Zika virus, like all other viruses, is mutating

Zika virusNot long after the appearance of an outbreak of viral disease, first scientists, and then newswriters, blame it all on mutation of the virus. It happened during the Ebolavirus outbreak in West Africa, and now it’s happening with Zika virus.

The latest example is by parasitologist Peter Hotez, who writes in the New York Times:

There are many theories for Zika’s rapid rise, but the most plausible is that the virus mutated from an African to a pandemic strain a decade or more ago and then spread east across the Pacific from Micronesia and French Polynesia, until it struck Brazil.

After its discovery in 1947 in Uganda, Zika virus caused few human infections until the 2007 outbreak on Yap Island. The virus responsible for this and subsequent outbreaks in Pacific Islands is distinct from the African genotype, but there is no experimental evidence to suggest that sequence differences in the Asian genotype were responsible for the spread of the virus. For this reason I disagree with Dr. Hotez’ conclusion that mutation of the virus is the ‘most plausible’ explanation for its global spread. It is just as likely that the virus was in the right place at the right time to spark an outbreak in the Pacific.

We will never have experimental evidence that emergence of the Asian genotype allowed pandemic spread of Zika virus, because we cannot test the effect of individual mutations on spread of the virus in humans. Consider this experiment: infect a room of humans (and mosquitoes) with either the African or Asian genotype of Zika virus, then measure virus replication and transmission. If there is a difference between the two viruses, engineer specific mutations into the virus, reinfect another batch of humans, and continue until the responsible mutations are identified. Obviously we cannot do such an experiment! We could instead use animal models, but these have limitations in extrapolating results to humans. For this reason we have never identified any specific mutation that allows an animal virus to replicate more efficiently in humans.

The same experimental limitations do not apply to animals. An example is Chikungunya virus, spread by Aedes ageyptii mosquitoes. Before 2004, outbreaks of infection were largely confined to developing countries in Africa and Asia. The virus subsequently spread globally, due to a single amino acid change in the envelope glycoprotein which allows efficient replication in Aedes albopictus, a mosquito with a greater range than A. ageyptii. It was possible to prove this point by assessing the effects of changing this single amino acid on virus replication in mosquitoes. The same experiment cannot be done in humans.

There is no evidence that the Asian genotype of Zika virus is any more competent to replicate in mosquitoes than the African strain. Results of a study of replication of Asian genotypes of Zika virus revealed that Aedes aegypti and Aedes albopictus are not very good vectors for transmitting ZIKV. The authors smartly suggest that “other factors such as the large naïve population for ZIKV and the high densities of human-biting mosquitoes contribute to the rapid spread of ZIKV during the current outbreak.” In other words, don’t blame the Zika virus genome for the expanded range of the virus.

The Zika virus that has been spreading in Brazil, and which has been associated with microcephaly, shares a common ancestor with the Asian genotype. In a recent study of the genomes of 7 Brazilian isolates, there was no evidence that specific mutations are associated with microcephaly. Those authors conclude (also smartly):

Factors other than viral genetic differences may be important for the proposed pathogenesis of ZIKV; hypothesized factors include co-infection with Chikungunya virus, previous infection with Dengue virus, or differences in human genetic predisposition to disease.

It’s easy to blame mutations in the viral genome for novel patterns of transmission or pathogenesis. Viral mutations arise during every replication cycle, due to errors made by viral enzymes as they copy nucleic acids. RNA viruses are the masters of mutation, because, unlike the polymerases of DNA viruses, RNA polymerases cannot correct any errors that arise. As viruses spread globally through different human populations, it is not surprising that different genotypes are selected. These may reflect adaptation to various selective pressures, including different humans, vectors, climate, or geography. There is no reason to assume that such changes influence virulence, disease patterns, or transmission in humans. Whether they do so can never be tested in humans.

Blaming the viral genome is nothing new. At the onset of the 2014 Ebolavirus outbreak in West Africa there were many claims that the unprecedented size of the outbreak was a consequence of mutations in the viral genome. Genomic analysis of isolates early in the epidemic suggested that the large number of infections was leading to rates of mutation not previously observed. This work lead to dubious claims of  “Ebolavirus mutating rapidly as it spreads” and Ebolavirus is mutating (Time Magazine). Richard Preston, in the New Yorker article Ebola Wars quoted scientist Lisa Hensley:

In the lab in Liberia, Lisa Hensley and her colleagues had noticed something eerie in some of the blood samples they were testing. In those samples, Ebola particles were growing to a concentration much greater than had been seen in samples of human blood from previous outbreaks. Some blood samples seemed to be supercharged with Ebola. This, too, would benefit the virus, by enhancing its odds of reaching the next victim. “Is it getting better at replicating as it goes from person to person?” Hensley said.

And let’s not forget the absurd speculation, fueled by these data, that Ebolavirus would go airborne.

Within a year all this nonsense was proven wrong. Ebolavirus had not sustained mutations any faster than in previous outbreaks. Furthermore, the observed mtuations  did not change the virus into a more dangerous strain.

Go back to any viral outbreak – MERS-coronavirus, SARS-coronavirus, influenza virus, HIV-1 – and you will find the same story line. Mutation of the virus is leading to more virulence, transmission, spread. But in no case has cause and effect been proven.

Let’s stop blaming viral mutation rates for altered patterns of virus spread and pathogenesis. More likely determinants include susceptibility of human populations, immune status, vector availability, and globalization, to name just a few. Not as spectacular as ‘THE VIRUS IS MUTATING!’, but nearer to the truth.

Comments on this entry are closed.

  • Tianhao Xu 14 April 2016, 11:47 pm

    The thing that I worried about Zika virus is we don’t know if it will cause a sequela effect, long term unseen neurological defects, to the once infected adults. And the virus has already taken over, spreading.

  • AdamNeira 15 April 2016, 8:17 am

    Vincent Racaniello’s presentation here has many holes in it. It is very flawed. A lightweight piece indeed. Let me explain…

    (1) It is a fact as clear as the light of day that the Zika virus, that has done and continues to do all the damage in Brazil and now in other countries, has changed behaviour from its earlier versions.

    The Zika outbreak can correctly be described as a pandemic now. Thus WHO’s declaration of a PHEIC on Feb.1st 2016 was correct.

    As I publically warned on Oct.30’15, there is a 100% causal link between the mutant Zika+ virus & increase in Microcephaly. It is not a case of “if” or maybe there is a link. The link is absolutely proven. See the 10th Feb. 2016 NEJM Paper. Just one proof. If a detective finds a dead woman in a chateau with three gunshot wounds to her head he can 100% say it is not a case of suicide.

    You get the point about not needing to wait to make important strategic decisions about a problem when there is ample proof.

    (2) Vincent like other “experts” in the virology and infectious diseases field may have a real problem. And that is that after decades of study he is not seeing the bigger picture. “Specialisation Blindness” is a bane in many scientific disciplines. He is too close to the forest to see the trees.

    There are a few people in the world that know a great deal about the mutant Zika+ virus now. And of course 99.999999% of the 7 billion people on the Planet know very little about the Zika+ virus. Too many scientists these days are specialists. To understand the Zika+ threat now a different breed is required. Many so called experts, health reporters, WHO staff & scientists fall into the 2nd category of people. Huge knowledge gaps. Think of these needed experts as Renaissance Men and Women. People able to understand all 54 squares on a Cube. Polymaths.

    Nearly everyone on this beach failed to appreciate what was going on for a number of reasons. Unfamiliarity with such an event; Lack of memory; Confusion; Denial; Toxic Groupthink; And not wanting to be “uncool” in a social setting.


    (3) Peter Hotez’s hypothesis that a mutation in the Zika virus is responsible for the huge increase in severe Microcephaly cases in Brazil after mid 2015, plus GBS etc, is largely correct. He just has the chronology of the mutation events wrong.

    FACT : On Oct. 30th 2015 I first warned publically of the dangers to the world of the mutant Zika+ virus outbreak in Brazil ! I am used to being ahead of the curve on key global issues…(I have certain inside information and facts from the ground in Pernambuco from Oct. 2015 which I used to discover the mutation and link to the Microcephaly outbreak. My sources are 100% reliable.)

    FACT : A mutation event with the Asian strain of Zika happened in late 2014 in NE Brazil. Thus you can call it Zika+ now.

    This is why the virulence increased, huge upsurge in severe Microcephaly cases, GBS etc. The virus went “nuclear”. The number of base pairs of the genome has increased from the earlier Asian strain. The base pairs number in all the verified Zika samples to date vary from 10,272 to 10,807. Number of base pairs in the genome has grown. Tiny changes in structure of a virus can change its behaviour dramatically. Mutations in a virus can either be : Benign; Neutral or Negative. i.e. They become more dangerous/virulent. A big block of Semtex on its own is largely harmless. But add a tiny detonator to it and it becomes very dangerous indeed.

    Proof of the mutation…Published online 16th March 2016. (Which proves I was correct on Oct. 30th 2015.)

    Comparative genomic analysis of pre-epidemic and epidemic Zika virus strains for virological factors potentially associated with the rapidly expanding epidemic

    Citation: Emerging Microbes & Infections (2016) 5, e22; doi:10.1038/emi.2016.48


    (4) Comparing the Ebola outbreak to the current Zika outbreak is puerile. All virus outbreaks are different. Each virus outbreak case needs to be assessed on its merits. The world of viruses is a very mysterious one indeed.

    (5) The “Dual Cause” hypothesis proposed by Scott Halstead, Ian Mackay et al. is dead wrong. It is easily refutable.


    (6) All of the mosquito vector studies to date, that have been published, that analyse the potential of various species to act as vectors for Zika+ have one major flaw in common. And that is that none of the laboratory mosquitoes were “fed” the new Zika virus strain that is doing all the damage. Thus more research needs to be done ASAP to see if there is indeed evidence that the Asian genotype of Zika virus IS more competent to replicate in mosquitoes than the African strain.

    Hopefully Prof. Fiona Hunter at Brock University in Ontario, Canada is on the case right now.

    (7) Vincent’s last paragraph is incredible glib.

    Let’s stop blaming viral mutation rates for altered patterns of virus spread and pathogenesis. (No. A good scientist will consider all the possibilities for virus outbreaks. Of course mutation is a suspect that must be investigated.) More likely determinants include susceptibility of human populations, immune status, (Bullshit line of argument once again with the current Zika+ outbreak. Zika= is new beast indeed.) vector availability, (Billions of mosquitoes live and die in various countries every year. Why hasn’t such an outbreak been observed before. Because the mutation didn’t happen until late 2014 in NE Brazil ! The Yap and French Polynesia earlier case do not show the same level of complications. Not even close.) Thus and globalization, (Stupid theory. “Globalisation” has been going on for decades. i.e. Rapid air travel etc.) to name just a few. Not as spectacular as ‘THE VIRUS IS MUTATING!’, but nearer to the truth. (No Vincent. You are wrong. You write as if you want to lead the hounds off the scent.)

    (8) Prior to Nov. 2015 the number of scientific research papers on Zika was less than 1% of those on Dengue. No one was really interested in the Zika virus since it was discovered in 1947 because it was not a threat. But then something happened. As I stated on Oct. 30th 2015 the Zika virus mutated.

    Thus the huge increase in public interest & concern about Zika+ & Microcephaly after WHO’s PHEIC Feb.1st 2016.

    See the incredible increase in interest from the public around the world in the Zika threat via Google searches…


    (9) Will it spread to many nations ? It’s just a question of time…


    (10) TO SUM UP…I repeat. On Oct. 30th 2015 I first warned publically of the dangers to the world of the mutant Zika+ virus outbreak in Brazil ! I am used to being ahead of the curve on key global issues…

    As far as I know I was the first person in the world (On Oct. 30 2015 to be exact) to use the “Zika+” term to describe mutant Zika strain.

    Recent statement about the current Zika+ pandemic by various “leaders” remind me of the movie “Idiocracy”.

    Is the Zika+ Outbreak a “Black Swan/Mosquito Event” that will impact the US Election Race, Rio 2016 etc. ? Stay tuned…

    P.S. The IOC should wait until at least the end of May before deciding on whether Rio 2016 should go ahead or not. The Brazilian MOH is “fudging” the Zika/Microcephaly statistics. Cooking the Books. Billions of $, £, NIS at stake. ie Rio 2016. The IOC should wait until at least the end of May before deciding on whether Rio 2016 should go ahead or not.

    The IOC/USOC and all responsible NOC’s must wait until the end of May to check on the true situation in Brazil and Rio ! They have a responsibility to protect the health and safety of their athletes, support crews and the spectators. If they don’t conduct an independent audit, with random spot checks, of birth centres, hospitals in Brazil to get the true statistics regarding Zika+ triggered severe Microcephaly it will be a dereliction of duty. Unless of course they only see their female employees, sorry, athletes as cash cows/guinea pigs/gladiators. “Ka Ching !”

  • AdamNeira 15 April 2016, 8:24 am

    The consequences to babies affected by mutant Zika+ virus triggered severe Microcephaly are catastrophic.

    Here is a list of “complications” for babies & adults proven up to now as a result of infection from the mutant Zika+ virus :

    1 : Microcephaly
    2 : Guillain-Barré Syndrome
    3 : Severe Ventriculomegaly, when the brain is more liquid than it should be.
    4 : Eye Damage
    5 : Atrophies such as Arthrogryposis, which harden the muscles and joints
    6 : Meningoencephalitis
    7 – Acute Disseminated Encephalomyelitis
    8 – Encephalitis
    9 – Myelitis
    10 – Other neurological disorders.

    Stay tuned for more “complications” that may be found from Zika+ infection…

    Proof of the mutation…Published online 16th March 2016


  • Eddie Holmes 15 April 2016, 10:08 pm

    Vincent, I couldn’t agree more with the title of this piece. It is a continual frustration for me to read scare-mongering stories based on the fact that mutations have occurred in the virus genome. There is clearly a challenge to inform non-experts that for RNA viruses mutation is a daily – even hourly – occurrence. Sadly, the word ‘mutation’ is highly emotive.

    However, I do need to correct you on your Ebola comments. In particular, the Gire et al. Science paper you cite (of which I am not an author) does not say that “the large number of infections was leading to rates of mutation not previously observed”. The actual text is “The observed substitution rate is roughly twice as high within the 2014 outbreak as between outbreaks ” and “the rate of nonsynonymous mutations suggests that continued progression of this epidemic could afford an opportunity for viral adaptation” . Nothing more. There is nothing wrong with the second statement about adaptation (although it really applies to all RNA viruses), and from the first statement it is clear that the authors are referring to the ‘substitution’ rate (i.e. the rate at which mutations are fixed in populations) rather than the ‘mutation’ rate (which is rate they are generated by faulty replication). Sadly, subsequent studies and articles confused ‘mutation’ and ‘substitution’ and things got very messy indeed. To cut a very long story short, the Gire et al. rate is a bit too high, but that necessarily reflects estimation from sequences sampled over a short time frame. To say this is all ‘nonsense’ is really stretching things too far (although I whole-heartedly agree about the airborne transmission stuff!).

    Genomic studies routinely estimate the substitution (i.e. evolutionary) rate and not the mutation rate. Please don’t fall into this trap yourself.

    Keep up the great work though. Virology needs you!

    Best wishes,

    Eddie Holmes

  • Andrew Rambaut 17 April 2016, 2:21 pm

    I would like to support Eddie’s statement here, but speaking as an author on the Gire et al. paper and subsequent papers (Park et al., Carroll et al., Quick et al.). We were very careful to say that the rate was an observed evolutionary rate and not mutation rate. The credible intervals for the Gire et al were extremely wide, covering nearly and order of magnitude as would be expected for the very limited data available at the time. The credible interval of Gire et al. entirely covers the much more precise evolutionary rate estimates of Tong et al., Carroll et al., Park et al. and Quick et al. as data and sampling range accumulated. We made no claim at any point about any genetic change resulting in enhanced transmission or phenotypic effects. Obviously the press coverage of the papers was ill-informed and sensationalist, but equally so was the coverage of the papers that suggested a lower rate (i.e., Hoenen et al which was later corrected to a higher rate consistent with all the other papers).

    In your posting you say “Ebolavirus had not sustained mutations any faster than in previous outbreaks” – no analytical paper that I have read claimed this to be the case. Firstly we are not measuring mutation rate as Eddie says, secondly there is no suitable data from previous human outbreaks with which to compare. The Gire et al. paper was comparing an evolutionary rate with the long-term, between-outbreak evolutionary rate. This is the virus evolving in a non-human host and we don’t necessarily expect it to be the same as within human hosts.

    Best regards,
    Andrew Rambaut

  • Andy 4 August 2016, 6:20 pm

    Hi everyone, I am from a little island called Trinidad, I work in a pharmacy and I have been seeing a lot of people coming in with zika like symptoms but no one is getting the virus full blown, most times they are coming in with a few symptoms most common is the rash, red eyes and joint pain which last about a week then goes away, has anyone seen or heard of a mutation or a weaker strain of the zika virus in any other part of the world or is this occurrence unique to Trinidad or the caribbean.

  • Anuvart Singh 22 February 2017, 10:16 am

    the destroyer of human cruelty.