What Enzyme Does AZT Inhibit? Understanding the Role of Reverse Transcriptase in HIV Therapy

October 9, 2025 •

4 min read

First approved in 1987, the drug azidothymidine (AZT), now known as zidovudine, was the first medication to be made available for the treatment of HIV/AIDS, offering a glimmer of hope during a critical period of the epidemic. Its effectiveness hinges on its ability to inhibit a specific viral enzyme: HIV reverse transcriptase.

Quick Summary

This article explores how the antiretroviral drug AZT inhibits HIV's reverse transcriptase enzyme. It details the mechanism by which AZT acts as a nucleoside analog to block viral DNA synthesis, contrasts its action with human enzymes, and explains its modern use within combination therapy to combat viral resistance and reduce side effects.

Key Points

Inhibits Reverse Transcriptase: AZT, or zidovudine, primarily inhibits the viral enzyme HIV reverse transcriptase, which is essential for HIV to replicate.
Acts as a Nucleoside Analog: As a thymidine analog, AZT gets phosphorylated inside cells and is mistakenly incorporated into the growing viral DNA chain by reverse transcriptase.
Causes DNA Chain Termination: The lack of a 3'-hydroxyl group on the incorporated AZT prevents further DNA elongation, effectively stopping viral replication.
Is Part of Combination Therapy (HAART): Due to resistance and toxicity with monotherapy, AZT is now used in combination with other antiretroviral drugs to maximize efficacy and minimize side effects.
Associated with Potential Toxicity: At higher doses, AZT can inhibit mitochondrial DNA polymerase, leading to side effects like myopathy and bone marrow suppression.
Can Lead to Viral Resistance: HIV can develop resistance through mutations in its reverse transcriptase that either increase its ability to excise AZT from the DNA chain or impede its incorporation.

The Mechanism of AZT: Inhibiting HIV's Blueprint Enzyme

AZT (zidovudine) functions by targeting a specific enzyme critical to the human immunodeficiency virus's (HIV) life cycle: reverse transcriptase (RT). As a retrovirus, HIV uses this enzyme to convert its genetic material, which is in the form of RNA, into DNA. This viral DNA then integrates into the host cell's DNA, essentially hijacking the cell's machinery to produce more viruses. By inhibiting this crucial step, AZT disrupts HIV replication and slows the progression of the disease.

How AZT achieves viral DNA chain termination

AZT's inhibitory effect is a masterstroke of pharmaceutical design, relying on its structural similarity to a natural building block of DNA. Here's a step-by-step breakdown of its mechanism:

Analog of a Nucleoside: AZT is a synthetic nucleoside analog, structurally mimicking the natural nucleoside thymidine.
Cellular Activation: Once inside a human cell, cellular enzymes phosphorylate AZT, adding phosphate groups to transform it into its active form, zidovudine triphosphate (ZDV-TP).
Competitive Inhibition: The HIV reverse transcriptase enzyme mistakes ZDV-TP for the natural building block, thymidine triphosphate, and incorporates it into the growing chain of viral DNA.
Chain Termination: Unlike the natural thymidine, AZT lacks a crucial hydroxyl (-OH) group at the 3' position. This deficiency means that once AZT is incorporated, no further nucleotides can be added to the viral DNA strand, effectively terminating its synthesis.

Selective affinity and potential toxicities

One of AZT's key features is its selectivity. It has a significantly higher affinity for HIV's reverse transcriptase than for the human DNA polymerases responsible for replicating our own cellular DNA. This selectivity allows it to primarily target the virus while sparing most uninfected host cells. However, at high concentrations, the active form of AZT can also inhibit mitochondrial DNA polymerase, an enzyme involved in mitochondrial replication. This can lead to mitochondrial damage, which was linked to severe side effects such as myopathy (muscle weakness) and myelosuppression (bone marrow toxicity) during the era of AZT monotherapy.

The Evolution of AZT in HIV Treatment

Originally used alone, AZT's role has evolved significantly since its introduction, largely due to the rapid development of drug resistance by HIV. Its history underscores key lessons in HIV pharmacology and the importance of combination therapy.

Monotherapy challenges and the rise of resistance

In the early years, AZT was prescribed as a standalone treatment, or monotherapy. Unfortunately, HIV has a high mutation rate, and with prolonged use, resistant viral strains would inevitably emerge and flourish. These resistant strains could either:

Develop mutations that enhance the RT enzyme's ability to selectively remove the incorporated AZT (excision).
Acquire mutations that decrease the efficiency with which the enzyme incorporates the AZT analog.

Combination therapy (HAART)

To address the issues of resistance and toxicity, the strategy shifted to Highly Active Antiretroviral Therapy (HAART), which involves using a combination of drugs from different classes. This approach creates a high genetic barrier, making it extremely difficult for the virus to mutate and develop resistance to multiple drugs simultaneously. In modern HAART regimens, lower doses of AZT are used in combination with other agents, which significantly reduces toxicity while maintaining viral suppression.

Comparison of Antiretroviral Drug Classes


Feature	AZT (NRTI)	Lamivudine (NRTI)	Protease Inhibitors (PIs)
Mechanism	Competitively inhibits reverse transcriptase, causing DNA chain termination.	Competitively inhibits reverse transcriptase, causing DNA chain termination.	Blocks the protease enzyme, preventing the cleavage of viral proteins into their final, functional forms.
Drug Class	Nucleoside Reverse Transcriptase Inhibitor (NRTI).	Nucleoside Reverse Transcriptase Inhibitor (NRTI).	Protease Inhibitor (PI).
Role in HIV Cycle	Prevents the conversion of viral RNA to DNA.	Prevents the conversion of viral RNA to DNA.	Blocks the maturation of new viral particles.
Side Effects	Myelosuppression (anemia), myopathy, lactic acidosis.	Generally well-tolerated; potential side effects include headache, nausea, and fatigue.	Hyperglycemia, hyperlipidemia, and potential for metabolic issues.
Current Use	Standard component of HAART, often in fixed-dose combinations.	Standard component of HAART, often in fixed-dose combinations.	Also a core component of HAART regimens.

Conclusion: The Legacy of AZT

AZT's discovery and development marked a pivotal moment in the history of HIV/AIDS treatment, demonstrating for the first time that an antiretroviral drug could effectively slow the course of the disease. While its initial use as monotherapy was hampered by significant toxicity and the rapid evolution of viral resistance, the pharmacological lessons learned paved the way for the development of combination therapies. Today, AZT remains a crucial component of modern HAART regimens and plays a vital role in preventing mother-to-child transmission. Its journey from a groundbreaking but flawed monotherapy to a standard component of potent combination regimens is a testament to the ongoing evolution of pharmacology in the fight against HIV/AIDS. Understanding what enzyme AZT inhibits and how the virus adapts remains central to improving treatment strategies and patient outcomes.

Frequently Asked Questions

AZT, also known as zidovudine, primarily inhibits the viral enzyme HIV reverse transcriptase.

AZT is a nucleoside analog that gets converted into its active triphosphate form inside the cell. The HIV reverse transcriptase mistakenly incorporates this active form into the newly synthesized viral DNA. Because AZT lacks a critical hydroxyl group, it causes premature DNA chain termination, halting the virus's replication.

AZT monotherapy led to rapid development of drug resistance by HIV, due to the virus's high mutation rate. Additionally, the high doses used resulted in significant side effects.

AZT has a much higher affinity for HIV reverse transcriptase compared to human DNA polymerases. This selectivity ensures it primarily targets the virus. However, at high concentrations, it can interfere with mitochondrial DNA polymerase, leading to toxic effects.

Historically, high-dose AZT monotherapy was associated with side effects such as myelosuppression (anemia), myopathy, and lactic acidosis due to mitochondrial toxicity.

HIV develops resistance by mutating its reverse transcriptase enzyme. These mutations can either improve the enzyme's ability to excise the incorporated AZT analog or reduce the efficiency with which the analog is initially incorporated.

Today, AZT is used as part of Highly Active Antiretroviral Therapy (HAART) in combination with other antiretroviral drugs from different classes. This approach lowers dosing, reduces side effects, and significantly minimizes the risk of resistance.

Yes, AZT remains a critical component of regimens used to prevent mother-to-child transmission of HIV during pregnancy and childbirth.