Herpesviruses: Topic 9

Herpesviruses Topic-9-  Introduction The herpes family contains 6 important human pathogens: HSV types 1 and 2, Varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, and human herpesvirus 8 (the cause of Kaposi’s sarcoma) Structurally th...

Herpesviruses Topic-9-  Introduction The herpes family contains 6 important human pathogens: HSV types 1 and 2, Varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, and human herpesvirus 8 (the cause of Kaposi’s sarcoma) Structurally they are similar; each having an icosahedral core surrounded by a baggy lipoprotein envelope with a linear dsDNA. The virion does not contain a polymerase. They are large (second in size to poxviruses). They replicate in the nucleus, form intra-nuclear inclusions, and are the only viruses that obtain their envelopes by budding from the nuclear membrane. They are known to cause latent infections whereby the acute disease is followed by an asymptomatic period during which the virus remains in a quiescent state. When the patient is exposed to an inciting agent or immunosuppression occurs, reactivation of virus replication and disease can occur. HSV-1 and 2 and Varicella-zoster virus cause a vesicular rash both in primary infections and in reactivations (primary infections are usually more severe than reactivations). CMV and EBV don’t cause a vesicular rash. The family can be divided into 3 categories based on the type of cell most often infected and the site of latency. 1. The alpha herpesviruses (HSV-1 and 2 and VZV) infect epithelial cells primarily and cause latent infection in neurons. 2. The beta herpesviruses (CMV and human herpesvirus 6) infect and become latent in a variety of tissues. 3. The gamma herpesviruses (EBV and human herpesvirus 8) infect and become latent primarily in lymphoid cells. Certain herpesviruses are suspected of causing cancer in humans; eg, EBV is associated with Burkitt’s lymphoma and nasopharyngeal carcinoma, and human herpesvirus 8 is associated with Kaposi’s sarcoma.  Herpes Simplex Virus HSV-1 and 2 are distinguished by 2 main criteria: Antigenicity Location of lesions. Lesions caused by HSV-1 are above the waist whereas those caused by HSV-2 are below the waist. Diseases: HSV-1 causes acute gingivostomatitis, recurrent herpes labialis (cold sores), keratoconjunctivitis, and encephalitis. HSV-2 causes genital herpes, neonatal herpes, and aseptic meningitis.  Important Properties - HSV-1 and HSV-2 are structurally and morphologically indistinguishable. - They can be differentiated by the restriction endonuclease patterns of their genome DNA and by type-specific monoclonal anti-sera. - Humans are the natural hosts of both HSV-1 and HSV-2. Electron micrograph of herpes simplex virus. The baggy appearance of the outer envelope ( arrowed) is characteristic, but is an artifact arising during preparation of the specimen  Summary of the Replicative Cycle Attachment of HSV-1 to the cell surface at the site of the receptor for fibroblast growth factor. Entry, uncoating and entrance of genome DNA into the nucleus. Within the nucleus, the incoming genome DNA changes its configuration from linear to circular. Transcription of early virus mRNA by host cell RNA polymerase and then its translation into early, nonstructural proteins in the cytoplasm. Two of these early proteins, thymidine kinase and DNA polymerase, are important because they are sufficiently different from the corresponding cellular enzymes to be involved in the action of antiviral drugs, eg, acyclovir. Early protein synthesis by HSV can be subdivided into 2 categories: 1. “Immediate early” proteins are those whose mRNA synthesis is activated by a protein brought in by the incoming parental virion; i.e, no new viral protein synthesis is required for the production of the five “immediate early” proteins. 2. The “early” proteins require the synthesis of new viral regulatory proteins to activate the transcription of their mRNA by host cell RNA polymerase. The viral DNA polymerase replicates the genome DNA, at which time early protein synthesis is shut off and late protein synthesis begins. Transport of the late structural proteins to the nucleus where virion assembly occurs. The virion obtains its envelope by budding through the nuclear membrane and exits the cell via tubules or vacuoles that communicate with the exterior. 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. Replication Cycle of HSV  Transmission and Epidemiology HSV-1 is transmitted primarily in saliva, whereas HSV-2 is transmitted by sexual contact. HSV-1 infections occur mainly on the face, whereas HSV-2 lesions occur in the genital area. Oral-genital sexual practices can result in HSV-1 infections of the genitals and HSV-2 lesions in the oral cavity (in 10-20% of cases). Although transmission occurs when active lesions are present, asymptomatic shedding of both HSV-1 and 2 does occur and plays an apparent role in transmission. The number of HSV-2 infections has markedly increased in recent years, whereas that of HSV-1 infections has not. Most primary infections by HSV-1 occur in childhood with early appearance of Ab. In contrast. Ab to HSV-2 does not appear until the age of sexual activity.  Pathogenesis and Immunity The virus replicates 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 lumbar and sacral ganglia. During latency, most viral DNA is located in the cytoplasm rather than integrated into nuclear DNA. 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 migrates down the neuron and replicates in the skin, causing lesions. The skin lesion is a vesicle that contains serous fluid filled with virus particles and cell debris. Multinucleated giant cells are found at the base of the lesions. When the vesicle ruptures, the virus is liberated and can be transmitted to other individuals. Immunity is type-specific, but some cross-protection exists. Immunity is incomplete  reinfection and reactivation occur in the presence of circulating IgG. Cell-mediated immunity is important in limiting herpesviruses because its suppression results in reactivation, spread, and severe disease.  Latency and recurrence in herpes simplex infections. From the primary lesion, the virus travels up the sensory nerves to the dorsal root ganglion and becomes latent. When reactivated, it returns to the skin by the same route and gives rise to a recurrent lesion  Clinical Findings HSV-1 causes several forms of primary and recurrent disease: 1. Gingivostomatitis  It occurs primarily in children and is characterized by fever, irritability, and vesicular lesions in the mouth.  The primary disease is more severe and lasts longer than recurrences. Many children have asymptomatic primary infections.  The lesions heal spontaneously in 2-3 weeks. 2. Herpes labialis (fever blisters or cold sores)  It is the milder, recurrent form and is characterized by crops of vesicles, usually at the mucocutaneous junction of the lips or nose.  Recurrences frequently reappear at the same site. 3. Keratoconjunctivitis  It is characterized by corneal ulcers and lesions of the conjunctival epithelium.  Recurrences can lead to scarring and blindness.  Clinical Findings 4. Encephalitis  It is caused by HSV-1 and is characterized by a necrotic lesion in one temporal lobe often revealed by MRI imaging.  Clinical features: fever, headache, vomiting, seizures, and altered mental status.  The onset may be acute or protracted over several days and the disease occurs as a result of either a primary infection or a recurrence.  Examination of the spinal fluid shows a moderate increase of lymphocytes, a moderate elevation in the amount of protein, and a normal amount of glucose.  HSV-1 encephalitis has a high mortality rate and causes severe neurologic sequelae in those who survive. 5. Herpetic whitlow  It is a pustular lesion of the skin of the finger or hand.  It can occur in medical personnel as a result of contact with patient’s lesions. 6. Dissseminated infections, such as esophagitis and pneumonia, occur in immunocompromised patients with depressed T-cell function. Clinical Findings HSV-2 causes several diseases, both primary and recurrent: 1. Genital herpes  It is characterized by painful vesicular lesions of the male and female genitals and anal area.  The lesions are more severe and protracted in primary disease than in recurrences.  Primary infections are associated with fever and inguinal adenopathy.  Asymptomatic infections occur in both men (in the prostate or urethra) and women (in the cervix) and can be a source of infection of other individuals. Many infections are asymptomatic, ie, many people have antibody to HSV-2 but have no history of disease. 2. Neonatal herpes  It originates chiefly from contact with vesicular lesions within the birth canal.  In some cases, although there are no visible lesions, HSV-2 is being shed (asymptomatic shedding) and can infect the child during birth.  It varies from severe disease (eg disseminated lesions or encephalitis) to milder local lesions (skin, eye, mouth) to asymptomatic infection.  Neonatal herpes may be prevented by performing cesarean section on women with either active lesions or positive viral cultures.  Both HSV-1 and 2 can cause severe neonatal infections that are acquired after birth from carriers handling the child.  Neither HSV-1 nor HSV-2 neonatal infection causes congenital abnormalities.  Serious neonatal infection occurs when the mother is experiencing a primary herpes infection rather than a recurrent infection for 2 reasons: 1. The amount of virus produced during primary infection is greater than during a secondary infection. 2. Mothers who have been previously infected can pass IgG across the placenta, which can protect the neonate from serious disseminated infection. 3. Aseptic meningitis caused by HSV-2 is usually a mild, self-limited disease with few sequelae.  Laboratory Diagnosis Isolation of virus from lesion by growth in cell culture, cytopathic effect occurs in 1-3 days, then identification of virus by fluorescent-Ab staining of the infected cells or by detecting virus-specific glycoproteins in ELISA. Rapid diagnosis from skin lesions by the Tzanck smear; cells from the base of the lesion are stained with Giemsa stain to detect multinucleated giant cells that suggest HSV infection. Rapid diagnosis of encephalitis by detecting HSV-1 DNA in the spinal fluid using PCR, but virus is rarely recovered from the spinal fluid. Diagnosis of neonatal herpes infection involves use of viral cultures or PCR. Positive Tzanck sme Serologic tests: neutralization test for diagnosis of primary infections because a significant rise in Ab titer is readily observed; they are of no use in diagnosis of recurrent infections because recurrences rarely cause a rise in the Ab titer of the already circulating Abs.  Treatment and Prevention Treatment: Acyclovir (acycloguanosine, Zovirax)  For the treatment of encephalitis and systemic disease caused by HSV-1, for primary and recurrent genital herpes and for neonatal infections caused by HSV-2.  Shortens the duration of the lesions and reduces the extent of shedding of the virus. Foscarnet can be used in cases of HSV-1 mutants that are resistant to acyclovir. Trifluridine (Viroptic), another nucleoside analogue, is used topically for HSV-1 eye infections. Penciclovir (a derivative of acyclovir) or docosanol (a long-chain saturated alcohol) can be used to treat recurrences of orolabial HSV-1 infections in immunocompetent adults. Valacyclovir (Valtrex) and famciclovir (Famvir) are used in the treatment of genital herpes and in the suppression of recurrences. No drug treatment of the primary infection prevents recurrences; drugs have no effect on the latent state, but prophylactic, long-term administration of acyclovir, valacyclovir, or famiciclovir can suppress clinical recurrences. Prevention: Avoiding contact with the vesicular lesion or ulcer. Cesarean section is recommended for women who have genital lesions or positive viral cultures.  Varicella-Zoster Virus (VZV) Disease: Varicella (chickenpox) is the primary disease; zoster (shingles) is the recurrent form. Important properties: VZV is structurally and morphologically identical to other herpesviruses but it is antigenically different. It has a single serotype. The same virus causes both varicella and zoster. Humans are the natural hosts. Summary of replicative cycle: The cycle is similar to that of HSV.  Transmission and Epidemiology The virus is transmitted by respiratory droplets and by direct contact with the lesions. Varicella is a highly contagious disease of childhood; most people have Ab by age of 10 years. Varicella occurs worldwide. There is infectious VZV in zoster vesicles. The virus can be transmitted, usually by direct contact, to children and can cause varicella. The appearance of either varicella or zoster in a hospital is a major infection control problem because the virus can be transmitted to immunocompromised patients and cause life-threatening disseminated infection.  Pathogenesis and Immunity VZV infects the mucosa of the upper respiratory tract, then spreads via the blood to the 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 whereby the viral DNA is located in the cytoplasm rather than being integrated into nuclear DNA. Later, 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. Zoster usually occurs only once. The frequency of zoster increases with advancing age, perhaps as a consequence of waning immunity.  Clinical Findings A.Varicella: After an incubation of 14-21 days, brief prodromal symptoms of fever and malaise occur. A papulovesicular rash then appears in crops on the trunk and spreads to the head and extremities. The rash evolves from papules to vesicles, pustules, and finally crusts. Itching (pruritis) is a prominent symptom, esp. when vesicles are present. Varicella is mild in children but more severe in adults. Varicella pneumonia and encephalitis are the major rare complications, occurring more often in adults. Reye’s syndrome, characterized by encephalopathy and liver degeneration, is associated with VZV and influenza B virus infection, esp. in children given aspirin.  Clinical Findings B. Zoster: The occurrence of painful vesicles along the course of a sensory nerve of the head or trunk is the usual picture. The pain can last for weeks, and post-zoster neuralgia can be debilitating. In immunocompromised patients, life-threatening disseminated infections such as pneumonia can occur.  Laboratory Diagnosis Most diagnoses are made clinically. A presumptive diagnosis by using Tzanck whereby multinucleated giant cells are seen in VZV lesions. The definitive diagnosis is by isolation of the virus in cell culture and identification with specific antiserum. A rise in Ab titer can be used to diagnose varicella but is less useful in the diagnosis of zoster, since Abs are already present.  Treatment No antiviral therapy is necessary in immunocompetent children. Immunocompetent adults with either moderate or severe cases of varicella or zoster often are treated with Acyclovir because it can reduce the duration and severity of symptoms. Immunocompromised children and adults with chickenpox, zoster or disseminated disease should be treated with Acyclovir. Disease caused by acyclovir-resistant strains of VZV can be treated with Foscarnet. Two drugs similar to Acyclovir, Famciclovir (Famvir) and Valacyclovir (Valtrex), can be used in patients with zoster to accelerate healing of the lesions, but none of these drugs can cure the latent state and none have any effect on post-zoster neuralgia.  Prevention Live attenuated VZV (Varivax):  It is very effective in preventing varicella, but zoster can still occur in those previously infected because the vaccine does not eliminate the latent state.  One dose is recommended for children 1-12 years of age. Teenagers and adults who have not had the disease should receive 2 doses.  Because it is a live vaccine, it should not be given to immunocompromised people or to pregnant women. Acyclovir is useful in preventing varicella and disseminated zoster in immunocompromised people exposed to the virus. Varicella-zoster immune globulin (VZIG), which contains high titer of antibody to the virus, is also used for such prophylaxis.  Cytomegalovirus (CMV) Diseases: It is most common cause of cytomegalic inclusion disease (esp. congenital abnormalities) in neonates. It also causes pneumonia and other diseases in immunocompromised patients and heterophile-negative mononucleosis in immunocompetent individuals. Important properties: CMV is structurally and morphologically identical to other herpesviruses but it is antigenically different. It has a single serotype. Humans are the natural hosts; animal strains do not infect humans. Giant cells are formed, hence the name “cytomegalo”. What is the Heterophile Antibody test (Monospot)?  Summary of Replicative Cycle The cycle is similar to that of HSV. One unique feature of CMV replication is that some of its “immediate early proteins” are translated from mRNAs brought into the infected cell by the parental virion rather than being translated from mRNAs synthesized in the newly infected cell.  Transmission and epidemiology CMV is transmitted by a variety of modes: 1. Early in life, it is transmitted across the placenta, within the birth canal, and quite commonly in breast milk. 2. In young children, its most common mode of transmission is via saliva. 3. Later in life it is transmitted sexually; it is present in both semen and cervical secretions. It can also be transmitted during blood transfusions and organ transplants. CMV infection occurs worldwide. More than 80% of adults have Ab against the virus. Mode of Transmission  Pathogenesis and 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 Abs that will neutralize the virus before it can infect the fetus. - The fetus usually will not be infected if the pregnant woman has Abs 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 has a specific mechanism of “immune evasion” maintains the latent state for long periods. In CMV-infected cells, assembly of the MHC-I – viral peptide complex is unstable, so viral Ags are not displayed on the cell surface and killing by cytotoxic cells does not occur. - CMV infection causes an immunosuppressive effect by inhibiting T cells. Host defenses against CMV infection include both circulating Ab and cell-mediated immunity. Cellular immunity is more important, because its suppression can lead to systemic disease.  Clinical Findings - 20% of infants infected with CMV during gestation show manifestations of cytomegalic inclusion disease: microcephaly, seizures, deafness, jaundice, and purpura. Hepatosplenomegaly and mental retardation are also very common. Infected infants can continue to excrete CMV, especially in the urine, for several years. - In immunocompetent adults, CMV can cause heterophile-negative mononucleosis, characterized by fever, lethargy, and the presence of abnormal lymphocytes in peripheral blood smears. - In immunosuppressed patients, eg, those with renal and bone marrow transplant, systemic CMV infections, esp. pneumonitis and hepatitis, occur. In AIDS patients, CMV commonly infects the intestinal tract  diarrhea and it also causes retinitis  blindness.  Laboratory Diagnosis Culturing in special tubes called shell vials coupled with the use of immunofluorescent Ab  diagnosis in 72 hours. PCR-based assays for CMV DNA or RNA in tissue or body fluids, such as spinal fluid, and amniotic fluid. Other diagnostic methods: fluorescent-Ab and histologic staining of inclusion bodies (intranuclear, oval owl’s-eye shape) in giant cells in urine and in tissue. A 4-fold or greater rise in Ab titer. Owl’s eye intranuclear inclusions of Cytomegalovirus, arrowed  Treatment and Prevention Treatment Ganciclovir (Cytovene) = moderately effective for treatment of CMV retinitis and pneumonia in AIDS patients. Valganciclovir = taken orally = effective against CMV retinitis. Foscarnet (Foscavir) = also effective but with more side effects. Cidofovir (Vistide) = also useful for treatment of CMV retinitis. Fomivirisen (Vitravene) = an anti-sense DNA approved for the intraocular treatment of CMV retinitis = first and only antisense molecule for treatment of human disease. Unlike HSV and VZV, CMV is largely resistant to acyclovir. Prevention: There is no vaccine. Ganciclovir can suppress retinitis in AIDS patients. Infants with cytomegalic inclusion disease who are shedding virus in their urine should be kept isolated from other infants. Blood for transfusion to newborns should be CMV Ab-negative. If possible, only organs from CMV Ab–negative donors should be transplanted to Ab-negative recipients. A high-titer Ig preparation (CytoGam) is used to prevent disseminated CMV infections in organ transplant patients.  Epstein-Barr Virus Diseases: EBV causes infectious mononucleosis. It is associated with Burkitt’s lymphoma, other B-cell lymphomas, and nasopharyngeal carcinoma. EBV is also associated with hairy leukoplakia, a whitish, nonmalignant lesion on the tongue seen esp. in AIDS patients. Important Properties: Structurally and morphologically identical to other herpesviruses but is antigenically different. The most important Ag is the viral capsid Ag (VCA) = used most in diagnostic tests. The early antigens (EA), produced prior to viral DNA synthesis and nuclear antigen (EBNA), located in the nucleus bound to chromosomes = diagnostically helpful. 2 other Ags = lymphocyte-determined membrane Ag and viral membrane Ag, have been detected also. Neutralizing activity is directed against the viral membrane Ag. 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. Some, but not all, genes are transcribed, and only a subset of those is translated into protein.  Epstein-Barr Virus Summary of replicative cycle: The cycle is similar to that of HSV. EBV enters B lymphocytes at the site of the receptor for the C3 component of complement.  Transmission and Epidemiology EBV is transmitted primarily by the exchange of saliva, eg, during kissing. The saliva of people with a reactivation of a latent infection as well as people with an active infection can serve as a source of the virus. In contrast to CMV, blood transfusion of EBV is very rare. Most common infections worldwide Infections in the first few years of life are asymptomatic. Early infections occur in individuals in lower socioeconomic groups. The frequency of clinically apparent infectious mononucleosis is highest in those who are exposed to the virus later in life, eg, college students.  Pathogenesis The infection first occurs in the oropharynx and then spreads to the blood, where it infects B lymphocytes. Cytotoxic T lymphocytes react against the infected B cells. The T cells are the “atypical lymphs” seen in the blood smear (atypical in appearance with bulky cytoplasm and irregular nuclei). 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 (diagnoses acute infection) antibody to the VCA. IgG (reveals prior infection) antibody to the VCA follows and persists for life. Lifetime immunity against second episodes of infectious mononucleosis is based on Ab to the viral membrane Ag. In addition to the EBV-specific Abs, there are nonspecific heterophile Abs:  They are detected by tests using Ags different from the Ags that induced them.  Those formed in infectious mononucleosis agglutinate sheep or horse red blood cells in the lab. (Cross-reacting Forssman Abs in human serum are removed by adsorption with guinea pig kidney extract prior to agglutination).  These Abs do not react with any component of EBV.  It seems that EBV infection modifies a cell membrane constituent such that it becomes antigenic and induces the heterophile Ab.  Heterophile Abs usually disappear within 6 months after recovery.  These Abs are not specific for EBV infection and are also seen in individuals with hepatitis B and serum sickness.  Clinical findings Infectious mononucleosis is characterized by fever, sore throat, lymphadenopathy, and splenomegaly. Anorexia and lethargy are prominent. Hepatitis is frequent; encephalitis occurs in some patients. Spontaneous recovery usually occurs in 2-3 weeks. Splenic rupture, associated with contact sports such as football, is a feared but rare complication of the splenomegaly. EBV causes 2 other diseases:  One is a severe, often fatal, progressive form of infectious mononucleosis that occurs in children with an inherited immunodeficiency called X-linked lymphoproliferative syndrome (in males who inherit a defective gene in the X- chromosome). The mutated gene encodes a signal transduction protein required for both T-cell and NK-cell function. The mortality rate is 75% by age 10. Bone marrow or cord blood transplants may cure the underlying immunodeficiency.  The other disease is hairy leukoplakia, a whitish lesion on the tongue of AIDS patients  Laboratory Diagnosis Diagnosis is based primarily on two approaches: 1) In the hematologic approach, absolute lymphocytosis occurs (30% abnormal lymphocytes are seen on a smear). These atypical lymphs are large and have a lobulated nucleus and a vacuolated, basophilic cytoplasm. They are cytotoxic T cells that are reacting against the EBV-infected B cells. 2) In the immunologic approach, there are 2 types of serologic tests. a) The heterophile antibody test = for early diagnosis of infectious mononucleosis because it is usually positive by week 2 of illness. The Ab titer declines after recovery  not used for detection of prior infection. Monospot test (more sensitive, more specific and less expensive slide agglutination than the tube agglutination test) is used to detect the heterophile Ab. b) The EBV-specific Ab tests = for diagnostically difficult cases = IgM VCA to detect early illness and IgG VCA to detect prior infection. Ab to EA and EBNA can be used diagnostically. Although EBV can be isolated from clinical samples, such as saliva, by morphologic transformation of cord blood lymphocyte, it is technically difficult procedure and is not readily available. No virus is synthesized in the cord lymphocytes; its presence is detected by fluorescent-Ab staining of the nuclear Ag.  Association with Cancer EBV infection is associated with cancers of lymphoid origin: Burkitt’s lymphoma in African children (malaria infection is a cofactor), other B-cell lymphomas (failure of T-cell control resulting from acquired immunodeficiencies = AIDS or organ graft recipients), nasopharyngeal carcinoma in the Chinese population (an association with certain human leucocyte antigen-HLA haplotypes and high consumption of nitrosamines in salted foods), and thymic carcinoma in the US. The initial evidence of an association of EBV infection with Burkitt’s lymphoma was the production of EBV by the lymphoma cells in culture  This was how EBV was discovered by Epstein and Barr in 1964. Additional evidence includes the finding of EBV DNA and EBNA in the tumor cells. EBV DNA and antigens are found in nasopharyngeal and thymic carcinoma cells also. EBV can induce malignant transformation in B lymphocytes in vitro. The role of EBV in carcinogenesis is unclear.  Treatment and Prevention Treatment: No antiviral therapy for uncomplicated infectious mononucleosis. Acyclovir has little activity against EBV, but administration of high doses may be useful in life-threatening EBV infections. Prevention: There is no EBV vaccine.  Human Herpesvirus 8 (Kaposi’s sarcoma-associated herpesvirus) Common in patients who acquired HIV sexually but rare in patients who acquired HIV via blood transfusion  a second virus transmitted sexually appeared to be the cause. Most KS cells taken from AIDS patients contain the DNA of this virus, but tissues taken from AIDS patients without KS had very little viral DNA. The DNA of this virus was also found in KS cells that arose in non-HIV-infected patients. On DNA analysis, HHV-8 resembles the lymphotropic herpesviruses, eg, EBV, more than it does the neorotropic herpesviruses such as HSV and VZV. Serologic studies show that most HIV-infected persons with KS had Abs to HHV-8. HHV-8 causes malignant transformation by a mechanism similar to that of other DNA viruses such as human papillomavirus by inactivation of a tumor suppressor gene. A protein encoded by HHV-8 called nuclear antigen inactivates the RB (retinoblastoma) tumor suppressor protein, which causes the cells to grow in an uncontrolled manner. Transmission of HHV-8: primarily sexually and also transmitted in transplanted organs such as kidneys (transplantation-associated KS) in whose cells DNA of HHV-8 was found.  Human Herpesvirus 8 (Kaposi’s sarcoma-associated herpesvirus) KS in AIDS is a malignancy of vascular endothelial cells that contains many spindle-shaped cells and erythrocytes. The lesions are dark purple, flat to nodular, and often appear at multiple sites such as the skin, oral cavity, and soles but not the palms. Internally, lesions occur commonly in the gastrointestinal tract and the lungs. The extravasated red cells give the lesions their purplish color. HHV-8 also infects B cells  proliferate and produce a lymphoma called primary effusion lymphoma. Laboratory diagnosis: biopsy of the skin lesions. HHV-8 DNA and RNA are present in most spindle cells = this analysis is not usually done. Virus is not grown in culture. Treatment depends upon the site and number of lesions. Surgical excision, radiation, and systemic drugs, such as alpha interferon or vinblastine, can be used. No specific antiviral therapy and no vaccine against HHV-8.  Human Herpesvirus 6 (HHV-6) Properties: First isolated from patients suffering from lymphomas or acute lymphocytic leukemia. Cytopathic effect: inclusion bodies in human B lymphocytes. Morphologically similar to other herpesviruses but varies in biological characteristics. Causes febrile illness of children, exanthema subitum, or roseola (Sixth disease). Depending on its genome structure, it was assigned to a new genus, Roseolovirus, within the subfamily Betaherpesvirinae. Two groups defined by differences in serological reactions and genetic composition. Clinical features: Both names of this illness refer to the rash. The cervical lymph nodes and sometimes the spleen are enlarged. Convulsions are common  involvement of the CNS. Nevertheless, complete recovery is the rule. In normal adults, it causes an illness resembling infectious mononucleosis. In immunocompromised patients, it may be severe, involving various organs, including the bone marrow.  Human Herpesvirus 6 (HHV-6) Epidemiology and transmission: The virus is widely disseminated, and is shed in body fluids, including blood. The prevalence of Ab in infants is biphasic:  Most are seropositive at birth having acquired it transplacentally.  Most of this maternal Ab disappears by 6 months of age, after which the seroprevalence rate increases as a result of silent infections.  By the second year of life nearly all children in developed countries are again seropositive. Laboratory diagnosis: This is unnecessary except in the case of a suspected infection in an immunosuppressed patient, when virus can be isolated in cell culture, or detected by tests with monoclonal Abs. Treatment: is symptomatic ( treats symptoms not cause)  Human Herpesvirus 7 (HHV 7) This one was isolated from CD4+ T cells taken from healthy person. Like HHV-6, it is wide-spread and most people have Abs by late childhood. It causes an illness resembling infectious mononucleosis. Some cases of exanthema subitum have been associated with HHV -7, and a possible association with pityriasis rosea, a transient inflammatory rash, has also been reported. Laboratory diagnosis follows the methods used for HHV-6  Clinical Features of Herpesviruses Viruses Giant Cells Fetal or Important Antiviral Produced Neonatal Laboratory Therapy Disease Diagnostic Commonly Important Technique Used HSV-1 Yes No Culture Acyclovir1 HSV-2 Yes Yes Culture Acyclovir VZV Yes No Culture Acyclovir2 CMV Yes Yes Culture Ganciclovir3 EBV No No Heterophile None HHV-8 No No DNA probes Alpha interferon 1 Not used in recurrent herpes labialis 2 Not used in varicella in immunocompetent children 3 Used in CMV retinitis and other severe forms of disease  Glossary Trigeminal ganglia: This ganglion is a collection of sensory nerve cells of the trigeminal cranial nerve responsible for sensation in the face. Papule: Small solid rounded bumps rising from the skin that are each usually less than 1 centimeter in diameter Vesicle: is a small (less than one centimeter), raised lesion filled with serous fluid Pustule: is a small, raised lesion filled with pus. Crust: result when serum, blood, or purulent exudate dries Mononucleosis: an abnormally high proportion of monocytes in the blood, especially associated with glandular fever (Glandular fever is a type of viral infection that mostly affects young adults. Common symptoms include fever, a sore throat and extreme fatigue). Purpura: Purplish discoloration of the skin caused by bleeding into the skin and mucous membranes due to low platelet count  Glossary Burkitt's lymphoma: is a cancer of the lymphatic system, particularly B lymphocytes found in the germinal center. Anorexia: Loss of appetite Heterophile antibodies react with antigens other than antigens that provoked their production Serum sickness: is a reaction to proteins in antiserum derived from a non-human animal source occurring 4-10 days after exposure. Lymphocytosis: An abnormal increase in the number of lymphocytes in the circulating blood. Cord blood: Blood obtained from the umbilical cord at birth Acute lymphocytic leukemia (ALL) is a type of cancer of the blood and bone marrow — the spongy tissue inside bones where blood cells are made. The word "acute" in acute lymphocytic leukemia comes from the fact that the disease progresses rapidly and creates immature blood cells, rather than mature ones. Extravasation: The process of exuding or passing out of a vessel into surrounding tissues. Pityriasis rosea: A mild skin condition in which flat scaly spots or an itchy rash develops over the trunk and extremities.