Back To CourseBiology 103: Microbiology
16 chapters | 156 lessons | 12 flashcard sets
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Katy teaches biology at the college level and did her Ph.D. work on infectious diseases and immunology.
If someone asked you which infection in the whole world you most wanted to avoid getting, what would you say? Many of us would say HIV, or Human Immunodeficiency Virus, the virus that causes AIDS, which is a disease that devastatingly weakens the human immune system. HIV is a really scary virus to most people and for good reason.
It stays quiet in the body for years before causing any symptoms, so people who don't even know they have it can transmit it to others through their blood and bodily fluids. If it's allowed to run its course and develop into AIDS, it eventually weakens the immune system so much that the patient will die of rare infections that would never be a problem for a healthy person.
And perhaps even more frightening, the HIV virus is designed for fast evolution because it makes a lot of mistakes when copying its own genome to make new virus particles. In an infected person, a mutation is most likely made at every single position in the HIV genome several times each day. Stop and think about that for a minute.
The viruses in an infected person's body are constantly changing, which helps HIV become resistant both to the immune system and to drugs that are used to treat it. As a result, HIV infections must always be treated with a combination of drugs, so that if a virus arises that is resistant to one drug, it is most likely still susceptible to the other drugs in the treatment regimen.
Every hour, nearly 300 people become infected with HIV worldwide. And 97% of HIV-infected people live in low- and middle-income countries where they often do not have access to good healthcare and expensive drugs. That said, the drugs that are currently available to fight HIV have drastically changed the outlook of the disease. For people who are fortunate enough to have access to the best medications, HIV infection no longer means certain death from AIDS. However, they must stick religiously to a complicated drug regimen that can include as many as 40 pills a day.
In this lesson, we will learn about Antiretroviral Drugs and how they work. The name 'antiretroviral' really means a drug that is used to fight any retrovirus, or RNA virus that inserts a DNA copy of its genetic material into a host cell's genome. However, nowadays, the term 'antiretroviral drugs' refers specifically to drugs that are used to treat HIV, since it is such an important retroviral disease.
As we discuss the various different drugs, we will see where they act in the replication cycle of the virus. It's not so important to remember all of the names of the drugs that are mentioned here. The most important thing is to learn the different strategies that can be used to block HIV infection.
At the beginning of its replication cycle, HIV attaches to receptor molecules on the outsides of helper T cells, which are an important type of immune cell in our body. After attaching to these receptors, the membrane of HIV fuses with the plasma membrane of the T cell, and the viral contents enter the cell.
These are key steps in HIV infection. Like all viruses, HIV cannot replicate, or make copies of itself, if it doesn't get into host cells. So, drugs that can prevent HIV from entering T cells would be very promising indeed.
So far, only a few antiretroviral drugs use this strategy. The first is maraviroc, which attaches to one of HIV's receptors on T cells, preventing the virus from binding. The second is enfuvirtide, which blocks the fusion of the viral membrane with the T cell's plasma membrane. You can envision these drugs' strategies as locking all of the doors of a house so that the virus can't get inside.
Once HIV is inside a T cell, it needs to use its genetic material to create new copies of itself. HIV is an RNA virus, and it needs to convert its genetic material into DNA first so that its proteins can be expressed by the cell. Conveniently, HIV has brought along its own enzyme called reverse transcriptase, which makes a DNA copy of the virus's RNA genome.
Many important antiretroviral drugs target reverse transcriptase. Two important classes of HIV drugs are the Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs/NtRTIs). Remember that a nucleoside is a nucleotide without the phosphate group, so it's a pentose sugar attached to a nitrogenous base. When one or more phosphate groups are added to a nucleoside, it becomes a nucleotide. DNA and RNA are made of strings of nucleotides.
NRTIs are analogs of nucleosides and nucleotides. It turns out that nucleoside and nucleotide analogs can inhibit reverse transcription very well. These analogs are like false, decoy components of the DNA strand that the virus needs to make. They compete with the real nucleosides and nucleotides in the cell. Here's how: when reverse transcriptase inserts one of the analogs into the growing DNA chain, instead of a real nucleotide, DNA synthesis stops. This is because the analogs don't have the right chemical structure for the next nucleotide to be added into the chain. Examples of these drugs are zidovudine (AZT), a nucleoside analog, and tenofovir, a nucleotide analog.
But hold up just a minute, what about selective toxicity? Our cells have to synthesize DNA, too, when they replicate. If a patient is being treated with a nucleoside or nucleotide analog, what will happen to their normal cells? It turns out that this is not too much of a problem because DNA polymerase, the enzyme that our cells use to synthesize DNA, doesn't bind very well to these analog drugs.
There's also another class of reverse transcriptase inhibitors that are not nucleoside or nucleotide analogs. Lucky for us, their name is easy enough to remember: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs). They are non-competitive inhibitors of reverse transcriptase. One example of an NNRTI is nevirapine. It binds to reverse transcriptase and changes its structure so that the active site is disrupted. It's kind of like if a key gets badly bent, it won't be able to unlock doors anymore. In this example, the drug is what bends the key, making it nonfunctional.
All three classes of reverse transcriptase inhibitors lead to the same effect: DNA can't be synthesized. Therefore, HIV can't convert its RNA genome into a DNA version that can be used in our cells to make new viruses.
Let's imagine that an HIV virus has not encountered the drugs that we've mentioned so far. It's managed to enter into a host cell and use its reverse transcriptase to convert its genome from RNA into DNA. Now it wants to incorporate its genome into the host cell genome so that the viral genetic material can be replicated and the viral proteins can be expressed.
This is accomplished by an HIV enzyme called integrase. Its name is easy to remember because it integrates the viral genetic material into the host cell's genome. You can envision this by thinking of putting pages into a copy machine so they can be photocopied. Integrase Inhibitors, like the drug raltegravir, inhibit integrase, stopping this important step in the HIV replication cycle. These drugs are kind of like someone preventing you from putting your pages into the copy machine.
Okay, let's say HIV has successfully entered a cell and converted its genome from RNA to DNA. The DNA has also been integrated into the host cell's genome. Now, using the cell's own machinery, it will express its proteins using the normal 'central dogma': DNA is transcribed to RNA, which is translated to protein.
The thing about HIV is that it synthesizes all of its important proteins, including the enzymes we've heard about today, like reverse transcriptase, integrase, etc., as large polypeptide chains with multiple proteins connected together. In order to use these proteins and form a mature viral particle, it must first cut the proteins apart from each other, using its own protease enzyme.
HIV Protease Inhibitors, like atazanavir, indinavir, and saquinavir have decoy amino acid sequences that match the sequences in the large polypeptide chain that HIV protease needs to cut. If the protease is busy cutting up these drugs, it won't get around to cutting apart HIV's real proteins, and thus, mature HIV particles won't be formed.
In this lesson, we've looked at various steps of HIV's replication cycle and seen where six major classes of antiretroviral drugs act. These days, the term Antiretroviral Drugs refers almost exclusively to drugs that are used to treat HIV infection, even though HIV is not the only retrovirus that infects humans.
We saw that Entry and Fusion Inhibitors block HIV's attachment to its receptors on helper T cells and the fusion of its membrane with the T cell plasma membrane.
Next, we learned that there are three major classes of Reverse Transcriptase Inhibitors that all prevent the conversion of HIV's RNA genome into DNA inside the host cell. There are nucleoside and nucleotide analogs (NRTIs and NtRTIs), which compete with real nucleotides to be included into the growing DNA chain and prevent it from elongating any further. There are also non-nucleoside inhibitors (NNRTIs) that bind to reverse transcriptase and change its active site structure so that it can't work anymore.
We also discovered that Integrase Inhibitors block the integration of HIV's genetic material into the host cell genome, so it can't be replicated and expressed into proteins.
Finally, Protease Inhibitors stop HIV's protease enzyme from cutting up HIV polypeptides into proteins that it needs to form mature viral particles.
Importantly, we learned that these drugs must always be used in combination to treat HIV because the virus mutates really quickly. If a virus happens to become resistant to one drug, it's best if there are multiple other drugs present that it will still be susceptible to.
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Back To CourseBiology 103: Microbiology
16 chapters | 156 lessons | 12 flashcard sets