Nucleoside reverse transcriptase inhibitors (NRTIs)

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.

Based on their structure, they can be classified into nucleoside reverse transcriptase inhibitors, or NRTIs; and non-nucleoside reverse transcriptase inhibitors, or NNRTIs.

NRTIs resemble nucleosides, which are tiny molecules which when attached to a phosphate group give rise to nucleotides, which are building blocks of nucleic acids like DNA and RNA.

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.

NRTIs are structural analogues of nucleosides.

So, when an NRTI molecule enters the cell, it gets phosphorylated, or a phosphate group is added, and it will resemble a nucleotide.

This fake nucleotide molecule now competes with the natural nucleotide in the infected cell for the attention of reverse transcriptase.

If it’s picked and inserted into the proviral DNA, it will screw up HIV’s entire plan.

Think of DNA like a written instruction for synthesizing proteins, and the nucleotides are the letters.

The NRTI molecule are like random foreign letters that disrupts the instruction so viral proteins can’t be made.

Also, additional nucleotides can not be added to the NRTI molecules inserted into the proDNA so this stops its synthesis.

So instead of the proviral DNA, what we end up with are a bunch of incomplete instructions full of gibberish.

This stops new viruses from being created and keeps other CD4+ cells from getting infected.