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Non-nucleoside reverse transcriptase inhibitors (NNRTIs)


Content Reviewers:

Yifan Xiao, MD

Reverse transcriptase inhibitors are an important part of HAART, or highly active antiretroviral therapy, which is the combination of medications used in the treatment of AIDS.

AIDS is caused by a RNA containing retrovirus called human immunodeficiency virus, or HIV. The “retro” part of retrovirus isn’t referring to its style, but refers to it needing to use an enzyme called reverse transcriptase to transcribe a piece of “proviral” DNA from its RNA.

As the name suggests, reverse transcriptase inhibitors go and inhibit this enzyme, and prevent HIV replication.

They can either be nucleoside reverse transcriptase inhibitors, or NRTIs, which resemble nucleosides, which are the building blocks of nucleic acids like DNA and RNA; or non-nucleoside reverse transcriptase inhibitors, or NNRTIs, which dont resemble nucleosides.

HIV is a single-stranded, positive-sense, enveloped RNA retrovirus that targets cells in the immune system that have a molecule called CD4 on their membrane.

These include macrophages, dendritic cells, and especially CD4+ T-helper cells. Normally, the CD4 molecule helps these cells attach to and communicate with other immune cells, which is particularly important when the cells are launching attacks against foreign pathogens.

HIV attaches to the CD4 molecule via a protein called gp120 found on its envelope. Now, inside its envelope, HIV contains a nucleocapsid which is a capsule containing a single-stranded RNA and some viral enzymes, like reverse transcriptase and integrase.

As HIV bind to the receptors, the viral envelope fuses with the cell membrane of the immune cell, releasing the contents of the nucleocapsid into the helpless host cell’s cytoplasm.

Once it’s inside the CD4+ cell, reverse transcriptase gets to work immediately. It uses the single stranded viral RNA as a template, and uses the nucleotides present in the cytoplasm of the CD4+ cell to transcribe a complementary double-stranded “proviral” DNA.

Proviral just means that it’s ready to be integrated into the host’s DNA, so it enters the T-helper cell’s nucleus and pops itself into the cell’s DNA, ready to be transcribed into new viruses, pretty sneaky, huh?

Well, here’s the actual sneaky part—when the immune cells become activated, they start transcribing and translating proteins needed for the immune response.

Ironically, this means that whenever the immune cell is exposed to something that causes it to start up an immune response, like any infection, the immune cell ends up inadvertently transcribing and translating new HIV viruses, which bud off from the cell membrane to infect more cells.

Very sneaky indeed! Over time, more and more immune cells are infected, and the immune system begins to fail, which is called immunodeficiency, and this increases the risk of infections and tumors that a healthy immune system would usually be able to fend off.

These complications are referred to as AIDS, or acquired immunodeficiency syndrome. Now there are two distinct types of HIV—HIV-1 and HIV-2, which have slightly different proteins and enzymes.

HIV-1 is the more commonly associated with AIDS in the US and worldwide, HIV-2 is more rare, and typically restricted to areas in western Africa and southern Asia.

NNRTIs are allosteric inhibitors of reverse transcriptase, particularly that of HIV-1. This means that they bind to the allosteric site of the enzyme, which is a tiny regulatory switch next to the active site, or nucleoside binding site.

Binding of NNRTI to the allosteric site sets forth a series of changes in enzyme, which alters the structure of its active site.

The end result is that the nucleosides cannot bind to the enzyme anymore, and new proviral DNA is not transcribed. This stops new viruses from being created and keeps other CD4+ cells from getting infected.

However, it’s important to note that NNRTIs have no effect on the completed proviral DNA already incorporated into the CD4+ cells, and the cells that are already infected remain infected. So, NNRTIs can only slow down the progression of the disease, but not cure it.

Some commonly used NNRTIs include efavirenz, etravirine, delavirdine, and nevirapine. These medications are rarely used alone, since HIV quickly develop resistance to them by point mutation of the enzyme.


Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a type of antiviral medication used to treat HIV infection. They work by inhibiting the HIV's reverse transcriptase enzyme, thus preventing the multiplication of the virus.

Some NNRTIs such as efavirenz and delavirdine are teratogenic. Non-teratogenic NNRTIs include nevirapine and etravirine. Common side effects of NNRTIs include hypersensitivity reactions, dizziness, hallucinations, vivid dreams, and in some cases, there may be toxic epidermal necrolysis and Stevens-Johnson syndrome.

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