Integrase and entry inhibitors

Entry inhibitors and integrase inhibitors are groups of medications that are used in HAART, or highly active antiretroviral therapy, which is the combination of medications used in the treatment of AIDS.

AIDS is caused by a retrovirus called human immunodeficiency virus, or HIV. Entry inhibitors act by preventing the binding of HIV to the CD4+ cell receptors, thereby preventing its entry into the cell.

Integrase inhibitors inhibit the viral integrase enzyme, which is needed to incorporate the HIV proviral DNA into the host cell DNA.

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 activate other immune cells when there’s an infection.

HIV has 2 proteins, gp120 and gp41 that form a complex on its envelope, which it uses to attach to the CD4 molecules. Next, it uses this complex to attach to a co-receptor on the immune cell before it can gain entry.

The most common co-receptor that HIV binds to the CXCR4 co-receptor on T-cells; or the CCR5 co-receptor found on T-cells, macrophages, monocytes, and dendritic cells.

When HIV binds to the CD4 and the co-receptors, the viral envelope fuses with the cell membrane of the immune cell, releasing its single-stranded RNA and some viral enzymes, like reverse transcriptase and integrase 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.

Integrase then helps to integrate this proviral DNA into the normal DNA of the cell. Now it’s 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, in order to prevent the HIV virus from infecting a cell, we can use entry inhibitors, also called fusion inhibitors.

The first medication, enfuvirtide, targets the HIV virus by binding to the gp41 present on its envelope and disabling it, so there’s no fusion of viral and cell membranes.

This medication is given to treat strains of HIV that developed resistance against other commonly used antiretroviral medications, like nucleoside reverse transcriptase inhibitors.

Enfuvirtide is given as subcutaneous injections. Its main side effects include pain and development of cysts or nodules at the injection site.

There’s also an increased risk of bacterial infections leading to problems like pneumonia. The second type of entry inhibitor is maraviroc, which targets the immune cells.

This medication binds to the CCR5 co-receptor on the surface of macrophages and T-cells, which prevents gp120 from binding.

This medication can’t be used against HIV strains that bind to CXCR4 receptor instead of CCR5. CCR5 receptor inhibitors are used as add-on medications in HAART regimens, which means that they’re used to boost the effect of the other antiretroviral medications.

CCR5 receptor inhibitors are generally well tolerated. The most common side effects include diarrhea, joint and muscle pain, and they can also damage the liver, leading to jaundice and elevated hepatic enzymes.Now, suppose the virus fuses with the immune cell and deposits its RNA and enzymes.

Now, we can use integrase inhibitors like raltegravir, elvitegravir, and dolutegravir. These guys enter the HIV infected cell and reversibly bind to the active site of viral integrase enzyme.

This means that the pro-viral DNA can no longer be incorporated into the host cell’s DNA, which stops the formation of new HIV viruses.

Integrase inhibitors are used as first line medications in HAART, along with two nucleoside reverse transcriptase inhibitors, or NRTIs.

Side effects of integrase inhibitors include nausea, headache, and myopathy which leads to elevated creatinine kinase. Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharmacology facts!

Let’s have some HIV viruses invade from the sea, while the land represents our immune cell. These viruses are carrying a pitchfork to represent the number 4, and a wand for 1, to help you remember gp41.

A tidal wave, representing enfuvirtide, is about to knock the weapons out of their hands and foil their invasion. On the beach, are 5 coconut trees, representing the CCR5 protein.

Patrolling by the trees is a soldier armed with a pair of maracas, representing maracavir. He’s pretty diligent in preventing the viruses from making it to the treelines, but the HIV that doesn’t target CCR5 can still make it past him.

Now some of these lucky viruses aren’t so lucky after all. Further inland, representing inside the cell, there’s a tiger waiting for them.

This represents the integrase inhibitors with “tegra” in their name, like raltegravir, elvitegravir, and dolutegravir. It’s got a heart shaped spot on his body to help you remember it’s used for HAART therapy.

For side effects, there’s a happy little bacteria surfing on the enfuviride-al wave for bacterial infections, and he’s got a syringe sticking out of his head for injection site pain.

Next to the maracavir soldier, there’s another guy doing push ups. He’s lifting a big liver shaped stone on his back for hepatic damage and elevated liver enzymes, and his joints and muscles are swollen since it’s too heavy for him.

Finally, the tiger has a bunch of weight training equipment to help you remember integrase inhibitors cause myopathy and elevated creatinine kinase.

##SummaryAll right, as a quick recap, entry inhibitors include enfuvirtide, which targets the gp41 on the envelope of HIV, and maraviroc, which targets the CCR5 co-receptor on certain immune cells.

These medications prevent the entry of HIV into the CD4+ cells, and are used as add-on medications in HAART therapy. Integrase inhibitors like raltegravir, elvitegravir, and dolutegravir inhibit viral integrase and prevent insertion of pro-viral DNA into host cell genome.

These medications stop the production of new HIV viruses, and are commonly used along with two nucleoside reverse transcriptase inhibitors in HAART therapy.

is lifting a big liver shaped stone on his back for hepatic damage and elevated liver enzymes and his joints and muscles are swollen since it's too heavy for him Finally the tiger has a bunch of weight training equipment to help you remember integrase inhibitors cause myopathy and elevated creatinine kinase All right It's a quick recap entry inhibitors include invert which targets the GP 41 on the Enlo of and Meave which targets a CCR five co receptor on certain immune cells These medications prevent the entry of HIV into the CD four positive cells and are used as add-on medications and heart therapy Integrase inhibitors like raltegravir elvitegravir and dolutegravir inhibit viral integrase and prevent insertion of pro viral DNA into the host cell genome These medications stop the production of new HIV viruses that are commonly used along with two nucleoside reverse transcriptase inhibitors and heart therapy But wait there's more here's a mind map with all the mnemonics from the video Go ahead and pause the video so you can test yourself to see what you remember Stay tuned for the answers after