Herpesviridae

Untitled3“Unlike love, herpes is forever.”

–Bob

Overview

Herpes is a lot more than a sexually transmitted infection. There are 9 human herpesviruses, and they comprise 3 subfamilies: Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae.

Herpes Viruses that you should know about:kshv_3d_high

– HSV-1

– HSV-2

– Varicella-Zoster virus

– Epstein-Barr virus

– Cytomegalovirus

– HHV-6a and 6b (roseola

– HHV-7

– Kaposi’s sarcoma-associated herpesvirus


Commonalities

Latency: Just because you had herpes once doesn’t mean you can’t get it again! The virus will hide away in your body and come back in force at an opportune time

Opportunistic Infection: Herpesviruses often cause opportunistic infections seen in people with weakened immune systems (immunocompromised), such as AIDS patients and organ transplant recipients. Kaposi’s sarcoma-associated herpesvirus causes a rare type of skin cancer that is an AIDS-defining illness.

Incurability: Once you’re infected with a herpesvirus, it stays in your body forever. To date, there are no drugs that can completely eliminate a herpesvirus from your body.

Variety of clinical symptoms: Even the same herpesvirus can cause more than one different syndrome

Ubuiquity: Herpesviruses are everywhere. About 50% of the US population has been infected with HSV-1. To give you an idea of how common they are, chickenpox is caused by a herpesvirus (Varicella-Zoster virus). So are cold sores (HSV-1) and mono (Epstein-Barr virus).


The Basics

Herpesviridae is an old and diverse family of viruses. They infect an astonishing variety of animal taxa, including mammals and mollusks, suggesting that the family could be hundred of millions of years old: long before humans were humans.

In the time that humans have been around, herpes has also distinguished itself as a ubiquitous pathogen:

A few hundred million years BCE: The first herpesviruses were infecting the ancestors of vertebrates and mollusks.

Ancient Greeks—Hippocrates have the name herpes to a mysterious disease that caused “creeping” skin lesions.

Emperor Tiberius of Rome is said to have banned kissing to reduce the transmission of HSV-1, as even at that time it was known that the creeping lip lesions could spread by contact.

Shakespeare also mentioned cold sores (HSV-1) in Romeo and Juliet, in which he writes, “O’er ladies lips, who straight on kisses dream, which oft the angry Mab with blisters plagues, because their breaths with sweetmeats tainted are.”

Numerous researchers of the 19th century applied the ways of science to the study of these mysterious infectious agents. One of the most important steps in determing the cause of the creeping lesions occurred in 1884 when American doctor Louis Duhring differentiated them from eczema and pemphigus, which are not contagious. German doctor Paul Unna determined a way to clinically differentiate herpes lesions from syphyllis lesions in 1896. In 1893, French scientist Emile Vidal proved experimentally that herpes lesions were indeed transferable from one person to another.

In the early 20th century, research on tobacco mosaic virus finally showed the world what viruses looked like.

Another important breakthrough in the understanding of herpesviruses came in 1925, when American virologist Ernest Goodpasture showed that herpesviruses travel through neurons. In 1939, Australian microbiologist suggested that herpesviruses reside primarily in neurons during a period of latency, when no symptoms occur. In 1973, American scientists Jack Stevens and Margery Cook confirmed this theory.

il_570xN.435470729_1e9zCytomegalovirus was discovered in the 1950’s, making it one of the more recently-discovered herpesviruses.

A 1960’s TV commercial jingle for Armour hotdogs claimed, “Big kids, little kids, kids who climb on rocks, fat kids, skinny kids, even kids with chickenpox love hot dogs, Armour Hotdogs!”

 https://www.youtube.com/watch?v=3fQwJdXFQlU

The first herpes antiviral drug , acyclovir, was FDA-approved in 1978. It is still used today to treat or prevent HSV-1, HSV-2, cytomegalovirus, varicella, and Epstein-Barr virus.


Contemporary Herpes

Herpesviruses may be old, but people are making new discoveries all the time.

Because herpesviruses infect so many people, there is a great impetus for the development of antivirals and vaccines. One of these new drugs is an enzyme nucleotidyltransferase inhibitor. This enzyme is normally used for transferring a phosphorous-containing group from one molecule to another. Nucleotidyltransferase is used in the synthesis of DNA and of tRNA. There are no licensed drugs that target the nucleotidyltransferase of HSV-1 or HSV-2, so this new drug could work in conjunction with existing ones.

http://www.sciencedaily.com/releases/2014/12/141218131937.htm

Another experimental therapy actually uses a herpesvirus as a diagnostic agent. A recent study from the University of Birmingham used host-derived, genetically modified cytotoxic T cells that selectively destroyed cancer cells infected with Epstein-Barr virus. Since Epstein-Barr virus is frequently implicated in the oncogenesis of nasopharylgeal carcinoma (representing 18% of cancers in Southeast Asia). The specific protein that the genetically engineered cytotoxic T cells target is viral protein LMP2, which blocks tyrosine kinase signaling so that the B-lymphocytes in which the virus goes latent don’t undergo apoptosis.

http://www.sciencedaily.com/releases/2015/03/150310105224.htm

The Immunology of Epstein-Barr Virus-Induced Disease:

DOI: 10.1146/annurev-immunol-032414-112326

http://www.annualreviews.org/doi/abs/10.1146/annurev-immunol-032414-112326

EBV Found in A Lymph Node of a Patient with Multiple Sclerosis:

doi: 10.1097/NEN.0000000000000082

http://journals.lww.com/jneuropath/Citation/2014/07000/Epstein_Barr_Virus_in_the_Central_Nervous_System.9.aspx

Effectiveness of Common Hand Washing Agents on Survivability of Cytomegalovirus on Human Hands:

doi:10.1128/AEM.03262-13

http://aem.asm.org/content/80/2/455.short


Morphology

herpes_eggHuman herpesviruses are among the most complex known viruses that infect humans. Their capsids are spherical or pleiomorphic, and they have envelopes. These structural features make herpesviruses look like “fried eggs” when viewed with a scanning electron microscope. While large for a virus, they are still quite small at 150-200 nm in diameter.

They have linear double stranded DNA genomes like we do. At 120-230 KB in length, their genomes are quite large for a virus. Herpesviruses genomes include between 70 and 200 genes.


Replication:

Herpesviruses replicate in 2 phases. A hallmark feature of herpesviruses is their ability to go latent. Oftentimes, the virus infects a different type of cell than it does when it is actively replicating.

Latent Replication: Replication of circular viral DNA inside of the host nucleus using host cell replication machinery.

Lytic: This is the phase in which the virus typically causes clinical symptoms.

For the virus to reproduce, it first has to enter the host cell, which it does by attaching its host gB, gC, gD, and gH proteins to the host cell receptors. The virus fuses with the host cell membrane, and loses its envelope. The capsid is transported to the nucleus, where its genome is replicated.


Kinetic classes

Herpesviruses express the genes of their genome in a series of steps, which are known as kinetic classes. The kinetic classes describe the manner in which certain herpesvirus genes are transcribed and translated at different times relative to each other. The early genes are accessory proteins involved in regulatory functions, while the later ones are proteins form the capsid and support the envelope: the structural proteins.


Clinical Stuff

Herpes(PHIL_1573_lores)HSV-1 causes cold sores

HSV-2—genital herpes

Varicella-Zoster virus—causes chickenpox

Epstein-Barr virus: mononucleosis; AKA the kissing disease

Cytomegalovirus

HHV-6a and 6b–Roseola

HHV-7–Roseola

Kaposi’s sarcoma-associated herpesvirus: causes a rare form of skin cancer typically seen in immunocompromised patients.

We have a safe and effective vaccine for Varicella-Zoster, but not for any of the others. In the future, science will likely yield vaccines for some of the other viruses. Some of these are in development now:


Drug Profile

At the time of writing, we don’t have the ability to completely clear a herpesvirus infection from the body. However, there are several drugs that help reduce viral load and symptoms.

One of the most iconic antivirals used to treat herpesviruses is Acyclovir

Acyclovir (trade name Zorivax and Cyclovir)

Is used to treat chickenpox, shingles (Varicella Zoster virus), genital herpes (HSV-2), herpes of the skin, lips, and mouth (HSV-1 or HSV-2), and neonatal herpes (typically HSV-2). It doesn’t cure herpes, but it can reduce the viral load and alleviate symptoms. Acyclovir can also be used to treat Epstein-Barr virus and cytomegalovirus infections, but it isn’t as effective as it is against HSV-1, HSV-2, and VZV.

Acyclovir is typically administered intravenously or as an oral capsule/tablet, or as an oral liquid. It is a guanosine analogue, which means that the drug is similar in chemical composition to a guanine base (found in DNA and RNA), but it inhibits the viral DNA polymerase, the main enzyme used to replicate DNA. Acyclovir is a well-established antiviral medication that the WHO endorses for treating herpesvirus infections.

(http://apps.who.int/iris/bitstream/10665/93142/1/EML_18_eng.pdf?ua=1).


References

http://www.virology.wisc.edu/virusworld/images/h1b_blue-red-yellow-outline.jpg

http://apps.who.int/iris/bitstream/10665/93142/1/EML_18_eng.pdf?ua=1

http://viralzone.expasy.org/viralzone/all_by_species/176.html

http://www.springer.com/cda/content/document/cda_downloaddocument/9783540694625-c1.pdf?SGWID=0-0-45-649307-p173830907

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