtRTIs can stop reverse transcription and interfere with workings of human cells. Because they resemble the natural building blocks of DNA, there is a risk that NRTI or NtRTI triphosphates may be taken up when host cells reproduce. Some researchers believe this is a not a major problem, since the equivalent human enzyme, called DNA polymerase, has a much lower affinity than reverse transcriptase for NRTI/NtRTI triphosphates. Moreover, human cells have mechanisms for recognising and correcting mistakes in DNA production.

Nevertheless, certain NRTIs do have side-effects that have been attributed to damage to a specific type of DNA found within the mitochondria, tiny structures responsible for energy production within cells. Mitochondrial DNA also must be copied when a cell divides, a process carried out by an enzyme called polymerase-gamma. Compared with DNA polymerase, this enzyme has a relatively high affinity for NRTI/NtRTI triphosphates, so mitochondrial DNA is more vulnerable to the effects these drugs.^{1 2} Symptoms thought to be related to mitochondrial damage include lactic acidosis, lipoatrophy (fat loss in the face and limbs), and peripheral neuropathy. For more information, see Mitochondrial toxicity in Side-effects.