Herpes replication

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Herpes replication

Intro:

Herpes is a family of DNA viruses called Herpesviridae. The herpes family of viruses consists of three families of viruses; Alphaherpesviridae, Betaherpesviridae, and Gammaherpesviridae.

Among these families are many commonly known viruses that are causative agents of many diseases, such as HSV-1 and HSV-2 for cold sores and genital warts, varicella zoster for chicken pox and shingles, and the Eppstein-Barr virus for mononucleosis.

Herpes virsues also tend to have latent, recurring infections in the infected organisms, where the virus remains in some part of the infected organism

The most well known examples of herpes are the herpes simplex viruses, HSV-1 and HSV-2. HSV-1 is the causative pathogen of most oral cold sores, while HSV-2 is the causative agent of genital warts.

It is thought that more than 50% of adults in the United States have HSV-1, and that nearly 20% have HSV-2. The widespread infection of the populace makes herpes a good target for medical research

Pathology:

HSV-1 and HSV-2 are both transmitted through skin-to-skin contact or through contact with an infected person’s bodily fluids. HSV-1 primarily infects the areas of the mouth, throat, face, eyes, and the central nervous system, while HSV-2 primarily infects the genitals.

However, both variants can infect all areas (Gupta, 2007).

Transmission can also be vertical through pregnancy, and neonatal HSV infection is more severe than childhood or adult.

Once infected, HSV causes blisters on the skin that are filled with active virus particles (Fig 1). Contact with these blisters carries the highest risk of transmission.

However, these blisters are not permanent, lasting typically a few weeks. The infection then goes into a latent stage, where the infected person is asymptomatic.

Though asymptomatic, the infected person may still transmit the virus. During the latent stage, HSV invades peripheral neurons and remains in the nuclei of these cells (Gupta, 2007).

Eventually, the virus is triggered and re-infection begins, as virions move out of neuronal nuclei and out to re-infect epithelial areas. It is unknown exactly what triggers the resurgence of the virus.

Interestingly, once infected other areas become resistant to infection: If an oral infection of HSV-1 occurs, then infections will not occur on the fingers (Gupta, 2007).

Also, contracting one variant confers some protection against the other, as those infected with HSV-1 are somewhat resistant to HSV-2, while those infected with HSV-2 are resistant to HSV-1 (Gupta, 2007).

Regardless of which strain is contracted, the immune system never eradicates the infection.

Re-activations of the virus often become less severe and more infrequent over time, with some infected individuals becoming completely asymptomatic

Cellular Invasion:

The virion invades the cell by fusing its envelope with the cellular envelope.

This fusion of virion membrane and cellular membrane is mediated by envelope glycoproteins.

Viral induced membrane fusion can be defined as three phases;

Phase I has the two membranes brought into close proximity by having a viral glycoprotein bind to a cellular surface receptor, Phase II consists of the initial mixing of membrane leaflets and the formation of a hemifusion intermediate pore, Phase III has the formation and expansion of a stable fusion pore (Subramanian, 2007).

HSV requires four glycoproteins to achieve fusion; glycoprotein D (gD), a complex of glycoprotein H and glycoprotein L (gHL), and glycoprotein B (gB). The presence of gD and gHL are indicated during leaflet mixing and hemifusion, while gB is present during full fusion and mixing of viral and cellular contents.

A sequential model has been proposed for glycoprotein involvement in envelope fusion, with gD being necessary for Phase I as the glycoprotein that is recognized by cell surface receptors, gHL being necessary for Phase II leaflet mixing, and gB being necessary for full fusion and pore formation.

All four proteins are necessary for HSV to be infectious, for without any one of the glycoproteins no cellular invasion occurs (Subramanian, 2007).

Once envelope fusion has completed, the viral tegument and capsid are transported to the nucleus of the infected cell.

The tegument remains attached to the capsid, and makes its way to the nucleus by using the cytoskeleton proteins of the infected cell (Zaichick, 2013).

Once the capsid reaches the nucleus, the capsid injects the linear viral DNA into the nucleus of the infected cell.

This injection is done through the capsid portal, created by the formation of a twelve units of the capsid protein pUL6 (Trus et al, 2004). There is but a single portal per capsid, and it is assembled at one of the capsid’s vertices

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Poxvirus

The virions of poxviruses consist of a surface membrane, a core, and lateral bodies, or a surface membrane, a core and lateral bodies.

They may or may not have an envelope.

They produce extracellular and intracellular particles during their life cycle and can occur in two phenotypes. They may be enveloped during their extracellular phase.

Extracellular virions initiate the infection.

The virus may be sequestered within inclusion bodies that are not occluded and typically contain one nucleocapsid. The virion capsid is enveloped.

The virions are generally ovoid and brick shaped, or phlemorphic. The ovoid virion is 140-260 nm in diameter, 140-260 nm in height and 220-450 nm in length while the pleomorphic virion is 160-190 nm in diameter and 250-330 nm in length.

The virion is composed of an external coat containing lipid and tubular or globular protein structures enclosing one or two lateral bodies and a core, which contains the genome, displaying tubular units, or globular units, or regular spiral filaments.

The core is unilaterally concave, or is biconcave, or is cylindrical with one lateral body, or two lateral bodies. Lateral bodies are usually lens-shaped and nested between the core membrane, or between the surface membrane.

The replication of the poxvirus occurs in the cytoplasm.

The virus is suficiently complex and has acquired all the functions necessary for genome replication.

Although the cell contributes to the process, it is not clear what exactly the cell does: poxvirus gene expression and genome replication occur in enucleated cells, but maturation is blocked.

The receptors for poxvirus repliation are not known yet, but there are probably more than one on different cell types. The penetration is complex ad probably involves more than one mechanism.

Two stages of uncoating take place.

The outer membrane is removed as the particle enters the cell and in the cytoplasm, the particle is further uncoated and the core passes into the cytoplasm.

Gene expression is carried out by viral enzymes associated with the core and is divided into two phases: early genes and late genes.

Early genes are expressed before genome replication while late genes are expressed after genome replication and the late promoters are dependent on DNA replication for activity.

The gene expression of poxviruses has been studied in detail because of the interest in the use of Vaccinia virus as a vector for the expression of heterologous genes.

The genome replication of the the poxvirus is believed to involve self-priming, leading to the formation of high m.w. concatemers that are isolated from infected cells which are subsequently cleaved and repaired to make virus genomes.

Thymidine kinase and many other virus-encoded enzymes involved in replication offer potential targets for chemotheraputic agents.

The assembly occurs in the cytoskeleton.

The events involved in putting together such a complex particle are not clearly understood yet, but probably involve interactions with the cytoskeleton, for example actin-binding proteins.

Inclusions are formed in the cytoplasm which mature into virus particles.

Actin 'comet tails' are formed and they shoot IEV through the cytoplasm to the cell surface, and possibly into adjacent cells. This movement has been timed and found to be 3µm/min.

This may be instrumental in providing an alternate mechanism for cell to cell transmission. The relication of this large, complex virus is rather quick.

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HPV

The replication cycle of HPV is tightly linked to differentiation of the epithelium it infects.

HPVs may access the basement membrane or dividing basal epithelial cells via microabrasions in the epithelium and certain HPVs may attach to cells using common cell surface molecules such as heparin sulphate proteoglycans.[14,15]

Some proteins that may act as the virus receptor[16,17] have been described but the true identity of the molecule(s) involved is still the subject of investigation.

At least in some cases, virus entry occurs through either calveolar or clathrin-mediated endocytosis.[14,18] Once inside the cell, uncoating occurs and the circular virus genome is transported to the nucleus.

Upon division of the infected cell the nuclear episomal genome is replicated to 20–100 copies and maintained in daughter cells upon segregation through attachment of virus genomes to host chromosomes via the virus replication/transcription factor E2 following the pattern established for BPV-1.

[19] One hypothesis is that during the first phase of infection of basal layer cells only the virus replication proteins E1 and E2 are expressed in order to establish and maintain the low copy number genomes.

[20] However, further work needs to be carried out to establish this as fact.

Although the E6 and E7 oncoproteins are also expressed soon after infection, the exact temporal lineage of early events in the virus lifecycle is difficult to evaluate.

This is because it is still very technically difficult to infect epithelial cells and follow the course of infection with HPVs. Infection may persist in the infected stem cell and its daughter cells, in the basal layer of the epithelium over a long period of time, up to several years.

Persistence is considered the major risk factor underlying cervical tumor progression.[21] However, a normal infection requires that division of a basal stem cell sometimes yields a daughter transit amplifying cell with the ability to differentiate to upper epithelia layers.

Normally, upon differentiation epithelial cells stop dividing and commence terminal differentiation.

Importantly, in HPV-infected epithelial cells the concerted action of the E6 and E7 oncoproteins and their partner proteins p53 and pRb, respectively, reactivates cell division, inhibits apoptosis and abrogates epithelial differentiation.[22]

Unscheduled division of infected cells in the differentiating epithelial layers gives rise to the physical manifestation of infection as a wart. Reactivated cell division allows further amplification of virus genomes to yield many thousands of copies.

Finally, upon differentiation to the granular epithelial layer, the virus capsid proteins L1 and L2 are expressed and encapsidate the newly synthesized virus genomes.[23]

For release, new virions may rely on mechanical breakage of infected cells sloughed off from the upper later of the epithelium.

However, evidence exists that the E4 protein has an active role in priming the infected differentiated cell by disrupting the keratin filamentous network[24] and inhibiting formation of the cornified envelope.

For example, cutaneous HPV E6 and E7 proteins do not appear to operate by the same mechanisms as anogenital HPVs in regulating the cell cycle, differentiation and apoptosis of the infected cell.

The temporal organization of the virus replication cycle is also different between different HPV types perhaps reflecting differences in sites of infection and in different modes of transmission.[27]