micro sheet# 15 - Wafa2 Is3aid

Herpes Viruses
Introduction:
This topic is very important for your profession. You'll observe a lot of cases related to herpes virus but sometimes, it's difficult to distinguish between the different types of this virus. And you might be infected during working if you contact this virus especially if you don't wear gloves. The infection can be easily acquired by introducing your fingers in the oral cavity of a symptomatic patient especially if an injury occurs while manipulating surgical instruments. Dentists are more prone to be infected with this type of viruses than any other professional group.
*Refer to slide # 3:
Herpes virus has a special structure. In the center there's a genome; this genome differs from one type to another by size; it might be larger or smaller than other types but this genome is associated with presence of a special layer; an amorphous protein layer surrounding the genome. This amorphous protein layer carries large number of enzymes which later contribute to replication of the virus in the infected tissue.
-In addition to the presence of capsomeres, there's an envelope which's associated with large number of protein spikes that are responsible for attachment.
-Once the virus particle is inhaled or reached the mucosal surface of the respiratory tract especially in the oral cavity and lips, the first stage is attachment to the cell membrane. This attachment results in developing of Fusions. In fusions, the envelope remains outside the infected tissue and only the nucleocapsid will enter the cytoplasm. Within the cytoplasm, the virus manages again to attach to a second nucleus cell membrane. Again, there's a form of interaction but less than that of fusions. This results in introducing the viral genome (double stranded DNA) and within the nucleus of the infected cell membrane developing necessary types of amino acids, proteins …etc. The number of these proteins reaches up to 100 types in order to produce the necessary components for the newly developed virus. Once all these components are formed, which are necessary to produce new mature virus particles, it'll migrate to the cell membrane by:
1. Budding from the nucleus cell membrane; again the virus reaches the cytoplasm.
2. Ectocytosis
Then it'll be released in large number of cells.
-According to Vitro-studies in tissue cultures, it was found that the cells undergo lysis following production of large number of viruses.
-The number of new virus particles may reach 1000-10000 then these new virus particles begin to spread from one tissue to another and begin produce the first feature of infection. The feature of infection depends on the type herpes virus. There're many types of herpes virus. Human herpes viruses are of 8 types. The most common one is associated with alpha-group.
-Alpha group>> includes:
• HSV-1 (Herpes Simplex Virus 1).
• HSV-2 (Herpes Simplex Virus 2).
Both are widely distributed and associated with human infection.
• HSV-3 (Varicella-zoster virus). Varicella-zoster viruses the same viruses manifested in two clinical entities (clinical forms of disease):
1. Varicella which's called chickenpox
2. Zoster which's called Shingle; it's a reactivation of the Varicella infection.
-Beta group>> includes:
• HSV-5 (Cytomegalovirus) This virus, in particular, has a larger genome than HSV-1 & HSV-2. This type produces multinucleated cells during infection and that's why it's called cytomegalovirus.
** The replication cycle for HSV-1 &HSV-2 is considered to be slow, whereas for HSV-5 it requires 4-8 weeks. This means that the incubation period of the infection for HSV-5 is longer than that in alpha group viruses.
** Cytomegalovirus (HSV-5) has certain inclusion bodies (perinuclear & intranuclear cytoplasmic inclusion bodies) and that's why HSV-5 is called cytomegalic inclusion disease.
Slide#5:
This is an example for HSV-1 & HSV-2 infection>> this infection usually results in developing of cytopathic effect. The infection is not necessarily to cause damage or lysis of the infected cells but it might only produce elongation. But elongation in relation to cytomegalovirus is less and not well pronounced. In this picture, there's something is called ballooning of cells including inclusion bodies.
Gamma group>> this type of viruses is associated with a special tissue of the body which's the lymphoid cells that produces specific type of disease. This type is related to a virus called Epstein-Barr virus (HSV-4).
Epstein-Barr virus is named according to the two scientists who discover it. This virus is associated with certain malignancy.
HSV-6, HSV-7 & HSV-8 belong to gamma herpes viruses group and each of these viruses is related to certain specific disease mainly in relation to developing malignancy.
*HSV-6 & HSV-7 are found in humans and animals.
*HSV-1, HSV-2 &HSV-4 are found only in humans and rarely associated with animals especially in types adapted malignancy.
*General information about herpes viruses:
- All herpes viruses replicate not in one stage but in more than one stage (2-3 stages). This means that after replication, the end result might not be formation of new virus particles. In other words, replication is not necessarily to end up with developing infecious particles but why?? Because not all genes of herpes viruses might reproduce new particles, there might be a mutation or false replication of the virus.
>> so infection with any type of viruses especially HSV- 1, HSV-2 & HSV-4 result in overt-disease and developing clinical entity of a disease which's manifested in forms of vesicles…etc.
-Despite the previous fact ((the end result might not result in formation of new virus particles. In other words, replication is not necessarily to end in developing infecious particles)), some parts of viral genome might be integrated with the chromosomal cells in form of extra-circular DNA segments known as episomes.
-Plasmids are independent of bacterial chromosome. But episomes aren't like plasmids instead they are part of the chromosome and replicates at the same time as with the cell chromosome.
-In relation to primary herpes simplex virus infection which might be type 1 or type 2. Both type 1 & 2 are related to body's mucosa.
Type1>> related t o upper respiratory tract mucosa especially oral cavity and oropharynx mucosa.
Type 2>> related to genital mucosa.
But despite that, under certain conditions, type 1 might affect the genital tract as well as, type 2 might affect the oropharynx.


** The infection can be transmitted by 2 routes:
1. Inhalation of dust particles or droplets from upper respiratory tract of an infected person. The droplets can also be lodged in the mucosa of the conjunctiva>> so the infection can be followed by the eye or by the oral cavity.
2. Carrying the virus particles in the hand of an infected person; his fingers are contaminated with the virus.
>>the end result of both routes is acquiring the infection.
-Once the virus is attached to the mucosa and replicates successfully in the nucleus of an infected cell>> the end result is developing of vesicles. These vesicles are eruptions of cell's mucosa and these vesicles contain proteinous fluid and later, after 1-2 days, these vesicles will be converted to ulcers (produce ulcerations). These ulcers are associated with multinucleated cells and with inclusion bodies which can be detected using special stain. This ulcer within few days (up to 10 days) might end up with crusting (i.e. ulcer becomes dry) and the ulcer will be eliminated (no ulcerations still present). But there's still an infection with herpes virus.
-In most of the cases, this infection won't end up like other viruses. When there's an infection, then developing of ulcerations and then crusting but the virus can be converted to a latent stage. Latent stage means that the virus presents for longer time in certain infected localized small mucosa of the respiratory tract but if the virus spread to sensory ganglia (nerve cells) and there, it might be integrated as episomes ( DNA of the virus) within the chromosomes of the infected nerve tissue.
-Not all of the genome but part of it which carries necessary genes for future replication. This latent stage means that later after one year or many years, if there's stimulatory reaction then the virus become reactivated and might develop reoccurrence of the infection which's exactly like the first type of infection and might be on the same location on the lips at the junction of the mouth. The virus might recognize the same feature.
-In general, children <5 years acquire HSV-1 in the first 5 years.
-Up to 95% of young children (up to 5 years) usually might be exposed to HSV-1>> this means that they have already contacted with the virus.
-Despite observing the developing of an infection in forms of vesicles or ulcers, the infection might be symptomatic or asymptomatic. Sometimes it's not easy to insure that this child is infected or not. Sometimes there's no any sign of infection.
-Generally, children when infected at the first time with HSV-1, they develop some fever, certain adenopathy and a mild form of sore throat. Most often, it can be easily observed and considered as a symptomatic infection.
-During infection, the infected person develops a form of immunity. This immunity is of 2 types:
-1st type: following the production of specific antibodies exactly like other viruses IgM & IgG which are called "total specific antibodies".
-2nd type: production of natural killer cells which are the cytotoxic T-cells & helper T-cells. Helper T-cells activate more specific antibodies and induce the delayed hypersensitivity.
-Immunity to herpes viruses associated with developing of specific antibodies as well as cell-mediated immunity in form of hypersensitivity.
-The severity of the infection between persons depends on the amount of antibodies produced during the infection. If enough antibodies are produced, the patients will suffer less from pain, ulcerations & complications. But in relation to the infection with herpes virus especially the immunocompromised patients, they might develop complications due to dissemination of the virus from the localized infected tissue to blood stream and may reach the internal organs including the CNS causing aseptic meningitis and encephalitis. In certain patients, this might be fatal without using specific antiviral drugs.
-Following the infection, there will be latent stage for the virus in nerve tissues. It depends on the type of the virus. In relation to HSV-1>> generally, small part of DNA gene of the virus travel and integrate in nerve chromosome and become as integrated part. In relation to HSV-1, sensory ganglia will be affected.
**Slide#10>> look at the left side of the picture; you can see the first primary infection in the oral mucosa whether in relation to the gingiva or to any part of the oral cavity including the pharynx following developing of clinical features of the disease and following recovery.
-Few amount of the viral genome including two trigeminal sensory nerves within the trigeminal ganglion will be integrated in the nerve tissue and enter in a latent (silent) stage. Later, if there's any stimulatory effect like exposure to sun light (ultra-violet), exposure to severe bleeding, trauma, exposure to stress condition, exposure to certain types of drugs & in immunocompromised patients, all these stimuli may contribute to reactivation. Reactivation means that small particles of DNA of the viral genome will be reactivated by production of necessary components for production of new virus particle and it'll begin to return back from the infected sensory nerve ganglia to the same previous localized infection in the oral cavity where it started the infection and begin to recognize the same feature of the infection. For example, if there was gingivostomatitis, it'll develop it again and so on.
-This reactivation can be observed during short period especially in children. During one year you can recognize eruptions in the oral cavity mucosa. It might not return back after few years but it might return back in 5, 10, 20…etc years.
-Types of HSV-1 infection which are manifested in various clinical forms, can be one of the following: most common in relation to mucocutaneous junction of lips where the majority of infections can be observed and usually occur in children <5 years up to 99%.This feature can often be recognized in HSV-1 but rarely HSV-2 develop such infection.
**Gingivostomatitis:
-Known as cold sores or fever blisters.
-As you see in slide #12>> it might be on the upper lip, lower lip or at the junction of the mouth and it might spread to the skin of the face and there might be some vesicles in any part of the face, So it's not only related to the junction of the lips.
-Gingivostomatitis can be painful especially if it's not found on the mucosa of the inner part of the oral cavity especially associated with the soft palate and the tongue.
-It might be more painful if the virus reaches the pharynx>> there'll be enlargement, redness, erythema, fever & adenopathy.
-Generally, herpetic stomatitis (which means that the virus spread and produce more lesions and ulcers in many parts of the oral cavity) recognized not only on the gingiva or gum and it's recognized in older children but in young children, there're one or two lesions. The presence of many lesions in older children indicates that the patient is suffering from immunosuppressed- condition.
-Herpetic stomatitis might end up with more severe complications especially in immunocompromised patients, but why?? Because the virus might spread to blood stream and produce viremia and later to the CNS to produce aseptic meningitis and encephalitis and even death in very rare cases.
-Reoccurrence of HSV-1 in the oral cavity is mainly recognized in children without complications but there are complications associated with immunocompromised patients.
-It's more dangerous if there's infection related to the eye. For example, many children put their fingers in their mouth and then put their contaminated fingers in their eyes and consequently cause conjunctivitis. This infection might be mild or severe according to the number of virus particles but generally, it's associated with mild conjunctivitis or in severe forms with keratoconjunctivitis. Keratoconjunctivitis means corneal infection, ulcerations, damage and might produce scaring and the end result is blindness if the patient not treated within a short period by specific antiviral drugs. If not treated, destruction of cornea occurs within few days. Infection of cornea by herpes virus is very painful like adenovirus and the patient will suffer a lot.
**Skin manifestations:
-Children might infect their skin especially the face and this is can be easily recognized but generally, skin infection is not so dangerous within the face.
-Infection of the skin of the fingers is more common especially among dentists. There'll be abrasions, damage in the epidermis but you might not recognize this type. If the virus reaches the epidermis and manage to establish infection, this can be so severe and not easily treated with antiviral drugs. It requires a lot of time to be cured. This type of infection is called herpetic whitlow.
-In herpetic whitlow, there'll be an inflammation in the epidermis & dermis with redness, warmness & pain.
-In some children who have problems with the skin, they might develop Eczema Herpeticum. It's a rare condition but very painful and may end up with viremia and aseptic meningitis.
-The majority of HSV-1 infections -in relation to oral mucosa & skin- are considered as harmless and not associated with any dissemination and only less than 1% undergoes dissemination especially in association with underlying disease and immunocompromised condition.


*Done by: Wafa'a Iseid
*Micro lec. # 15
*Date of the lec. : 14.3.2011
*Dr. Asem Shehabi