Infectious Disease: Evolving Challenges to Human Health
ANTIRETROVIRALS & THE HIV PANDEMIC

How Do Antiretroviral Drugs Work? -- Text-only Version

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HIV is a retrovirus. It enters the cells, inserts into host genomes, makes new virus, and can persist for the life of an individual.

We open on a field of virons, and the camera follows one as it heads towards a T cell.

HIV reproduction involves several steps, and each step presents an opportunity for antiretroviral drugs to stop the virus.

The HIV viron model approaches the T cell membrane in closer view, and docks.

The outer shell of the HIV particle is called the envelope. It is studded with sugar-protein spikes that allow the virus to attach itself to specific molecules called “CD4 receptors” on some human cells.

Surface proteins are identified on the HIV model. GP 120 and GP 41 proteins are labeled. CD4 receptors are labeled.

The viral core contains two important features. The HIV genome is carried on two strands of RNA. These strands contain only nine genes, in contrast to the 500 genes in the typical bacterium, and roughly 20,000 genes in a human cell.

The viral core (capsid) is identified. The two strands of RNA are also identified.

The core also contains three enzymes. These molecules, called reverse transcriptase, integrase, and protease are necessary for reproduction.

The viral enzymes are identified, then the virus model fades out.

When an HIV interacts with a CD4 receptor and co-receptor on the surface of certain human immune system cells, HIV’s envelope fuses with the membrane of the cell, and the virus releases its RNA and enzymes into the cell, leaving the envelope behind.

The virus model reappears and bumps into an immune system cell. Dissolve or zoom in on HIV surface proteins fusing to CD4 and release of the virus contents into the cell.

Drugs called entry inhibitors can block this step in the HIV life cycle.

Entry inhibitors are shown overlaid on CD4. The fade away near the end of the scene, allowing an HIV viron to fuse to the cell and release its contents into the cell (a different view of the action in scene 7).

If HIV enters the cell, the first step of viral reproduction can begin. Reverse transcriptase copies the HIV RNA into DNA, which is compatible with human DNA.

Zoom in on a strand of RNA (or the RNA from multiple virons might be visible). Reverse transcriptase transcribes RNA into DNA strands.

Reverse transcriptase lacks the elaborate proofreading machinery used by the cell to copy DNA. As a result, reverse transcriptase is prone to many copying errors, or mutations. HIV mutates so readily during these transcriptions that every HIV virus in an infected person has some genetic differences from every other virus in the same person.

Zoom in on reverse transcriptase to see the assembly of nucleotides into new DNA strands. Errors appear in the process.

AZT was the first drug in a class of reverse transcriptase inhibitors. Some inhibitors are altered building blocks of DNA. When they are inserted into a DNA strand their incomplete structures block further synthesis of strands.

Reset the zoomed in animation with reverse transcriptase inhibitors supplying incomplete nucleotides that halt assembly of DNA strands.

Other inhibitors block the action of reverse transcriptase by binding directly to the enzyme. These actions prevent HIV reproduction. Proper use of these drugs can reduce the viral load in the blood to undetectable levels.

Zoom out to show transcription of viral RNA into DNA stopped in mid-process.

If reverse transcriptase is not blocked then the newly made DNA strands migrate into the cell’s nucleus.

Reset to the zoomed view of DNA assembly. As DNA assembly is completed, zoom out as the DNA migrates into the nucleus.

The HIV enzyme integrase splices the DNA into the cell’s genome. At this stage, HIV infection becomes a permanent part of the immune system cell, and a permanent infection. Drugs to block integration are in development.

Integrase splices DNA into the cell’s DNA. (Note that the DNA strands to not present open gaps to the viral genes. Rather, integrase splices viral genes into unbroken strands of DNA.

When activated, the viral DNA is transcribed into many strands of messenger RNA using human cell’s machinery to make new virus proteins. Viral messenger RNA is exported out of the nucleus, where it will now serve as the blueprint for HIV proteins and the genetic material for new virions.

Human DNA and the DNA created by reverse transcriptase are transcribed by the host cell’s RNA polymerase into strands of messenger RNA. The messenger RNA migrates out of the nucleus.

The messenger RNA is translated into new strings of viral proteins.

mRNA is translated into polypeptides and proteins.

The HIV enzyme called protease cuts the string of proteins into new copies of the structural proteins and enzymes. The viral RNA, proteins, and enzymes gather near the cell membrane and new virons begin to bud at the membrane.

The viral components migrate to the cell membrane. Zoom in to see protease cutting polypeptides into new enzymes.

This stage in the viral life cycle can be blocked by a powerful class of antiretroviral drugs called “protease inhibitors.” When present, protease inhibitors prevent the protease from cleaving to the strings of proteins. This action inhibits the production of HIV structural proteins and enzymes, and blocks the maturation of new viruses.

Zoom in on protease, which is blocked from cleaving to the polypeptides. Zoom back out to see fragments of HIV left inactivated near the cell membrane.

Scene continues, then fades.

Developing an effective antiretroviral therapy program for HIV infection is a complex process that considers each individual patient’s health status.

Antiretroviral drugs can present toxicity problems and significant side effects for some HIV patients.

Patients on anti-retroviral therapy must be monitored for adverse reactions to medications and the emergence of drug-resistant HIV.

Combinations of three or four different drugs are used simultaneously to interfere with multiple points in the HIV lifecycle and delay the emergence of drug-resistant HIV for as long as possible.

Once an untreatable and fatal disease, HIV can now be managed as a chronic infection. Although substantially prolonging quality of life for HIV-infected people, treatment can present significant challenges and burdens to patients and society. And, because of the rise of drug-resistance, new drugs are constantly needed.