I have a question concerning reverse transcriptase. Why is it that when the viral rna is converted to viral dna( as in the case for hiv), the virus develops resistance to medicine? Under what circumstances does reverse transcriptase causes a viral mutation?

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Via: https://en.wikipedia.org/wiki/Reverse_transcriptase#Replication_fidelity

There are three different replication systems during the life cycle of a retrovirus. First of all, the reverse transcriptase synthesizes viral DNA from viral RNA, and then from newly made complementary DNA strand. The second replication process occurs when host cellular DNA polymerase replicates the integrated viral DNA. Lastly, RNA polymerase II transcribes the proviral DNA into RNA, which will be packed into virions. Therefore, mutation can occur during one or all of these replication steps.[17]

Reverse transcriptase has a high error rate when transcribing RNA into DNA since, unlike most other DNA polymerases, it has no proofreading ability. This high error rate allows mutations to accumulate at an accelerated rate relative to proofread forms of replication. The commercially available reverse transcriptases produced by Promega are quoted by their manuals as having error rates in the range of 1 in 17,000 bases for AMV and 1 in 30,000 bases for M-MLV.[18] (Emphasis added.)

Polymerases are proteins (enzymes) that make copies of genetic material: DNA or RNA. https://en.m.wikipedia.org/wiki/Polymerase

These enzymes have different fidelity or error rates. This means that different polymerases can make fewer or more mistakes when copying genetic information.

To accommodate errors, DNA polymerases have proofreading mechanisms that go back and fix errors. Most of the time, this works as expected. https://en.m.wikipedia.org/wiki/Proofreading_(biology)

However, the reverse transcriptase that copies RNA into DNA does not do any proofreading, so there will be various mutations in some fraction of copies, depending on the transcriptase's fidelity rate. https://en.m.wikipedia.org/wiki/Reverse_transcriptase

For viruses, it is a pure numbers game. All they are programmed to do is make copies of themselves, and as many copies as possible, when they are in infectious, non-dormant state. https://en.wikipedia.org/wiki/Lysogenic_cycle and https://en.wikipedia.org/wiki/Lytic_cycle

Most mutations will be deleterious and the virus won't infect, integrate, and replicate successfully. A random mutation will often break a needed protein involved in the viral reproductive cycle.

Some mutations are "neutral" or "silent" and won't change how the virus copies itself. Consider that the genetic code is redundant β€” substitute a base here or there and you can still get the same amino acid sequence. https://en.wikipedia.org/wiki/Silent_mutation

But if you have enough virus particles copying themselves, all you need are mutations in the parts of the virus genome that allow it to keep replicating and also change the proteins it makes, just enough to evade the host's immune system.

If a mutated virus can still replicate and also change the proteins it gets the infected cell to make on its behalf, it can be more successful at copying itself. Immune cells will have to "relearn" whatever changes were made in order to trigger the usual immune response and fight back.

In the case of HIV, it also attacks the immune system directly, which is another complication.

Medications try to interfere with the different ways in which HIV works to infect immune cells and to make copies of themselves.

For example, one class of medication tries to "compete" with the part of HIV that binds to the surface of T cells. It's like a night club, where the bouncers at the doors are more likely to keep HIV from getting into the cell/club and partying.

Other classes of medication interfere with a protein called integrase that HIV makes to integrate its viral DNA into the host DNA. Integration of the HIV DNA into the host cell's DNA is a critical step for infection, so that's one way to target the virus. https://en.wikipedia.org/wiki/Integrase

Still other drugs try to inhibit the reverse transcriptase that turns HIV RNA into DNA. If the virus RNA is inhibited from being made into DNA, then that can help keep further infection in check. PrEP is a combination of two drugs (tenofovir and emtricitabine) which are RT inhibitors. https://www.cdc.gov/hiv/basics/prep.html

An overview of some of these medications is available here: https://www.webmd.com/hiv-aids/aids-hiv-medication

These medications all try to target the proteins involved in how HIV infects and replicates inside immune cells.

In turn, reverse transcriptase is sloppy enough in turning HIV RNA into DNA that it can get lucky and mutate enough to make one or another medication less effective.

Treatments are sometimes put into so-called "cocktails" of multiple drugs. A multi-drug regimen that attacks the virus by different means will give HIV a harder time in getting lucky enough to mutate in ways that it can get past a multi-pronged attack in those who are HIV+. Another good summary of such medications β€”Β many of which target reverse transcriptase activity β€” is available here: http://www.aidsinfonet.org/fact_sheets/view/403


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