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Q: Why and how do viruses mutate making them immune to vaccines?

Krishna: Viruses are just parasitic fragments of RNA or DNA. Most viruses are specialists. They establish long associations with preferred host species.  

But a virus that appears different from other viruses that have infected the host has an advantage. The host has no pre-existing immunity, in the form of antibodies, to that virus. Many viral adaptations involve changes to the virus’s outer surface.

 In nature, most viruses are confined to particular hosts because of specific protein “lock and key” interactions. These are needed for successful replication, movement within the host, and transmission between hosts.

For a virus to infect a new host, some or all protein “keys” may need to be modified. These modifications, called “mutations”, can occur within the old host, the new one, or both (2). For instance, a virus can jump from host A to host B, but it won’t replicate well or transmit between individuals unless multiple protein keys mutate either simultaneously, or consecutively. 

Mutations are the building blocks of most of evolution—they are the variation upon which natural selection can act, and they are the cause of much of the novelty we see occur in evolution.  

  During the genetic copying process, if the instructions are not followed properly, mistakes occur. It may miss a word, or add a new word or phrase to the story, subtly changing it. These changed virus stories are called “mutants”.   

There are three types of DNA Mutations: base substitutions, deletions and insertions.  

Reasons for RNA mutations:

Here I give examples of  how evolution occurs in influenza viruses and in the human immunodeficiency virus (HIV). Both of these viruses are RNA viruses, meaning that their genetic material is encoded in RNA, not DNA. DNA is a more stable molecule than RNA, and DNA viruses have a proofreading check as part of their reproductive process. They manage to use the host cell to verify viral DNA replication. If the virus makes a mistake in copying the DNA, the host cell can often correct the mistake. DNA viruses, therefore, do not change, or mutate, much. RNA, however, is an unstable molecule, and RNA viruses don’t have a built-in proofreading step in their replication. As a consequence of the lack of proofreading activity of RNA virus polymerases, new viral genetic variants are constantly created. Mistakes in copying RNA happen frequently, and the host cell does not correct these mistakes. Then a new mutant variety emerges. Therefore, RNA virus mutations are frequent and can have important consequences for their hosts (1). This is one reason why it is difficult to make effective vaccines to prevent diseases caused by RNA viruses—diversity is their strength.

Causes for DNA mutations:

Errors in DNA Replication

On very, very rare occasions DNA polymerase will incorporate a noncomplementary base into the daughter strand. During the next round of replication the missincorporated base would lead to a mutation. This, however, is very rare as the exonuclease functions as a proofreading mechanism recognizing mismatched base pairs and excising them.

Errors in DNA Recombination

DNA often rearranges itself by a process called recombination which proceeds via a variety of mechanisms. Occasionally DNA is lost during replication leading to a mutation.

Chemical Damage to DNA

Many chemical mutagens, some exogenous, some man-made, some environmental, are capable of damaging DNA. Many chemotherapeutic drugs and intercalating agent drugs function by damaging DNA.

Radiation

Gamma rays, X-rays, even UV light can interact with compounds in the cell generating free radicals which cause chemical damage to DNA.

DNA Repair

Damaged DNA can be repaired by several different mechanisms.

Rates of spontaneous mutation vary amply among viruses. RNA viruses mutate faster than DNA viruses, single-stranded viruses mutate faster than double-strand viruses, and genome size appears to correlate negatively with mutation rate. Viral mutation rates are modulated at different levels, including polymerase fidelity, sequence context, template secondary structure, cellular microenvironment, replication mechanisms, proofreading, and access to post-replicative repair. Additionally, massive numbers of mutations can be introduced by some virus-encoded diversity-generating elements, as well as by host-encoded cytidine/adenine deaminases. Our current knowledge of viral mutation rates indicates that viral genetic diversity is determined by multiple virus- and host-dependent processes, and that viral mutation rates can evolve in response to specific selective pressures (4).  

  Consequences of viral mutations: Mutations can make viruses jump species, become immune to a particular vaccine. reduce or increase pathogenicity or virulence. A small increase in mutation rate can also cause RNA viruses to go locally extinct (3)!  

Footnotes: 

1. https://www.historyofvaccines.org/content/articles/viruses-and-evol...

2. https://theconversation.com/how-do-viruses-mutate-and-jump-species-...

3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107253/

4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5075021/

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