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Why is it that our immune systems can protect us from some viruses but not others? We’ve eradicated smallpox by using vaccines, so why do influenza and HIV remain such dangerous health risks? In this lesson about viruses, we’ll explore these questions and learn how influenza and HIV continue to evade the human immune system.

Influenza Viruses

The infection of the same cell by two viruses can lead to genetic reassortment
flu viruses 1

In this lesson, we’re going to take a look at influenza and HIV, two different human viruses that continue to be a health concern, and look at some of the features that allow them to evade the human immune system.You may remember that a virus is a biological entity that is only capable of reproducing by using a living cell. There are lots of different types of viruses that can infect human cells.

Some are extremely deadly, like the ebola virus, which thankfully is also extremely rare. Others cause short and mild infections that are rarely dangerous, like the picorna viruses that cause the common cold. And then there’s everything else in between, like the influenza viruses that cause the flu. The disease we know of as the flu is actually caused by several related viruses that all belong to the same group. Within this group, there are many different strains of human influenza viruses and several strains that infect other animals, like birds, pigs, horses and dogs.

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Influenza viruses are enveloped, single-stranded RNA viruses, meaning they are surrounded by a plasma membrane like the cells they infect, and their genetic material is in the form of single-stranded RNA. But in the case of influenza viruses, the genome is composed of eight separate segments. Each RNA segment is sort of like one of our chromosomes, except that they are much shorter, and each one encodes for only one or two genes. When an influenza virus infects a cell, it uses the host cell’s enzymes, organelles, nutrients and energy to make its own proteins. It then replicates all eight of its RNA segments, which are packaged into a piece of the plasma membrane and bud off of the host cell as a free virus in search of a new host cell to infect.

Influenza Reassortment

The hemagglutinin protein in also known as the H antigen
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Usually, there is only one strain of influenza virus present in a host; however, if there are two, it is possible for both viruses to infect the same cell. Then when those viruses replicate their RNA, there will be two different versions of each RNA segment. This allows for genetic reassortment, or shuffling of gene segments between two different strains of a virus, to take place.With eight segments and two different versions of each, there are theoretically 2^8, or 256 different combinations that can be created between the two original strains that infected the cell. In this way, successful combinations of influenza viruses will almost always reproduce the exact same viral strain millions of times over.

Then, once in a while when chance allows two different strains to infect the same cell, they have the potential to recombine and form hundreds of new combinations that haven’t been seen by the host population.Most human antibodies to influenza viruses recognize one main antigen of the virus’s Hemagglutinin protein, which is sometimes called the H antigen.Genetic reassortment allows flu viruses to periodically and abruptly switch the H antigen that human antibodies recognize in a process called antigenic shift. This is a sudden, significant change to a major antigen of a pathogen, usually through reassortment. Throughout history, whenever an antigenic shift occurred in the predominating influenza strain, the number of influenza infections has spiked significantly higher, often causing pandemics, or outbreaks, of infectious diseases that spread over very large distances in more than one continent and even worldwide. These pandemics are caused by a lack of immunity in the human population to an H antigen that hasn’t been in widespread circulation for a generation or more. So where do these new antigens come from? Most of them are actually old antigens existing in rarer influenza strains that persist in small pockets in the human population.

But there is another source of influenza that can cause really dramatic antigenic shifts, and that source is other animals.

Species-Based Influenza Reassortment

Birds can be infected by influenza viruses from birds and humans
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Some animals, especially pigs, can be infected by influenza viruses from other species, like birds and humans.Genetic reassortment between various flu viruses occurs in these animals, and if humans live in close quarters with the animals, flu viruses containing RNA segments from all sorts of different strains can start infecting humans. Maybe you’ve heard news reports of Swine Flu or Asian Bird Flu outbreaks in other countries along with lots of speculation about how dangerous these exotic strains can be, and not without reason. In 1918, an antigenic shift occurred in the human influenza virus, which changed the H antigen to a swine flu antigen that nobody had immunity to. The largest, most deadly flu pandemic ever seen soon followed this change, infecting an estimated one third of the world’s population and killing 50 million people in just six months.

This pandemic, called the Spanish Flu, was by far the fastest, most deadly pandemic of any type in human history. The swine flu antigen that started the pandemic is now a part of the human influenza virus gene pool. Many people have immunity to this antigen, which is now far less likely to cause such a devastating pandemic, but it serves as a reminder of what could happen if a new antigen were to emerge again in the human population.

HIV

We’re going to shift gears a little here and talk about a completely different strategy that some viruses use to evade the human immune system, and that strategy is rapid mutation. We’ll use HIV as an example since it has mastered the art of rapid mutation and used this strategy not only to evade the human immune system, but to attack it directly.HIV, or Human Immunodeficiency Virus, is a very interesting virus in many ways. First of all, HIV is a retrovirus, which means that it has an RNA genome that it uses as a template to make double-stranded DNA, which is then incorporated into the host genome.

This is completely backwards compared to the way that living organisms use DNA and RNA. As you may remember, living organisms have DNA genomes that they use as templates to make RNA transcripts, which are then translated into proteins. In contrast, HIV has an RNA genome that it uses to make double-stranded DNA, which is then incorporated into the host cell’s genome. Human cells do not make DNA from RNA templates, so there are no human enzymes capable of this process, and HIV must therefore provide its own enzyme. This is called reverse transcriptase. Reverse transcriptase creates double-stranded DNA from an RNA template, but that is not all that it does. Reverse transcriptase isn’t the most precise enzyme.

When it creates DNA from RNA, it makes a lot of errors, and the result is that it creates lots of mutations in the HIV DNA before it is incorporated into the host genome. This is the source of the high mutation rate of HIV. The rate is so high that once the body’s immune system starts responding to an HIV antigen, somewhere in the body another HIV antigen has probably already been created by mutation.

Viruses with this new antigen will begin infecting cells while viruses with the old antigen are being targeted by the immune system.

HIV infects helper T cells in the immune system
flu viruses

HIV Infects Helper T Cells

Another interesting feature of HIV is its choice of host cell. You see, HIV doesn’t infect all human cells; instead, it specifically targets helper T cells in the immune system.An HIV virus must bind to the CD4 receptor present on all helper T cells before it can fuse its plasma membrane with that of the helper T cell and enter.

Reverse transcriptase then creates double-stranded DNA from the RNA template, and this DNA is incorporated into the host cell’s genome. HIV can remain inactive in the genome as a provirus, or a virus that has been incorporated into the host genome, for several years before it becomes active and starts producing new viruses. This long incubation time for HIV allows the virus to remain in a host undetected for a very long time and greatly increases the distance over which the virus can spread before it destroys its host’s immune system and leaves it susceptible to other diseases.

Lesson Summary

In review, there are several ways in which viruses can evade the human immune system. Two very successful evasion techniques are rapid mutation and antigenic shifts, which are sudden, significant changes to a major antigen of a pathogen, usually through reassortment. Influenza viruses periodically experience antigenic shifts, which usually lead to higher rates of infection in the human population. In very rare cases, a completely new antigen is introduced into the human influenza gene pool from viruses that infect other animals.

One such case occurred in 1918, and because nobody had immunity to the new antigen, this strain of flu caused the fastest and deadliest pandemic in human history.HIV, or Human Immunodeficiency Virus, evades the human immune system in a different way. It uses rapid mutation to stay one step ahead of the immune system.

HIV is a retrovirus, which means it has an RNA genome that it uses as a template to make double-stranded DNA that is then incorporated into the host genome. The reverse transcriptase enzyme that HIV uses to make double-stranded DNA from RNA is very error prone, which creates a high rate of mutation in the HIV genome and allows it to mutate faster than the immune system can develop immunity to it. It also doesn’t help that HIV infects helper T cells and destroys the immune system as it reproduces.

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