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How can HIV mutations lead to resistance to antiretroviral drugs?

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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.

HIV develops resistance to antiretroviral drugs primarily due to its high rate of mutation during replication. This process is driven by the viral enzyme reverse transcriptase, which lacks the "proofreading" function found in most DNA-synthesizing enzymes.12

Because reverse transcriptase frequently makes errors while converting viral RNA into DNA, the virus evolves rapidly—approximately one million times faster than the human genome. These mutations allow the virus to alter its structure or function, enabling it to escape the inhibitory effects of drugs such as nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs).12

When a virus acquires a mutation that renders a specific drug ineffective, the drug can no longer suppress viral replication. To combat this, clinicians use combination therapies, such as highly active antiretroviral therapy (HAART), which target the virus at multiple points in its life cycle. Using multiple drugs simultaneously makes it significantly more difficult for the virus to develop resistance to all of them at once.342