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How do nucleoside reverse transcriptase inhibitors block HIV replication?

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Diagram illustrating the process of retrovirus infection and reverse transcription, showing a retrovirus entering a host cell, releasing viral RNA, reverse transcriptase converting RNA to DNA, integration into the host genome, transcription of new viral RNA, assembly of new virions, and budding from the cell. — Reverse transcriptase After a retrovirus infects a cell, an enzyme known as reverse transcriptase converts viral RNA into proviral DNA in the cytoplasm. Proviral DNA then enters the nucleus, where it is incorporated into the host cell's DNA.

Nucleoside reverse transcriptase inhibitors (NRTIs) block HIV replication by interfering with the function of reverse transcriptase, the enzyme responsible for converting viral RNA into DNA.12

To become active, these drugs must first be phosphorylated within the cell. Once activated, they function as structural mimics of the natural nucleosides required for DNA synthesis. Because these drugs have a high affinity for reverse transcriptase, the enzyme mistakenly incorporates them into the growing strand of viral DNA instead of the correct building blocks.12

Crucially, these inhibitors lack the necessary chemical group (the hydroxyl group) required to attach subsequent nucleosides to the DNA chain. By incorporating themselves into the chain, they act as "chain terminators," effectively halting the synthesis of viral DNA. This prevents the virus from integrating its genetic material into the host cell's genome, thereby stopping the production of new viral particles.21