Integrase and entry inhibitors

Transcript

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.

Sources
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  2. "Rang and Dale's Pharmacology" Elsevier (2019)
  3. "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition" McGraw-Hill Education / Medical (2017)
  4. "Metabolic, mitochondrial, renal and hepatic safety of enfuvirtide and raltegravir antiretroviral administration: Randomized crossover clinical trial in healthy volunteers" PLOS ONE (2019)
  5. "Structure of the CCR5 Chemokine Receptor-HIV Entry Inhibitor Maraviroc Complex" Science (2013)
  6. "HIV-1 Antiretroviral Drug Therapy" Cold Spring Harbor Perspectives in Medicine (2012)