Viruses and Evasion of the Immune System
I am on twitter (@travishale) as well as reddit and on occasion I see threads and questions about why some viruses can be ‘destroyed’ by the immune system (I.e., a cold) but then other viruses are more persistent and can recur (I.e., Herpes Simplex I (HSV-I) also known as Cold Sores).
I wanted to explore this a little bit more, but before I do I wanted to note that whilst I have a background in Microbiology, I am not a virologist so I will only be providing a fairly basic answer and if you want more detail you can have a bit of a google or see if there are any virologists who also have posts on this area. I apologise in advance as there is a bit to cover as I wanted to explore what viruses are, how they replicate, how the body tries to destroy them, and how they can trick the body.
What are Viruses?
One of the important things to discuss is what actually is a virus, whilst oversimplified a virus is basically a microscopic and infectious agent which contains genetic material (either RNA or RNA) and proteins, the genetic material is usually encapsulated by a protective coat called a capsid, and sometimes an additional spiky coat (called an envelope). I use the term virus and virion interchangeably in this post as most people would know them, but note for the purpose of this article the virion is the virus in its protective coating, the virus is essentially the infected cell which is producing new virions.
How do Viruses Replicate?
There is some conjecture around viruses/virions and if they are ‘alive' because a virus cannot replicate itself and must invade a host cell in order to replicate. Whilst the mechanism varies based on the type of virus, in general viruses are specific to a host and they bind to that host due to interactions between proteins on the surface of the virus (often called spike proteins) and specific receptors on the host cellular surface (this is called attachment).
Following attachment, a process called penetration or viral entry takes place. This is here the virions enter the host cell either through membrane fusion, or receptor-mediated endocytosis. Membrane fusion is where the lipid bilayers of the virus and the host cell essentially merge and the internal contents of the two structures can mix, whilst receptor mediated endocytosis is the process of essentially bringing the virus into the cell in a capsule before it is ultimately released into the cell (vast oversimplification).
Once the virion is within the cell, a process called uncoating takes place. This is where the protective coat (capsid and/or envelope) is removed (usually by viral or host enzymes, or simple dissociation) to expose the viral genomic nucleic acid (the viral DNA/RNA).
Once the genomic information is within the cell, the genome is replicated (by the host cell) in a process called replication. This is a complex process that ultimately leads to the creation of viral DNA/RNA, viral protein synthesis, and possible assembly of viral proteins. Again this is hugely over-simplified but in effect this process of replication is to make copies of the virus genetic information, and proteins. This is in many ways what people know as the infectious virus.
Following replication, a process called Assembly takes place which is essentially the self assembly of the virus particles, and some modification of the protein can also occur. This process is essentially about taking all of the virus pieces and turning it into a virus with the genetic information inside, and the protective envelopes and capsids. It is worth nothing that in some viruses, some modification can take place once released from the host cell (often called maturation).
The final process is called release, this is where the host cell is killed by bursting the cell membrane (and cell wall if present) through a process called lysis. This in effect releases all of the viruses that were produced by the cell, which can then go off and infect other cells and continue to multiply. It should be noted that in some cases viruses can undergo a lysogenic cycle where the genome of the virus is incorporated into a specific place in the host genome through a process called genetic recombination, this is then known as a provirus or in the case of a bacteriophage (a virus that infects bacteria) a prophage. When this occurs whenever the host cell divides the viral genome is also replicated.
How does the human body fight Viruses?
Now that we have a basic understanding of the process of viral infection and replication, it is worth exploring how viruses are fought off (in humans). Again for the purpose of this article this will be very much simplified!
The body consists of two main parts of the immune system, innate immunity which is basically the physical barriers around the body (i.e., skin) and the learned immune system (known as acquired or adaptive immunity). There are multiple components of the adaptive immune system, but for the purpose of this I have broken it down into how viruses are controlled through Cytotoxic Cells, Interferons and by Antibodies.
When a virus enters a cell, the cells of the immune system cannot ‘see' the virus and thus don't know the cell is infected. To get around this the cells have a system that allows them to show other cells what is inside them through a series of molecules called Class I Major Histocompatibility Complex Proteins (MHC Class I). Basically what this system does is show pieces of the proteins inside the cell (which is expected to include virus proteins) so that other immune system cells can see what is inside.
Within the body there is a special type of cell called a T Cell, which circulates looking for infections. The T cell looks at the proteins that are being shown by nearby cells through MHC Class I, and the T cell has special proteins on its surface that help them identify virally infected cells (called T Cell Receptors / TCR). When the TCR identifies a part of a virus on the MHC I, it tells the T Cell that there is an infection in the cell presenting the viral fragment, and the T Cell releases a range of chemicals (called cytotoxic factors) to kill the infected cell and prevent survival of the invading virus.
Some viruses have developed techniques to avoid detection by blocking the MHC I system which means that the T Cells can't identify if the cell is infected. That said, there is also a type of cell called a naturally killer cell (NK Cell) which will kill cells displaying fewer than normal MHC proteins.
Interferons are a slightly different approach, virally infected cells produce and release these small proteins called interferons which prevent replication of viruses by interfering with their ability to replicate within an infected cell, but they also act as a signal module to tell nearby cells of viral presence which also triggers nearby cells to increase the number of MHC Class I molecules on the surface so T cells can identify and eliminate viral infection.
Antibodies are a third approach, these are proteins that specifically recognise an invading pathogen (i.e., the virus) and stick to them. The aim of binding or sticking to the virus is to aim to neutralise it so that it cant infect the cell, to cause virus cells to stick together (through multiple antibodies in a process called agglutination) which makes it easier for the immune cells to target these, to trigger phagocytes to consume the virus and destroy it, and finally to activate other systems of the immune system to damage the virus thus preventing its activation and infection.
So how do some viruses remain persistant?
For most viruses, these are active almost all of the time and the body detects them and then begins to respond accordingly to fight the infection, whilst ultimately results in the virus being destroyed. In other cases a virus can enter a dormant state as part of its life-cycle which is typically what occurs in persistent viral infections (note this is different to say a chronic viral infection).
It is this dormant state that is the key to the survival and persistence of these viruses, in the dormant stage the proliferation of the viral particles ceases but the viral genome (the genetic information that codes the virus) is not removed, this remains dormant and can then reactivate producing large amounts of viruses without the host becoming reinfected with a new outside virus.
Different viruses can maintain their genome through different mechanisms, but this is usually called Episomal latency or Proviral latency.
Aside from this, it is also worth noting that maintaining the virus genetic information also requires some tricks, so viruses may also be doing other things like trying to interfere with MHC Class I, interfering with the process of cell death and playing other tricks (which are not discussed in this post for simplicity).
In Episomal latency, the genetic information (viral genes) are stabilised and floating in the cytoplasm or the nucleus of the cell as objects. The downside to this is that the genes can be more vulnerable to gene degradation and breakdown. An example of Episomal latency is a coldsore (the Herpes Simplex Virus HSV-1), this virus enters a dormant phase in neurons and leaves genetic information floating in the cytoplasm. The HSV-1 virus is reported to be identified to fuse with DNA in the neurons (i.e., nerve ganglia) and can reactivate when the body is stressed.
Proviral latency is a bit different, in this case the virus genome is integrated into the DNA of the host cell, which means that when the host cell divides it results in replication of the viruses genes. This also means that it is nearly impossible to remove the virus genes from the infected cell without killing the whole cell as well. This method does have a disadvantage in that for the virus it is harder to get genetic information into the nucleus, but once it is there it will remain for the life of the cell. An example of a virus that exhibits proviral latency is Human Immunodeficiency Viruses (HIV), these viruses use an enzyme to create a DNA copy of their RNA genome which is inserted into the host cell (in this case the CD4+ T Cells) and persists there with the virus being produced under specific conditions / stresses.
Apologies this has been a huge article to write, I wanted to make sure that I had covered the basics of the individual systems. In essence in a normal viral infection (i.e., the flu) the virus enters the body and the genetic information is brought into the cell where the cell machinery reads the genetic information, and creates copies of the virus genetic material and proteins and assembles copies of the virus. Parts of the virus are presented to the surface of the cell and the immune system of the body starts to signal for the cell to be destroyed, or the virus proteins to be removed. In the case of a normal infection the virus is always aiming to create copies of itself.
In the case of those viruses which are persistent, they enter a dormant or latent phase where the virus stops producing copies of itself and as such the body does not identify it and the virus can remain. Whilst the viral proteins don't remain, the genetic information that codes the virus remains inside the cell until specific conditions arise that allow for its reactivation (i.e., Stress). In some cases the genetic information of the virus can hide inside cells (i.e., in the cytoplasm or necleus) which is what happens in the case of Episomal Latency (and an example of this is cold sores where the genetic information hides in the neurons floating in the cytoplasm) whilst in other cases the actual genetic information of the virus is incorporated into the host cell which is known as Proviral latency which occurs with Human Immunodeficiency Viruses where the genetic information of the virus is incorporated into the genome of CD4+ T Cells.
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