Herpesviridae

• It is the largest and perhaps the most frequently encountered group of DNA viruses. 
• The herpesviruses are characterized by their ability to establish latent infection. 
• The initial infection for all herpesviruses is in epithelial or mucosal cells, and they establish their latency in neurons. 
•  It is divided into three subfamilies: alpha-, beta-, and gammaherpesvirinae. 
• These viruses are the paradigm for the temporal control of viral replication that all DNA viruses use. Upon first entering the cell, the proteins made are those necessary for replication of the genome efficiently. After the genome has been replicated, then the virus will begin to make capsid material. 
  

1. Alphaherpesvirinae are the rapid, lytic viruses, and include HSV-1 and HSV-2, VZV, and Simian herpesvirus B. 

• HSV-1 usually causes gingivostomatitis, or oral herpes. 
• When the disease is primary, it may affect much more than just the mouth, including the oral mucosa and throat, along with systemic symptoms. 
• It goes into the nerves as the cell-mediated immunity starts up, and the virus resides in the ganglia until reactivated by stress, UV light, illness, injury, etc. 
• When it comes back, it is now called herpes labialis, and it is generally not associated with any systemic symptoms. It may return several times, but it is not as serious as the original infection unless the person becomes immunocompromised. 
• HSV-1 is associated with a primary encephalitis during the primary infection. It enters through the nose or eye and goes directly to the brain, killing the patient. This was one of the most common causes of sporadic encephalitis in the US. 

• HSV can also cause eye infections, skin infections (herpetic whitlow), herpes gladiatorum, and many others. 
• HSV-2 usually causes lesions in the genital and anal area. 
• The lesions are very painful and easily spread. 
• The viruses usually cause systemic symptoms during the primary infection, and then they go latent by hiding in ganglia in the lumbar area. 
• When the virus reactivates, it returns along the distribution of the nerves supplied by the ganglia it resides in. However, HSV-2 lesions can wind up anywhere on the body, just like HSV-1 can. The secondary infection is called recurrent genital herpes. 
• HSV-2 is particularly associated with meningitis during its primary infection. 

• Varicella virus enters through the respiratory tree, multiplying there first before going to the lymph glands and then the whole body. 
• It has a preference for the skin and mucous membranes, resulting in lesions all over the body, called chickenpox. 
• Chickenpox can be differentiated from smallpox in that chickenpox lesions are not in phase with each other, so you will see different stages of lesions in the patient instead of lesions all of the same type. 
• The virus goes away when cell-mediated immunity begins, hiding out in the nerves similar to HSV. 
• When a series of stressors causes the virus to come out, the condition is known as shingles. The lesions follow the distribution of the nerve, causing pain and vesicles along a particular dermatome. The older the patient is, the worse shingles is, and the pain can last for months after the rash resolves. Shingles can transmit the virus, but the recipient gets chickenpox and not shingles.

• Simian herpesvirus B is a natural pathogen of rhesus monkeys. The virus can be transmitted to humans through biting. The virus forms vesicles, and then in a short period of time it goes straight to the brain, killing the patient. You can attempt to treat it with acyclovir, but once the disease progresses beyond the vesicle stage there is little hope. This is a biosafety level 4 virus.
• Most of the alphaherpesvirinae are spread through direct contact, except for VZV, which is spread by respiratory secretions during the prodrome.

1. The betaherpesvirinae are slower, non-lytic viruses. 

•  CMV is the prototype beta virus. 
• Only neonates (acquired congenitally) and immunosuppressed patients get sick with CMV. In a normal adult, you may see heterophile-negative mononucleosis if he is mildly immunosuppressed or no symptoms at all.
• Most people will acquire CMV by the time they are in their 60’s. 
• This virus is dangerous during pregnancy. The virus infects many cells in the body, and it is periodically reactivated and shed in genital secretions. If the mother is reactivated during pregnancy, she has a small chance of spreading CMV to her baby. This chance is increased 10-fold if the mother acquires the primary infection while pregnant. A primary infection early in pregnancy can result in a stillborn baby and problems such as microcephaly with severe mental retardation, deafness, hepatitis, and rash. 
• If the baby first contracts the virus right around birth, the brain is already formed, so problems will most likely surface as hepatitis, thrombocytopenia, or later on as epilepsy or a form of mental retardation. 
• The child can also be infected in the post-natal period through breast milk or saliva, and infections in the first month of life can result in mental retardation. 
• Patients who are immunosuppressed will not be retarded, but they will shed the virus in their urine, will experience viremia, pneumonitis, pneumonia, failure of the graft in renal patients, retinitis, encephalitis, and/or enterocolitis. The level of problems caused is correlated with the level of immunosuppression. 
• CMV in immunosuppressed patients is treated with gancyclovir or foscarnet. 

• HHV-6 is another beta virus. 
• It has been associated with roseola infantum, in which the baby has a high fever for several days, then the fever drops and the baby breaks out in a rash. This disease does not cause any harm but may concern parents. 
• There is no particular treatment for roseola, but drugs for CMV may be effective. You generally would not want to treat roseola, but a reactivation after immunosuppression may cause serious symptoms and lead you to intervene pharmacologically. Gancyclovir or foscarnet are both used. 

• HHV-7 may cause some cases of roseola, but it does not have any specific disease assigned to it.

1. Gammaherpesvirinae are Epstein-Barr virus and HHV-8. 

• EBV usually affects young adults, causing a heterophile-positive infectious mononucleosis.
• It can be diagnosed in the lab by using the heterophile test (involves agglutination with RBCs). You will also see a proliferation of atypical lymphocytes on a blood smear. 
• The virus is acquired through saliva, and it infects the epithelial cells in the respiratory tract and B cells. 
• When it gets into the nasopharyngeal cells, it produces a lytic infection because they are permissive. 
• When EBV gets into B cells, they are non-permissive, so they are transformed and begin to replicate. This increases the patient’s white count, even so high as to be mistaken at times for leukemia. However, what are seen in the peripheral blood are not transformed B cells but cytotoxic T-lymphocytes attempting to control the virus. 
• If the CTLs win, the virus quiets down, and all the infected B cells are killed. In some people this process doesn’t work, and the virus manages to produce a lymphoma known as African Burkitt’s lymphoma. This is generally a lymphoma of the head and neck seen in children in Africa. Plasmodium falciparum seems to be a cofactor, which may explain why we don’t see this disease in the US. 
• EBV can also be associated with other types of lymphoma, including a fatal lymphoma in people with X-linked immune disorders like agammaglobulinemia.
• In the Orient, the virus may replicate in nasopharyngeal cells and lead to carcinoma, particularly in Cantonese and Eskimos. 
• The virus may cause chronic disease, reactivation disease, and lymphomas in immunosuppressed. 

• HHV-8 is a gamma virus associated specifically with Kaposi’s sarcoma in AIDS patients.

1.  Treatment of herpesvirus infections: Acyclovir is a nucleoside analogue, which gets incorporated into growing viral DNA chains, halting replication. This drug is particularly good in that it requires the viral thymidine kinase to activate it, rendering it less toxic to non-infected cells. 

1. Famcyclovir and vidarabine are other drugs used for HSV-1 and 2 and VZV. 

1. A vaccine is being developed for the simplex viruses, and one is already in use for VZV. The VZV vaccine may change the pattern of chickenpox infections that we see in practice. Although it appears safe through 20 years of use, we are not sure about the potential for shingles as children grow older.

Category: Virology