How herpes simplex virus exits latency

vp16-promoter-activation-neuronsMany of us have experienced herpesvirus reactivation from latency. Suddenly a sore erupts on the lip, festers for a week, then subsides. Years later, for no apparent reason, it happens again. Did you ever wonder what causes these recurrent blisters?

Herpes simplex viruses are associated with latent infections, a type of persistent viral infection that lasts for the life of the host. Infection with herpes simplex virus begins with intimate contact with an individual who is shedding the virus. Virions enter the oral or genital mucosal tissue and replicate, perhaps producing one or more lesions. While the infection runs it course and the lesion disappears,  the virus makes its way into sensory nerve endings and finds a permanent home in neurons. There the viral DNA remains silent until an insult – stress, ultraviolet light, hormonal changes – triggers viral replication. New virions are made, which travel to the epithelial surface, resulting in a lesion. Shed virus may be transmitted to others. The lesion heals and viral replication ceases until the next insult.

There have been many hypotheses to explain how the viral genome emerges from latency. One includes a central role for a viral gene called ICP0, which is known to encode a transcriptional activator – a protein that turns on the production of viral messenger RNAs, the templates for proteins. Another idea was that viral DNA replication begins first, which then leads to increased viral protein synthesis and initiation of the lytic cycle. Both hypotheses have been disproven by experimental data.

New findings indicate that another viral protein, VP16, is crucial for emerging from latency. This protein is a component of the virion and is a very strong transcriptional activator. However, it is produced late in the viral replication cycle. How could a late viral protein be crucial for the initiation of the lytic cycle? Because of this conundrum a role for VP16 in reactivation was discounted some years ago.

Herpes simplex virus latency is usually studied in mice. The animals are infected with virus, which replicates and then establishes latency in neurons. Bundles of neurons called ganglia are then removed and cultured for several weeks, and infectious virus is assayed as a measure of reactivation. In these experiments, VP16 is produced at the end of the replication cycle. But what if the temporal regulation of VP16 is very different in the intact mouse? To answer this question, a herpes simplex virus was constructed carrying the promoter sequence for VP16 fused to a reporter gene, beta-galactosidase.  Mice were infected with this virus, and ganglia recovered and examined for expression of the reporter protein. The results showed that the VP16 promoter was active in cells in the absence of any other viral protein. This finding was not consistent with the previous conclusion that VP16 is a late gene.

To determine if VP16 is produced during reactivation in mice, animals were infected with virus, subjected to hyperthermic stress to induce reactivation, and then ganglia were removed and examined for production of virus and VP16. The protein was always observed during reactivation, even when other viral proteins were not observed.

The authors then studied reactivation in mice using mutants of VP16 that cannot activate viral mRNA synthesis. These viruses were unable to exit the latent stage in mice. However, when ganglia were cultured, the VP16 mutant virus entered the lytic cycle, confirming previous observations.

These findings underscore the crucial role of VP16 in exiting latency and entering the lytic cycle. Although VP16 is produced late during infection of cultured cells, in neurons within a mouse it is an early trigger of reactivation. How stress leads to the production of VP16 is not known but will certainly be the focus of future experiments.

For years investigators did not understand how herpes simplex virus enters the lytic cycle because they were studying the wrong model. The practice of infecting mice, removing ganglia and placing them in culture does not faithfully mimic reactivation in the animal. The key, as shown by these investigators, was to stress the animals and then remove the ganglia and assay reactivation.

This seminal finding will undoubtedly stimulate research to better understand the workings of a virus that infects over half of the world’s population.

Thompson, R., Preston, C., & Sawtell, N. (2009). De Novo Synthesis of VP16 Coordinates the Exit from HSV Latency In Vivo PLoS Pathogens, 5 (3) DOI: 10.1371/journal.ppat.1000352

Comments on this entry are closed.

  • Kelly

    This will be interesting to follow as pathogens are implicated more and more often in chronicity of disease as well as acute illness and or mortality. As other herpes viruses such as EBV (HHV-4) and HHV-6A are also being studied regarding latency and reactivation this will be an interesting area of development.

    Stress is the loose canon. Psychological stress, particularly in humans, is such a complex variable confounded by temperment, situation, and resiliency. Physical stressors are often the forgotten “stress.” Is it possible that stress means that exposure to toxins or infection by other microbes can also lead reactivation?

    I'm on the edge of my seat. How about you?

  • NB

    Viral Latency is an important and interesting area of research. Researchers have suggested viral latency could protect the host from other infections. For example: murine gammaherpesvirus 68 (MHV-68) increases resistance to infection with Listeria monocytogenes with so called “latency-mediated protection”.
    Barton et al.: Herpesvirus latency confers symbiotic protection from bacterial infection. Nature 2007;447:326-329

    Recently, another group Yager et al. argued that latency mediated protection of mouse with MHV-68 lasts between 5-6.5 months and it appears to be transient effect rather than lifelong symbiotic protection. Yager et al.: gammaherpesvirus-induced protection against bacterial infection is transient. Viral Immunology 2009;22,1:67-71

    It is unclear whether viral latency mediated protection is transient or lifelong, but it is interesting to know those hidden bugs have potential to protect their host.

  • Rashid G M

    Its true that a latent Virus can protect the host,the simple and basic example is of lamda virus of bacteria,which induces phage immunity in order to resist the reinfection to the same cell.The gene regulation mechanism plays vital role in this regard.

    Can we use the Gene regulatory Science in order to decode the Viruses? If yes How?

  • hi am 26 years old,i mad HIV blood checkup they told me that i am negative for the time

  • hi am 26 years old,i mad HIV blood checkup they told me that i am negative for the time

  • Beto

    Can a virus which has latency period, infected non-neuronal cells?

    scientist

  • Yes. For example herpes simplex virus establishes latency in neurons

    but can also infect other cell non-neuronal cell types.

  • Landon

    Wondering whether argenine is a primary aa in VP16?

  • Yes, VP16 contains arginine residues. If you are thinking about the
    proposed relationship between recurrence and high arginine diets, this
    is not likely to be involved.

  • Landon

    OK, so if high arginine level is not key factor in VP 16 activity, is it known if and how arginine facilitates an exit from latency in Herpes 1?

  • No, it is not know if arginine facilitates exit from herpes latency. I asked David Bloom this question on TWiV #84 and he said that the data in support of this idea are weak.

  • Sanket

    what is the underling mechanism for viral latency?

  • Spahi77

     I am no genius, by far, i am a general contractor who once upon a time wanted to do a lot in biology, yet i like to read on my spare time… however here is a crazy idea, and i mean u might fall off your seat laughing…has anyone considered using prions to attack virus proteins or body cells that have been infected by viruses…Could prions attack the proteins that essentially hide viruses from the immune system, or cause them to start reproducing..of course prions introduced to someone would kill them, but is there a way to denature the prions after they do their damage, and have something useful to work with?….kinda like creating a virus that has altered proteins which would be like target sign on it, so the body could see and kick its ass…lol…thats why i fix houses now, but i love the SyFy channel.

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  • Rc

    I was just informed I have herpes type 1 but I have no cold sores. The only thing I know of doing is drinking after someone. I do however have a sea of small bumps on my knee. I’m not sure if it is small pimples or a symptom?

  • Alfie

    Could you tell me why it is that HSV establishes latency in neuronal tissue and not other tissues sites?

  • question

    *Why the lips for outbreaks?
    *Are there any tracers when hsv-1 is dormant?
    *Can we create tracers? And ways to detect hsv-1 in dormancy?
    *Cooling with ice cubes within seconds of feeling an outbreak can slows down or can stop blistering process.
    *When HSV -1 is active, biting on the unblistered area can cause blistering.
    *When Hsv -1 is active can a frequency wave used by naturopathic medicine kill the virus?

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    {1} HIV/AIDS
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    {4}DIABETES
    (5}HERPERTITIS B
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  • lilian moore

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  • NUNU CALIGRIL

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  • Tamara Quincy

    who will believe that a herb can cure herpes, i never believe that this will work i have spend a lot when getting drugs from the hospital to keep me healthy, what i was waiting for is death because i was broke, one day I saw this great man testimonies in internet who is well know of HIV and Cancer cure and Herpes Simplex Virus, i decided to email him, unknowingly to me that this will be the end of the herpes in my body, he prepare the herb for me, and give me instruction on how to take it, at the end of the one month, he told me to go to the hospital for a check up, and i went, surprisingly after the test the doctor confirm me negative, i thought it was a joke, i went to other hospital was also negative, then i
    took my friend who was also herpes positive to the Dr AGBO,after the treatment she was also confirm
    negative . He also have the herb to cure cancer. please i want every one with this virus to be free, that is why am dropping his email address, agbo_herbalhome@hotmail.com or agbo_herbalhome@hotmail.com
    do email him he is a great man. the government is also interested in this DR, thank you for saving my life, and I promise I will always testify for your good work email him at agbo_herbalhome@hotmail.com

  • Susan Cruso

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  • Susan Cruso

    My name is Susan Cruso I live in united state, i am here to give my testimony about a Herbal Doctor (Dr Okadukpon Herbal Home). who helped me in my life. I was infected with HERPES SIMPLEX VIRUS in 2014, i went to many hospitals for cure but there was no solution, so I was thinking how can I get a solution out so that my body can be okay.So One day I went online on the internet to know more clue about the Herpes Simplex Virus i came across a review of a lady called Helen saying that she got her Herpes Simplex Virus cured by A Herbal Doctor (Dr Okadukpon Herbal Home). So i gave a try by contacting him through his email and explain my problem to him. He told me all the things I need to do and also give me instructions to take, which I followed properly. Before I knew what is happening after two weeks the HERPES SIMPLEX VIRUS that was in my body got vanished . so if you are also heart broken by any deadly diseases like HERPES HIV, shingles,low sperm count or bringing back your ex lover, this great man is extremely the best in which I have seen and applauds and if you also need a help, you can also email him via email (okadukpon_herbalhome@hotmail.com) or (okadukponherbalhome@gmail.com)…

  • Susan Cruso

    My name is Susan Cruso I live in united state, i am here to give my testimony about a Herbal Doctor (Dr Okadukpon Herbal Home). who helped me in my life. I was infected with HERPES SIMPLEX VIRUS in 2014, i went to many hospitals for cure but there was no solution, so I was thinking how can I get a solution out so that my body can be okay.So One day I went online on the internet to know more clue about the Herpes Simplex Virus i came across a review of a lady called Helen saying that she got her Herpes Simplex Virus cured by A Herbal Doctor (Dr Okadukpon Herbal Home). So i gave a try by contacting him through his email and explain my problem to him. He told me all the things I need to do and also give me instructions to take, which I followed properly. Before I knew what is happening after two weeks the HERPES SIMPLEX VIRUS that was in my body got vanished . so if you are also heart broken by any deadly diseases like HERPES HIV, shingles,low sperm count or bringing back your ex lover, this great man is extremely the best in which I have seen and applauds and if you also need a help, you can also email him via email (okadukpon_herbalhome@hotmail.com) or (okadukponherbalhome@gmail.com)….

  • Susan Cruso

    My name is Susan Cruso I live in united state, i am here to give my testimony about a Herbal Doctor (Dr Okadukpon Herbal Home). who helped me in my life. I was infected with HERPES SIMPLEX VIRUS in 2014, i went to many hospitals for cure but there was no solution, so I was thinking how can I get a solution out so that my body can be okay.So One day I went online on the internet to know more clue about the Herpes Simplex Virus i came across a review of a lady called Helen saying that she got her Herpes Simplex Virus cured by A Herbal Doctor (Dr Okadukpon Herbal Home). So i gave a try by contacting him through his email and explain my problem to him. He told me all the things I need to do and also give me instructions to take, which I followed properly. Before I knew what is happening after two weeks the HERPES SIMPLEX VIRUS that was in my body got vanished . so if you are also heart broken by any deadly diseases like HERPES HIV, shingles,low sperm count or bringing back your ex lover, this great man is extremely the best in which I have seen and applauds and if you also need a help, you can also email him via email (okadukpon_herbalhome@hotmail.com) or (okadukponherbalhome@gmail.com).,

  • NUNU CALIGRIL

    My Name are Nunu Caligril i am really happy that i was cured, form (HERPES SIMPLEX VIRUS AND THROAT) with the using of herbal medicine of Dr EDE-MEME , i have been suffering from this disease for the past 3 years without solution until i came across the email of this herbal man who have cure so

    many people with his herbal medicine, i also choose to give him a chance to help me and my husband, he told me what to do and i kindly did it, and he gave us his herbal medicine and direct me on how to use it, i also follows his instruction for use and he ask us to go for a check up after 7 days and which i did, to my greatest surprise our result came out as negative, we are really happy that there is someone like this DR.EDE-MEME who is ready to help anytime any day. to all the readers and viewers that is doubting

    this testimony stop doubting it and contact this Doctor and see if he will not actually help you. i am not a stupid woman that i will come out to the public and start saying what someone have not done for me. he is really a great man contact him now. with this email: edeharbelhome@gmail.com he is

    waiting for your email: edeharbelhome@gmail.com

  • NUNU CALIGRIL

    My Name are Nunu Caligril i am really happy that i was cured, form (HERPES SIMPLEX VIRUS AND THROAT) with the using of herbal medicine of Dr EDE-MEME , i have been suffering from this disease for the past 3 years without solution until i came across the email of this herbal man who have cure so

    many people with his herbal medicine, i also choose to give him a chance to help me and my husband, he told me what to do and i kindly did it, and he gave us his herbal medicine and direct me on how to use it, i also follows his instruction for use and he ask us to go for a check up after 7 days and which i did, to my greatest surprise our result came out as negative, we are really happy that there is someone like this DR.EDE-MEME who is ready to help anytime any day. to all the readers and viewers that is doubting

    this testimony stop doubting it and contact this Doctor and see if he will not actually help you. i am not a stupid woman that i will come out to the public and start saying what someone have not done for me. he is really a great man contact him now. with this email: edeharbelhome@gmail.com he is

    waiting for your email: edeharbelhome@gmail.com ……

  • Tamara Quincy

    who will believe that a herb can cure herpes, i never believe that this will work i have spend a lot when getting drugs from the hospital to keep me healthy, what i was waiting for is death because i was
    broke, one day I saw this great man testimonies in internet who is well know of HIV and Cancer cure and Herpes Simplex Virus, i decided to email him, unknowingly to me that this will be the end of the herpes in my body, he prepare the herb for me, and give me instruction on how to take it, at the end of
    the one month, he told me to go to the hospital for a check up, and i went, surprisingly after the test the doctor confirm me negative, i thought it was a joke, i went to other hospital was also negative, then i
    took my friend who was also herpes positive to the Dr AGBO,after the treatment she was also confirm
    negative . He also have the herb to cure cancer. please i want every one with this virus to be free, that is why am dropping his email address, agbo_herbalhome@hotmail.com or agbo_herbalhome@hotmail.com
    do email him he is a great man. the government is also interested in this DR, thank you for saving my life, and I promise I will always testify for your good work email him at agbo_herbalhome@hotmail.com

  • Tamara Quincy

    ..who will believe that a herb can cure herpes, i never believe that this will work i have spend a lot when getting drugs from the hospital to keep me healthy, what i was waiting for is death because i was
    broke, one day I saw this great man testimonies in internet who is well know of HIV and Cancer cure and Herpes Simplex Virus, i decided to email him, unknowingly to me that this will be the end of the herpes in my body, he prepare the herb for me, and give me instruction on how to take it, at the end of the one month, he told me to go to the hospital for a check up, and i went, surprisingly after the test the doctor confirm me negative, i thought it was a joke, i went to other hospital was also negative, then i
    took my friend who was also herpes positive to the Dr AGBO,after the treatment she was also confirm
    negative . He also have the herb to cure cancer. please i want every one with this virus to be free, that is why am dropping his email address, agbo_herbalhome@hotmail.com or agbo_herbalhome@hotmail.com
    do email him he is a great man. the government is also interested in this DR, thank you for saving my life, and I promise I will always testify for your good work email him at agbo_herbalhome@hotmail.com