Herpes Viruses

Bacteriology at UW-Madison

The Microbial World

Lectures in Microbiology by Kenneth Todar PhD University of Wisconsin-Madison Department of Bacteriology

Herpes and Related Viruses

The replication cycle of Herpes Simplex virus. 1. Specific proteins in the viral envelope attach to host cell receptors on the cell membrane. 2. Penetration is achieved when the viral envelope fuses with the cell membrane releasing the nucleocapsid directly into the cytoplasm. 3. The virion is uncoated and the viral DNA is transported into the nucleus. 4. In the nucleus, the viral DNA is transcribed into early mRNAs which are transported to the cytoplasm for the translation of early proteins. These early proteins are brought back into the nucleus and participate in the replication of the virus DNA into many copies. The viral DNA is then transcribed into the late mRNAs which exit to the cytoplasm for translation into the late (nucleocapsid and envelope) proteins. 5. The capsid proteins encapsidate the newly replicated genomes. The envelope proteins are imbedded in the nuclear membrane. 6. The nucleocapsids are enveloped by budding through the nuclear membrane, and the mature viruses are released from the cell through cytoplasmic channels. To view an animation of the life cycle of Herpes go to the Homepage of Dr. Edward K. Wagner at U Cal Irvine

Herpes

Herpes viruses are a leading cause of human viral disease, second only to influenza and cold viruses. They cause overt disease such as cold sores and chickenpox, or they may remain latent for many years to be reactivated in later life, as in shingles.

The name herpes is derived from the Greek word herpein which means to creep. This reflects the spreading or creeping nature of the skin lesions caused by many herpes viruses.

There are 25 types of herpes viruses. Six types cause medical problems in humans.

Table: Herpes Viruses that are Pathogens of Humans

1. Herpes simplex virus (HSV)
HSV-1 - causes fever blisters (cold sores), gingivostomatitis, herpes keratitis, eczema herpeticum, HSV encephalitis
HSV-2 - causes genital lesions, neonatal infections, HSV meningitis, HSV proctitis

2. Varicella-Zoster virus (VZV) - chickenpox, congenital varicella syndrome, shingles

3. Epstein-Barr Virus (EBV) - infectious mononucleosis, Burkitt's lymphoma, nasopharyngeal cancer

4. Cytomegalovirus (CMV) - usually asymptomatic infections

5. Human herpes virus 6 (HHV-6) - exanthum subitum or roseola infantum

6. Human herpes virus 8 (HHV-8) or Kaposi's sarcoma-associate herpes virus (KSHV) - found in the saliva of many AIDS patients and associated with Kaposi's sarcoma

Herpes viruses are fairly large, icosahedral, enveloped dsDNA viruses. Their pattern of infection and replication is illustrated and explained in the introductory material on viruses that occurs earlier in this chapter.

Two Herpes viruses are shown in this TEM negative stain.
http://www.wadsworth.org/databank/herpes.htm

Herpes Viruses Pathogenic for Humans

Herpes simplex 1 and 2

Herpes simplex 1 and 2 (HSV-1 and HSV-2) can infect both humans and other animals, but only humans show symptoms of disease. The hallmark of herpes infection is the ability to infect epithelial mucosal cells or lymphocytes. The virus then travels up peripheral nerves to a nucleated neurone where it may stay for years and be followed by reactivation.

Pathogenesis of HSV-1 and HSV-2 Infections

The site of the initial infection is usually the oral or genital mucosa, depending on the way in which the person acquires the virus. It is often noted that HSV-1 infects above the waist and HSV-2 infects below the waist, but either virus can infect at either locale, and this reflects the mode of transmission rather than any intrinsic property of the virus. Both types of HSV can also persistently infect macrophages and lymphocytes.

Once mucosal epithelial cells are infected, the virus replicates around the lesion and enters into the innervating neurone. The virus travels along the neurone (by a process called retrograde axoplasmic flow) to the ganglion. In the case of herpes infections of the oral mucosa, the virus goes to the trigeminal ganglia, whereas in genital infections the virus invades the sacral ganglia.

When the virus infects neurones it enters into latency. If breakage of latency occurs in these cells, the virus travels back down the nerve axon and recurrence of infection (and therefore symptoms) occurs at the same site as the initial infection. Vesicles containing infectious virus are formed on the muscosa and the virus spreads. As long as the virus is kept moist it can remain infectious. The vesicle heals and there is usually no scar as a result.

There are several agents that seem to trigger recurrence, most of which are stress-related. It also appears that exposure to strong sunlight and perhaps fever can lead to recurrence. Recurrent infections are usually less pronounced than the primary infection and resolve more rapidly.

HSV-1 and 2 infections are life-long and although latency is soon set up, the infected patient can infect others as a result of recurrence. The virus is found in the lesions on the skin but can also be present in a variety of body fluids including saliva and vaginal secretions. Despite the apparent "above the waist/below the waist" rule, both types of HSV can infect oral or genital mucosa depending on the regions of contact.

HSV-1 can set up a primary infection in the lips, move to the trigeminal ganglion where it can remain latent. The virus can subsequently reactivate, move to the original site of infection and result in cold sores.

HSV-1 is usually spread mouth to mouth (kissing or the use of utensils contaminated with saliva) or by transfer of infectious virus to the hands after which the virus may enter the body via any wound or through the eyes.

A large proportion of the population has evidence of HSV-1 infection as judged by presence of antibodies. As a result of poor hygiene in underdeveloped countries, HSV-1 antibodies are found in more than 90% of children.

HSV-2 is normally spread sexually and is found in the anus, rectum and upper alimentary tract as well as the genital area. In addition, an infant can be infected at birth by a genitally-infected mother. The infant can also be infected in utero if the mother's infection spreads. Because of the infant's underdeveloped immune system, the resulting infection can be very severe and sometimes lead to death.

Anyone who comes in contact with fluid containing infectious virus is at risk. There is a disease that affects health care workers called herpetic whitlow that results in lesions on the fingers (it can be caused by either type of HSV).

HSV-2 infections are more prevalent later in life as the number of sexual contacts increases. Thus, the lowest rates of infection are found in children and the highest rates in prostitutes among whom as many as 80% are infected with HSV-2.

Diseases caused by HSV-1 and HSV-2

Cold sores can be the result of an HSV-1 or an HSV-2 infection. The initial lesion looks the same - a clear vesicle containing infectious virus with a red (erythomatous) lesion at its base. From this vesicle, encrusted lesions and ulcers may develop.

Cold sore on the lower lip caused by HSV-1 on the second day after onset. CDC.

In primary herpetic gingivostomatitis, the typical clear lesions develop first followed by ulcers that have a white appearance. The infection, often initially on the lips, spreads to all parts of the mouth and pharynx. Reactivation from the trigeminal ganglia can result in cold sores.

Herpes pharyngitis is often associated with other viral infections of the upper respiratory tract. The disease is more severe in immunosuppressed people such as AIDS patients.

Herpes keratitis is an infection of the eye and is primarily caused by HSV-1. It can be recurrent and may lead to blindness. It is a leading cause of corneal blindness in the United States.

Herpes whitlow is disease of persons who come in manual contact with herpes-infected body secretions. It can be caused by either type of HSV and enters the body via small wounds on the hands or wrists. It can also be caused by autoinoculation of HSV-2 from genitals to the hands.

Eczema herpeticum is found in children with active eczema. The virus spreads over the skin at the site of eczema lesions. It can spread to other organs such as the liver and adrenals.

Genital Herpes is usually the result of HSV-2 infection with about 10% of cases being caused HSV-1. Primary infection is often asymptomatic but many painful lesions can develop on the glans or shaft of the penis in men and on the vulva, vagina, cervix and perianal region of women. In both sexes, the urethra can be involved. In women, the infection may be accompanied by vaginal discharge.

Genital herpes on the penile shaft. CDC

Genital herpes on the vagina. HSV-2 typically causes one or more blisters to form on or around the genitals or rectum, which break, leaving tender ulcers which may take 2-4 weeks to heal after their initial appearance. CDC

Primary infections involve a transient viremia and can be accompanied by a variety of symptoms including fever, myalgia, and glandular inflammation of the groin area.

Secondary episodes of genital herpes, which occur as a result of reactivation of virus in the sacral ganglion, are frequently less severe and of shorter duration than the first. Some people have only infrequent recurrences but others experience recurrences as often as every 14-21 days. Whether there is an apparent active disease or not, an infected person remains infectious and may be a source of herpes in its spread and maintenance in the population.

HSV Encephalitis. This is usually the result of an HSV-1 infection and is the most common sporadic viral encephalitis. HSV encephalitis is a febrile disease and may result in damage to one of the temporal lobes. As a result there is blood in the spinal fluid and the patient experiences neurological symptoms such as seizures. The disease can be fatal, but in the US there are fewer than 1000 cases per year.

HSV Meningitis
This is the result of an HSV-2 infection. The symptoms seem to resolve spontaneously.

HSV Infection of Neonates

This results from HSV-2 and is often fatal, although such infections are rare. Infection is especially possible if the mother is shedding virus at the time of delivery. Thus, prospective mothers should avoid contracting herpes during pregnancy.

A primary HSV-2 infection during pregnancy creates a greater risk of transmission to the newborn. If a woman has active genital herpes at delivery, a cesarean-section delivery is usually performed. The virus can either be obtained in utero or during birth with the latter being more common. Because the neonate has an underdeveloped immune system, the virus can spread rapidly to many peripheral organs (e.g. lungs and liver) and can infect the central nervous system.

Treatment of HSV

There are a variety of nucleoside analog drugs used to treat herpes infections, though the person still harbors the virus for life. Some of these drugs are very specific and are only activated by specific viral enzymes, meaning that these drugs show few side effects.

The best known of the nucleoside analogs is acyclovir. Other approved drugs including famciclovir and valacyclovir. These drugs act against the replicating virus (they are incorporated into the DNA as it is copied) and therefore they are ineffective against latent virus.

The best way to avoid HSV infection is by not coming in contact with the virus. However, this is not always possible as many people experiencing active viral replication are asymptomatic. Needless to say, people with active genital herpes or cold sores should avoid intercourse, oral sex and kissing during such episodes in order to prevent transmission of the virus.

Varicella-Zoster Virus (VZV)

Zoster means "girdle" from the characteristic rash that forms a belt around the thorax in many patients. The structure of Varicella virus is very similar to Herpes Simplex virus although the genome is somewhat smaller.

This virus causes two major diseases, chickenpox (Varicella), usually in childhood, and shingles, later in life. Shingles (Zoster) results from reactivation of an earlier varicella infection.

Chickenpox
Varicella is highly infectious. More than 90% of the population of the United States have antibodies against varicella proteins. In the household of an infected patient, 90% of contacts who lack immunity (from previous disease or vaccination) will contract the disease. It is spread by respiratory aerosols or direct contact with skin lesions. Infection is via the mucosa of the respiratory tract.

The average period between the initial infection and the occurrence of the chickenpox lesions is about two weeks, with a range of 10 to 23 days. The virus is spread by respiratory secretions (by a cough) or from contact with ruptured vesicles on the skin containing infectious virus.

Characteristic chickenpox lesions. The blister-like lesions appearing on the face scalp and trunk, have a pus-filled center. CDC

The disease is more severe in older children and adults. This is particularly the case in immunocompromised patients (AIDS, transplantation, etc.) where the disease may linger for several weeks and the fever may be more pronounced. The spread of the virus may lead to problems in the lungs or liver, or to meningitis. In these cases, the mortality rate may be 20%. In about 15% of adult patients, pneumonia can be a complication and may be fatal. Although most children recover rapidly from the disease, there may be some complications, including fulminant encephalitis and cerebellar ataxia. Reye syndrome may be caused by aspirin used in chickenpox infections.

Congential Varicella Syndrome
Major problems may be caused by infection in utero during the first trimester. This is congenital varicella syndrome (CVS) which leads to scarring of the skin of the limbs, damage to the lens, retina and brain, and microphthalmia.

Infection of the mother, at around the time of birth can lead to infection of the infant. Since the infant will not have maternal antibodies against varicella and has immature cell-mediated immunity, it may succumb to the disease with a mortality rate of up to 35%.

Shingles
After the infectious period of chickenpox, the virus may migrate to the ganglia associated with areas in which the virus is actively replicated. The virus may then be reactivated under stress or with immune suppression. This usually occurs later in life. The recurrence of varicella replication is accompanied by severe radicular pain in areas innervated by the nerve in which latent infection has occurred. A few days later, chickenpox-like lesions occur in restricted areas (dermatome) that are innervated by a single ganglion.

The skin lesions are somewhat different from chickenpox, being restricted to small areas of the skin. They are small and close together and usually heal in about two weeks. Chronic burning or itching pain called post-herpetic neuralgia may occur in the elderly. The pain may last well after the rash has healed, sometimes months or years.

Generalized herpes outbreak (shingles) due to VZV. CDC

Epstein- Barr Virus (EBV)

Epstein- Barr Virus Epstein-Barr virus is the causative agent of Burkitt's lymphoma in Africa, nasopharyngeal cancer in the orient and infectious mononucleosis in the west. It was first discovered as the causative agent of Burkitt's lymphoma and it was later found that patients with infectious mononucleosis have antibodies that react with Burkitt's lymphoma cells.

Epstein-Barr Virus attached to its CD21 receptor on a B lymphocyte.

EBV only infects a small number of cell types that express the receptor for complement C3d component (CR2 or CD21). These are certain epithelial cells (oro- and naso-pharynx) and B lymphocytes. This explains the cellular tropism of the virus.

The virus is replicated in pharyngeal epithelial cells, shed into the saliva and is taken up by CD21+ B lymphocytes. These cells are normally short-lived. Although B cells do not show any histological alterations as a result of EBV infection, they are stimulated to divide and are protected from undergoing apoptosis (cell death). They become transformed cells and they begin to appear in high levels as monocytes in the bloodstream. T cell responses are inhibited while growth of B cells and antibody secretion are stimulated. The virus also causes the cells to produce other cytokines including IL-5 and IL-6.

Burkitt's lymphoma
Burkitt's lymphoma is a tumor of the jaw and face found in children. The tumor cells show evidence of EBV DNA and tumor antigens, and patients show a much higher level of anti-EBV antibodies than other members of the population. The tumor cells display a particular chromosomal abnormality. Burkitt's lymphoma is endemic in equatorial Africa and only occurs rarely elsewhere. There is thought to be a genetic explanation possibly involving an association with malaria.

Nasopharyngeal cancer
This disease occurs in a number of areas in south China, as well as Alaska, Tunisia and east Africa. It is also associated with EBV. There may be a genetic predisposition to the development of EBV cancers in these populations or there may be an environmental cofactor involved. The disease is a tumor of the epithelium of the upper respiratory tract and the tumor cells contain EBV DNA.

Infectious mononucleosis
The disease is characterized by malaise, lymphadenopathy, tonsillitis, enlarged spleen and liver, and fever. The fever may persist for more than a week. There may also be a rash. The severity of disease often depends on age (with younger patients resolving the disease more quickly) and resolution usually occurs in 1 to 4 weeks. The primary infection is often asymptomatic, but a person may shed infectious virus for many years. Sometimes infectious mononucleosis is not developed until 1- 2 months after primary infection.

Although infectious mononucleosis is usually benign, there may be complications. These include neurological disorders such as meningitis encephalitis, myelitis and Guillain-Barrè syndrome. A chronic syndrome may also occur, the symptoms of which are similar to those reported for chronic fatigue syndrome (headaches, sore throat and low fever). However, EBV is probably not the cause of chronic fatigue syndrome.

In infectious mononucleosis, infected B cells are also transformed. The infected B cells proliferate and activate suppressor CD8 T cells. The T cells increase in number in the circulation and may account for up to 80% of the white blood cells. This T cell response results in enlarged lymph glands (and enlarged liver and spleen). It is the activation of the T cells that limits the proliferation of B cells, so that the disease resolves.

A large proportion of the population (90-95%) is infected with Epstein-Barr virus, and these people, although usually asymptomatic, will shed the virus from time to time throughout life. The virus is spread by close contact (kissing). Up to 80% of students entering college in the U.S. are seropositive for the virus, and many of those that are negative will become positive while at college. The virus can also be spread by blood transfusion.

Virus infection involves two types of cells: (1) B cells, where infection is predominantly latent and has the potential to induce growth-transformation of infected cells; and (2) epithelial cells, where infection is predominantly replicative. The B-cell acts as the main mediator of primary as well as persistent infection. Following primary infection of B cells, a chronic virus carrier state is established in which the outgrowth of EBV-transformed B cells is controlled by an EBV-specific cytotoxic T lymphocytes. Latently infected B cells can become permissive for lytic EBV infection. Infectious virus released from these cells can be shed directly into the saliva or might infect epithelial cells and other B cells. In this way a virus-carrier state is established that is characterized by persistent, latent infection in circulating B cells and occasional EBV replication in B cells and epithelial cells.

Cytomegalovirus (CMV)

Cytomegalovirus has the largest genome of all herpes viruses and appears only to replicate in human cells. Some cells such as macrophages and fibroblasts support productive (virulent) infection, while latent infection is set up in other cell types, including T lymphocytes and stromal cells of the bone marrow. There is only one serotype of CMV.

Cytomegalovirus infection of cell in urine. CDC.

Cytomegalovirus infection is found in s significant proportion of the population. Seropositivity increases with age. By college age, about 15% of the US population is infected and this rises to about 50% by 35 years of age. The virus is spread in most secretions, particularly saliva, urine, vaginal secretions and semen. Cytomegalovirus infection is therefore transmitted by sexual contact, as well as kissing . It can also spread to a fetus in a pregnant woman and to the newborn via lactation. In the hospital, the virus can spread via blood transfusions and transplants. In developing countries with more crowded conditions, the virus is found in a much higher proportion of the population than in western countries.

The virus first infects the upper respiratory tract and then local lymphocytes. Circulating lymphocytes then spread the virus to other lymphocytes and monocytes in spleen and lymph nodes. The virus finally spreads to a variety of epithelial cells including those of salivary glands, kidney tubules, testes, epididymis and cervix.

Infection is usually asymptomatic (sub-clinical) but glandular fever is sometimes seen in young adults. The virus can inhibit T cell responses. The virus elicits both humoral antibodies and cell-mediated immunity but the infection is not cleared. Although suppressed, the virus may later reactivate, particularly in cases of immunosuppression.

There are two instances in which cytomegalovirus can cause serious disease.

1. During a primary infection of the mother, the virus can spread via the placenta to the fetus and congenital abnormalities can occur; in fact, this virus is the most common viral cause of congenital disease.

2. In immunosuppressed patients who have received an organ transplant or have an immunosuppressive disease (e.g. AIDS), cytomegalovirus can be a major problem. Particularly important is cytomegalovirus-retinitis in the eye, which occurs in up to 15% of all AIDS patients. In addition, interstitial pneumonia, colitis, esophagitis and encephalitis are seen in some patients.

Ganciclovir, which inhibits the replication of all human herpes viruses, is usually used in treatment, especially for retinitis. Foscarnet is also approved, but Acyclovir is not effective. A vaccine is being developed, but the best way to avoid the virus is to restrict contact between infected children and pregnant women. Also, since cytomegalovirus is sexually transmitted, condoms can limit spread.

Human herpes virus 6 (HHV-6)

This herpes virus is found worldwide and is found in the saliva of the majority (90%) of adults. It infects almost all children by the age of two and the infection is life-long. It replicates in B and T lymphocytes in the oropharynx. It can set up a latent infection in T cells which can later be activated when the cells are stimulated to divide.

Human herpes virus-6 has two forms, HHV-6A and HHV-6B. The latter causes exanthem subitum, otherwise known as roseola infantum. This a common disease of young children. Symptoms include fever and sometimes upper respiratory tract infection and lymphadenopathy. The symptoms last a few days after an incubation period of around 14 days. The fever subsides leaving a macropapular rash on the trunk and neck that last a few days longer.

In adults, primary infection by HHV is associated with a mononucleosis. It has also been associated with a number of neurological disorders, including encephalitis and seizures. It has been postulated to play a role in multiple sclerosis and chronic fatigue immunodeficiency syndrome.

Human herpes virus (HHV-8)
This virus is also known as Kaposi's sarcoma associated herpes virus (KSHV) and is found in the saliva of many AIDS patients. It infects peripheral blood lymphocytes. The distribution of the virus may explain why some populations of HIV-infected people come down with Kaposi's sarcoma while others do not.

HHV-8 is an opportunist and generally does not cause disease in healthy hosts. Immunosuppression or AIDS is usually required before disease is manifested.

The virus infects CD19+ B cells and endothelial-derived spindle cells of Kaposi's sarcoma lesions. In addition to its role in Kaposi's sarcoma, it is known to cause a primary lymphoma and a B cell lymphoproliferative disorder.

Herpes Links
CDC Epstein-Barr Virus and Infectious Mononucleosis
CDC Genital Herpes (Fact Sheet)
Department of Health and Human Services - Genital Herpes
Expert Views in Molecular Medicine: Epstein-Barr Virus (EBV) infections in normal healthy virus carriers
Genital Herpes, NIAID Fact Sheet
Genome News Network: Small Genes May Help Mono Virus Hide in Humans
Herpes - Minnesota Dept. of Health
Science News Online.: New studies suggest how Epstein Barr virus infects and persists
University of South Carolina School of Medicine: Herpes Viruses