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title: Büşra Ece Günaydın - Herpesviruses

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# Büşra Ece Günaydın - Herpesviruses

# ****Herpesviruses****


The word herpes is came from the Greek word “to creep or crawl” that reference to the spreading nature of herpetic skin lesions. They are not just cause life long infection. Some of them used as a vector at reaserch and help some diseses therapy.

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# Herpesvirus Nucleocapsid
![](https://i.imgur.com/KY4uKAW.png)

***Figure 1. Herpes Virus Nucleocapsid***
<p style='text-align: justify;'>They have icosahedral capsid of diameter 100 nm. It has a total of 162 tubular capsomeres surrounding core of the DNA. They have core which is consists of a cylindrical protein. Figure shows  the herpes simplex virus type 1 nucleocapsid 
with VP5 hexamers and pentamers colored blue and red, respectively, and the triplexes that reinforce 
the connections among these structural units in green. VP5 hexamers, but not pentamers, are capped by a hexameric 
ring of VP26 protein molecules. </p>

Source of image: Principles of Virology,Volume 1 Molecular Biology”, 4th Edition,page:115
           

# Herpesvirus Virion
![](https://i.imgur.com/f5se0do.png)
***Figure 2. Herpes Virus Virion***
<p style='text-align: justify;'>Herpesviruses are 120–200 nm in diameter and memeber of Baltimore class I. They have double-stranded DNA. They have envelope. Envelope is the outermost layer composed of all lipid with numerous small glycoprotein peplomers. They have  Tegument which is  between the envelope and capsid.Tegument contains few differnt proteins. </p>

Source of image: Principles of Virology,Volume 1 Molecular Biology”, 4th Edition,page:13






![](https://i.imgur.com/UcRmizG.png)
***Figure 3. Double Stranded DNA Genome***
The genome consists of linear dsDNA with molecular weights varying from 125 to 229 kbp.
Source of image: Principles of Virology,Volume 1 Molecular Biology”, 4th Edition,page:56






# Genome Organization
![](https://i.imgur.com/ujuCOOX.png)
***Figure 4. Herpesviridae Genome Organization***
The genes are labelld in the genome as their locations.
* Ori is origin of replication.
*  L means long region.
* S means short region.
* UL, US means long and short unique regions.
*  IRL means internal repeat sequence, long region. 
* IRS means internal repeat sequence, short region.
* TRL means terminal repeat sequence, long region.
* TRS means terminal repeat sequence, short region.
* OriL means origin of replication of the long region.
* OriS means origin of replication of the short region.

Source of image: Principles of Virology,Volume 1 Molecular Biology”, 4th Edition,page:268



![](https://i.imgur.com/C0unyhY.png)
***Figure 5. Herpes Simplex (HSV-1) Genome Organization (HSV-1)***
<p style='text-align: justify;'>The herpes simplex virus type 1 genome can or recombine through the large inverted repeat sequences like TRL and IRL, or IRS and TRS that all populations consist of four equimolar isomers in which unique long and short sequences (UL and US) are inverted with respect to each other. There are at least 84 open reading frames in this 152-kbp genome, as well as three origins of replication.</p>

Source of image: Principles of Virology,Volume 1 Molecular Biology”, 4th Edition,page:268


# Attachment and Entry to Cell

![](https://i.imgur.com/PlOfQGq.png)
***Figure 6. HSV-1 Attachment and Cell Receptors***
<p style='text-align: justify;'>Gp42, gB, gH/gL, and gD which are four viral glycoproteins  shown binding with attachment molecule heparin sulfate proteoglycan(HSPG) or cell receptors (integrin, nectin-1, HVEM, 3-OS-HS). Virus does not nees all interactions for entry to the cell.</p>

Source of image: Principles of Virology,Volume 1 Molecular Biology”, 4th Edition,page:132





![](https://i.imgur.com/bZK7cgv.png)
***Figure 7. Entring into The Nucleus***
<p style='text-align: justify;'>The herpes simplex virus type 1 (HSV-1) capsid connect to the nuclear pore complex and is minimally disassembled to allow to transit of the viral DNA into the nucleus.</p>

Source of image: Principles of Virology,Volume 1 Molecular Biology”, 4th Edition,page:149



# Transcription and Translation
![](https://i.imgur.com/7zTf8pR.png)
***Figure 8. HSV-1 Transcriptional Programs***
<p style='text-align: justify;'>The immediate-early (IE), early (E), and late (L) transcriptional phases are indicated, as are viral proteins that participate in regulation of transcription. Stimulation of transcription by these proteins and effects contingent on viral DNA synthesis in infected cells are indicated by green and 
purple arrows, respectively.VP16 initiates first step.

Source of image: Principles of Virology,Volume 1 Molecular Biology”, 4th Edition,page:246


![](https://i.imgur.com/G6GELzX.png)
***Figure 9. Replication Fork*** 

<p style='text-align: justify;'> 
Parental DNA is blue, RNA primers are green and newly synthesized DNA are shown in red and pink. Only few double-stranded DNA viruses are synthe sized through a replication fork. One of them is HSV-1. DNA synthesis through a replication fork is always initiated from an RNA primer. 

Source of image: Principles of Virology,Volume 1 Molecular Biology”, 4th Edition,page:268


# **Life Cycle of HSV-1**
<p style='text-align: justify;'>Life cycle of HSV-1 has 7 main steps. They are attachment, entry, transcription, translation, genome replication, assembly and exit. </p>

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![](https://i.imgur.com/8br9SYJ.png)

***Figure 10. Cell Cycle of HSV-1***

<p style='text-align: justify;'>Cycle starts with virions binding to the extracellular matrix and their interactions with receptors. Particles can enter cells through pH-independent fusion of viral envelope with the plasma membrane. Viral and plasma membrane fusion is mediated by viral membrane glycoproteins such as gD, gB, gH, and gL.  After membrane fusion, VP16 which is goes to nucleus and the nucleocapsid are released into the cytoplasm. Viral nucleocapsids attach to microtubules and are transported to the nucleus. Viral nucleocapsids releasing DNA into the nucleus where it is becoming circular. VP16 interacts with host transcription proteins to stimulate transcription of immediate early genes by host cell RNA polymerase II. Transcription and translation happens. After that viral DNA synthesis is initiated from viral origins of replication. Newly replicated viral DNA is packaged into nucleocapsids. Immature enveloped particles fuse with the outer nuclear membrane from within, releasing the nucleocapsid into the cytoplasm. This structure is transported to the trans-golgi network or an endosome that contains mature viral membrane proteins. Tegument proteins added in the nucleus remain with the nucleocapsid, and others are added in the cytoplasm. As nucleocapsids bud into the golgi or endosome compartment, they acquire an envelope containing mature viral envelope proteins and the complete tegument layer.  The enveloped virus particle then buds into a vesicle that is transported to the plasma membrane for release by exocytosis.</p>

Source of image :Principles of Virology,Volume 1 Molecular Biology”, 4th Edition,page:515




# **Latency of Herpesviruses**
The virions of this family, have the capacity to establish life long latent infections. They are frequently reactivated in following immunosuppressive therapy for organ transplantation or in cancer, AIDS or stress.

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![](https://i.imgur.com/y8yFcMi.png)

***Figure 11. Establishment and Reactivation of HSV-1 Latency***
<p style='text-align: justify;'>Herpes simplex virus type 1 is establishes latency through sensory neurons. After primary infection, the virus replicates productively within mucosal epithelial cells and enters sensory neurons. After that the virus is transported to neuronal cell bodies where latency can be happening. The ability to establish lifelong latency within the host and to periodically reactivate to simplify its spreading. Because of that it is center of the survival strategy of HSV-1.</p>

Source:Taylor, T., Brockman, M., McNamee, E.E., & Knipe, D. Herpes simplex virus. Frontiers in bioscience : a journal and virtual library, 7, d752-64,2002





# **Family Herpesviridae**

There are eight type herpesviruses known in people. Most of the adults has infected by them. According to WHO %67 of population has infected by HSV-1.


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![](https://i.imgur.com/oWuWUeJ.png)
***Table 1.*** ***Family Herpesviridae***

Source of image: Principles of Virology,Volume 1 Molecular Biology”, 4th Edition,page:514



# **Types of Herpesviruses**
**Herpes Simplex Viruses 1-2 (HSV-1, HSV-2)**
* Virus that can cause painful cold sores, blisters on the lips, in the mouth or around the eyes. 
* HSV-1 commonly infects young children.
* It enters to neurons and transported to nuclei and may become latent infection.
* The latent virus can reactivate due to emotional stress, physical trauma, other infections, or suppression of the immune system. 


**Varicella-Zoster Virus**
* The varicella virus causes chickenpox in children and sometimes adults.
* It can be may reappear in adulthood as herpes zoster. 
* If varicella spread nerve pathways it may become latent infection. 
* When it reactivated very painful blisters come out on the skin. It called shingles.

**Epstein-Barr Virus**
* Epstein-Barr virus (EBV) known as human herpesvirus 4 one of the most common human viruses.Most people get infected with EBV at some point in their lives. 
* EBV spreads most commonly through bodily fluids especially by saliva. 

**Human Cytomegalovirus**
* The mode of HCMV transmission from person to person is unknown but it can transmitted by bodily fluids. 
* CMV infections are most significant in the perinatal period and in people who are immunocompromised.


**Human Herpesvirus 6-7-8**
* Human herpes viruses 6, 7 and 8 are the last identified viruses of this group. They have similar properties like other herpes viruses. 
* They can cause primary infection, remain latent in host cells, and reactivate in response to immune status changes. 
* HHV most commonly affects young kids between 6 months and 2 years old. It transmits by saliva. It is similar to HHS-7. 
* Human herpesvirus 8 (HHV-8) infection is known to be associated with Kaposi's sarcoma, especially in patients with who has HIV.

