Herpesviruses

The name herpes comes from the Latin herpes which, in turn, comes from the Greek word herpein which means to creep. This reflects the creeping or spreading nature of the skin lesions caused by many herpes virus types. The herpesvirus family contains important human pathogens: herpes simplex virus type 1(HSV-1), herpes simplex virus type 2(HSV-2),human herpes virus type 6( HHV-6),human herpes virus 7(HHV-7),varicella zoster virus (VZV), cytomegalovirus (CMV), EpsteinBarr virus (EBV) and Human herpes virus type 8 HSV-8 (Kaposi's sarcoma associated virus).
General characteristics

1-All herpesviruses are structurally similar 2-Each has an icosahedral nucleocapsid. 3-All herpesviruses are enveloped. 4-The genome is linear double-stranded DNA. 5-They are large (120_130nm) in diameter, second in size only to poxviruses. 6-They replicate in the nucleus. 7-Form intranuclear inclusions (inclusion bodies). 8-The only viruses that obtain their envelopes by budding from nuclear membrane. 9-Herpesviruses are noted for their ability to cause latent infection

In latent infection , the acute disease is followed by asymptomatic period during which the virus remains in a latent state. When the patient exposed to an initiating agent or immunosuppression occurs, reactivation of virus replication and disease occur.

Virus
HSV-1 HSV-2

Primary infection
Gingivostomatitis Herpes genitalis ,perinatal disseminated disease Varicella

Usual site of Recurrent infection latency

Cranial sensory ganglia Lumber or sacral ganglia Cranial or thoracic sensory ganglia B lymphocyte Uncertain Herpes labialis ,encephalitis, Keratitis Herpes genitalis

Route of transmission
Via respiratory secretions and saliva Sexual contacts , perinatal infection Via respiratory secretions

VZV

Zoster

EBV CMV

Infectious mononucleosis Congenital infection (in utero ), mononucleosis

None Asymptomatic ,shedding

Via respiratory secretions and saliva Intrauterine infection, transfusions , sexual contact, via secretions (eg. saliva and urine , transplanted organs) Sexual contact, organ transplantation

HHV-8

Uncertain

Uncertain

Kaposi's sarcoma

The herpesvirus family can be subdivided into three categories based on the type of cell most often infected and the site of latency.

1-The alpha herpesviruses consisting of HSV-1& HSV-2 and VZV infect epithelial cells primarily and cause latent infection in neurons. 2-The beta herpesviruses, consisting of CMV and HHV-6, infect and become latent in a variety of tissues. 3-The gamma herpesviruses, consisting of EBV and HHV-8, infect and become latent primarily in lymphoid cells.

Herpes simplex viruses

HSV-1 and HSV-2 are distinguished by two main criteria: antigenicity and location of lesions. Lesions caused by HSV-1 are in general, above the waist, whereas those caused by HSV-2 are below the waist. Diseases HSV-1 causes acute Keratoconjunctivitis, and encephalitis.HSV-2 causes genital herpes, neonatal herpes, and aseptic meningitis. Note : humans are the natural habitats of both HSV-1 and HSV-2.

Summary of replicative cycle HSV-1 attaches to the cell surface at the

site of receptor for fibroblast growth factor. After entry into the cell, the virion is uncoated and the genome DNA enters the nucleus. Within the nucleus, the incoming genome DNA changes its conformation from linear to circular. Early virus mRNA is transcribed by host cell RNA polymerase and then translated into early, nonstructural proteins in the cytoplasm. The viral DNA polymerase replicates the genome DNA, at which time early protein synthesis is shut off and late protein synthesis begins. These late, structural proteins are transported to the nucleus, where virion assembly occurs. The virion obtains its envelope by budding. In latently infected cells, multiple copies of HSV-1 DNA are found in the cytoplasm of infected neurons. Only a few genes are transcribed, and none are translated into protein. Transmission & Epidemiology HSV-1 is transmitted primarily in saliva, where as HSV-2 is transmitted by sexual contact. Although transmission occurs most often when active lesions are present, asymptomatic shedding of both HSV-1 and HSV-2 does occur and plays an important role in transmission

HSV envelope surrounds virion

since HSV-2 is usually acquired as a sexually transmitted disease, so antibodies to this virus are seldom found before puberty. It is estimated that there are about 4060 million infected individuals in the United States. Roughly 80% of people in the USA are infected with HSV-1 , and 40% have recurrent herpes labialis. Infction by HSV-1 occurs early in childhood , as evidenced by the early appearance of antibody.

Pathogenesis & Immunity The virus replicate in the skin or mucous membrane at the initial site of infection then migrates up the neuron and becomes latent in the sensory ganglion cells. In general, HSV-1 becomes latent in the trigeminal ganglia, whereas HSV-2 becomes latent in the lumber and sacral ganglia. The virus can be reactivated from the latent state by a variety of inducers eg. sunlight, hormonal changes, trauma, stress and fever, at which time it immigrates down the neuron and replicates in the skin, causing lesions. The typical skin lesion is a vesicle contains serous fluid with virus particles and cell debris. When the vesicle ruptures, virus is librated and can be transmitted to other individuals. Multinucleated giant cells are typically found at the base of herpesvirus lesions. Immunity is type specific, but some cross protection exists. However immunity is incomplete, and both reinfection and reactivation occur in the presence of circulating IgG. Cell mediated immunity is important in limiting herpesviruses, because its suppression often results in reactivation, spread, and sever disease.

Clinical Findings HSV-1 causes several forms of primary and recurrent disease 1-Gingivostomatitis occurs primarily in children and is characterized by fever, irritability, and vesicular lesions in the mouth. Herpes labialis (fever blister or cold sores) is the milder, recurrent form and is characterized by crops of vesicles, usually at the mucocutaneous junction of lips or nose. 2-Keratoconjunctivitis is characterized by corneal ulcers and lesions of conjunctival epithelium. Recurrence can lead to scaring and blindness. 3-Encephalitis is characterized by a necrotic lesion in one temporal lobe. Fever, headache, vomiting, seizures and altered mental status are typical clinical features. 4-Herpetic whitlow is a postural lesion of the skin of the finger or hand. It can occur in medical
personnel as a result of contact with patient's lesions. 5-Disseminated infections, such as esophagitis and pneumonia, occur in

immunocompromised patients with depressed T cell function.

*HSV-2 causes several diseases, both primary and recurrent:-. 1-Genital herpes is characterized by painful vesicular lesions of the male and female genital area. 2-Neonatal herpes originates chiefly from contact with vesicular lesions within the birth canal. 3-Aseptic meningitis caused by HSV-2 is usually mild, self limited disease with few sequelae.

Laboratory Diagnosis *The most important diagnostic procedure is isolation of the virus from the lesion by growth in cell culture (cell culture techniques). *The typical cytopathic effect occurs in 1-3 days , after which the virus is identified by fluorescent staining of the infected cells ( fluorescence immune assay) *Detecting the virus glygoproteins in ELISA (enzyme linked immuno sorbant assay). *A rapid diagnosis from skin lesions can be made by using Tzanck smear, in which cells from the base of the lesions are stained with Giemza stain. The presence of multinucleated giant cells suggests herpesvirus infection. *A rapid diagnosis of encephalitis can be made by detecting HSV-1 DNA in the spinal fluid using a PCR assay, but virus is rarely recovered from the spinal fluid. Treatment, prevention& control several antiviral drugs have proved effective against HSV infections, including acyclovir and vidarabine. All are inhibitors of viral DNA synthesis. Experimental glyucoprotein recombinant vaccines of various types are being developed.

Multinucleated giant cells

Cold sore HSV-1

Herpetic whitlow of hands and fingers

Varicella Zoster virus (VZV) Important properties VZV is structurally and morphologically identical to other herpesviruses but is antigenically different. It has a single serotype. The same virus causes both varicella and zoster. Humans are the natural hosts. Note: Summary of replicative cycle the cycle is similar to that of HSV. Transmission & Epidemiology the virus is transmitted by respiratory droplets and by direct contact with the lesions. VZV DNA has been detected using a PCR amplification method, in air samples from hospital rooms of patients with active varicella (82%) and zoster (70%) infections. Varicella (chickenpox) is a highly contagious disease of childhood (peak incidence in children age 2-6 years). Zoster (shingles) occurs sporadically, chiefly in adults . 10-20 percent of adults will experience at least one zoster attack during their life time. Pathogenesis & immunity VZV infects the mucosa of the upper respiratory, and then spreads via the blood to skin, where the typical vesicular rash occurs. Multinucleated giant cells with intranuclear inclusions are seen in the base of the lesions. After the host has recovered, the virus becomes latent, probably in the dorsal root ganglia Later in life , frequently at times of reduced cell-mediated immunity or local trauma, the virus is activated and causes the vesicular skin lesions and nerve pain of zoster .

Immunity following varicella is lifelong: a person gets varicella only once, but zoster can occur despite this immunity to varicella. Varicella occurs only once. The frequency of zoster increases with advancing age, perhaps as a consequence of waning immunity. Clinical findings Varicella: After incubation period of 14-21 days, brief prodromal syndromes of fever and malaise occur. A papilovesicular rash then appears in crops on the trunk and spreads to the head and extremities. The rash evolves from papules to vesicles, postules, and, finally crusts. Itching is a prominent symptom, especially when vesicles are present. Varicella pneumonia and encephalitis are the major rare complication. Reye's syndrome, characterized by encephalopathy and liver degeneration, is associated with VZV and influenza B virus infection, especially in children given aspirin. Zoster : The occurrence of painful vesicles along the course of sensory nerve of the head or trunk is the usual picture. The pain can last for weeks, and postzoster neuralgia can be debilitating. In immunocompromised patients, life threatening disseminated infections such as pneumonia can occur .

Person with typical chickenpox

varicella

Laboratory diagnosis although most diagnoses are made clinically, laboratory tests are available. *A presumptive diagnosis can be made by using Tznack smear. *Definitive diagnosis by isolation of the virus in cell culture. *Identification with specific antiserum *Specific antibody rise can be used to diagnose varicella

Treatment Gamma globulin of high varicella-zoster virus antibody titer (varicella zoster immune globulin) can be used to prevent the development of illness in immunocompromised patients exposed to varicella. It has no therapeutic value once varicella has started. Several antiviral compounds are effective against varicella, including acyclovir, valacyclovir, vidarabine, and interferons. Prevention and control A live attenuated varicella vaccine was proved in 1995 for general use in USA. A similar vaccine has been use successfully in Japan for about 30 years.

Epstein Barr Virus (EBV) Diseases EBV causes infectious mononucleosis. It is associated with Burkett's lymphoma, other B cell lymphomas, and nasopharyngeal carcinoma .EBV is also associated with hairy leukoplakia, a whitish, nonmalignant lesion on the tongue seen especially in ADIS patients. Important properties EBV is structurally and morphologically similar to other herpesviruses but is antigenically different. The most important antigen is the viral capsid antigen (VCA), because is used most often in diagnostic tests. The early antigen is (EA), which are produced prior to viral DNA synthesis, and nuclear antigen (EBNA), which is located in the nucleus bound to chromosomes, are sometimes diagnostically helpful as well. Humans are the natural hosts. EBV infects mainly lymphoid cells, primarily B lymphocytes. In latently infected cells, multiple copies of EBV DNA are found in the cytoplasm of infected B lymphocytes. EBV enters B lymphocytes at the site of the receptor for C3 component of complement.

Transmission and epidemiology EBV is transmitted primarily by saliva. EBV infection is one of the most common infections worldwide; more than 90% of adults USA have antibody. Infection in the first few years of life is asymptomatic. Pathogensis & Immunity The infection first occurs in the oropharynx and then spread to the blood, where it infects B lymphocytes. Cytotoxic T lymphocytes react against the infected B lymphocytes. The T lymphocytes are the atypical lymphocytes seen in the blood smear. EBV remains latent within B lymphocytes. A few copies of EBV DNA are integrated into the cell genome; many copies of circular EBV DNA are found in the cytoplasm. The immune response to EBV infection consists first of IgM to the VCA. IgG antibody to the VCA follows and persists for life. The IgM response is therefore useful for diagnosing acute infection. Whereas the IgG response is best for revealing prior infection. Lifetime immunity against second episodes of infectious mononucleosis is based on antibody to the viral membrane antigen.

Clinical Findings (A) Infectious mononucleosis is characterized primarily by fever, sore throat, lymphadenopathy, and splenomegaly. Anorexia and lethargy are prominent. Hepatitis id frequent; encephalitis occurs in some patients. Spontaneous recovery usually in 2-3 weeks. In certain immunocomromised patients , a sever , often fatal EBV infection called X- linked immunoproliferative syndrome occurs. (B) Burkett's lYmphoma occurs throughout the world, but its incidence in Africa is higher than any other areas. (C) Nasopharyngeal carcinoma. Laboratory diagnosis The diagnosis of infectious mononucleosis in the clinical laboratory is based primarily on two approaches: (1) In the hematologic approach, absolute lymphocytosis and as many as 30% abnormal lymphocytes are seen on a smear. These "atypical lymphs" are large and have lobulated nucleus and a vaculated, basophilic cytoplasm. They are cytotoxic T cells that are reacting against the EBV- infected B cells. (2) In the immunologic approach, there are two types of serologic tests (a) The heterophil antibody test is useful for the early diagnosis of infectious mononucleosis because it is usually positive by week 2 of illness. (b) The EBV - specific antibody tests are used primarily in diagnostically difficult cases. The IgM VCA antibody response can be used to detect early illness; the IgG VCA antibody response can be used to detect prior infection.

Hairy leukoplakia

Atypical lymphocyte

Treatment & prevention No antiviral therapy is necessary for uncomplicted infectious mononucleosis. Acyclovir has little activity against EBV, but administration of high doses may be useful in life threatening EBV infections. There is no EBV vaccine. Association with cancer EBV infection is associated with cancers of lymphoid origin: Burkett's lymphoma in African children, other B cell lymphomas, nasopharyngeal carcinoma in the Chinese population, and thymic carcinoma in USA.

Cytomegalovirus (CMV) Important properties CMV is structurally and morphologically similar to other herpesviruses but it antigenically different. Humans are the natural hosts; animal CMV strains do not infect humans. Giant cells are formed hence the name "cytomegalo". Transmission & Epidemiology CMV is transmitted by a variety of modes. Early in life it is transmitted across the placenta, within the birth canal, and quite commonly in breast milk. In young children, its most common mode of transmission is via saliva. Later in life it is transmitted sexually; it is present in both semen and cervical secretions. It can also be transmitted during blood transfusion and organ transplants. CMV infection occurs worldwide, and more than 80% of adults have antibody against the virus. In Iraq about 96% of the populations carry CMV specific IgG antibodies in their sera.

Pathogenesis & Immunity Infection of the fetus can cause cytomegalic inclusion disease, characterized by multinucleated giant cells with prominent intranuclear inclusions. Many organs are affected, and widespread congenital abnormalities result. Infection of the fetus occurs mainly when a primary infection occurs in the pregnant woman, ie, when she has no antibodies that will neutralize the virus before it can infect the fetus. The fetus usually will not be infected if the pregnant woman has antibodies against the virus. Congenital abnormalities are more common when a fetus is infected during the first trimester than later in gestation, because the first trimester is when development of organs occurs and the death of any precursor cells can result in congenital defects. Infections of children and adults are usually asymptomatic, except in immunocompromised individuals. CMV enters a latent state in leukocytes and can be reactivated when cell-mediated immunity is decreased. CMV can also persist in kidneys for years. Reactivation of CMV from the latent state in cervical cells can result in infection of the newborn during passage through the birth canal. CMV infection causes an immunosuppressive effect by inhibiting T cells. Host defenses against CMV infection include both circulating antibody and cell-mediated immunity. Cellular immunity is more important, because its suppression can lead to systemic disease.

Clinical Findings Approximately 20% of infants infected with CMV during gestation show clinically apparent manifestations of cytomegalic inclusion disease such as microcephaly, seizures, deafness, jaundice. Hepatosplenomegaly is very common. Cytomegalic inclusion disease is one of the leading causes of mental retardation. Infected infants can continue to excrete CMV, especially in the urine, for several years. In immunocompetent adults. CMV can cause "heterophil-negative" mononucleosis, which is characterized by fever, lethargy, and the presence of abnormal lymphoctyes in peripheral blood smears. Systemic CMV infections, especially pneumonitis and hepatitis, occur in a high proportion of immunosuppressed patients, eg. those with renal and bone marrow transplants. In AIDS patients, CMV commonly infects the intestinal tract and causes intractable diarrhea. CMV also causes retinitis in AIDS patients, which can lead to blindness.

Laboratory diagnosis The preferred approach involves culturing in special tubes called "shell vials" coupled with the use of immunoflourescent antibody which can make a diagnosis in 72 hours. PCR- based assay that detect viral nucleic acid is also useful. Fluorescent antibody and histologic staining of inclusion bodies in giant cells. The inclusion bodies are intranuclear and have an "owl's-eye "shape A four fold or greater rise in antibody titer is also diagnostic.

Treatment Gancyclovir is moderately effective in the treatment of CMV retinitis and pneumonia with AIDS patients. Foscarnet is also effective but causes more side effects. Prevention There is no vaccine. Infants with cytomegalic inclusion disease who are shedding virus in their urine should be kept isolated from other infants. Human herpes virus 8 (kaposi's Sarcoma-associated herpesvirus) HHV-8 the cause of kaposi's Sarcoma the most common cancer in patients with AIDS.

Overview of congenital viral infections Few viruses produce disease in human fetus. Most maternal viral infections do not result in viremia and fetal involvement. However, if the virus crosses the placenta and infection occurs in utero, serious damage may be done to the fetus. Three principles involved in the production of congenital defects are (1) The ability of the virus to infect the pregnant woman and be transmitted to the fetus. (2) The stage of gestation at which infection occurs. (3) The ability of the virus to cause damage to the fetus directly, by infection of the fetus, or indirectly, by infection of mother resulting in an altered fetal environment (eg, fever).