Herpes viruses. Dr.farah hazem. Classification:

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1 Dr.farah hazem Herpes viruses Herpesviridae are a large family of viruses contains several of the most important human viral pathogens. Clinically, the herpesviruses exhibit a spectrum of diseases. Some have a wide host-cell range, and others have a narrow host-cell range.herepsviruses are treatable viruses: they are susceptible to antiviral chemotherapy. The herpesviruses that commonly infect humans includeherpes simplex virus types 1 and 2 (HSV-1, HSV- 2), varicella-zostervirus, cytomegalovirus (CMV), Epstein-Barr virus (EBV). Classification: The family herpes virus is subdivided into 3 subfamilies: 1. Alphaherpesvirus: fast growing cytolytic viruses that tend to establish latent infection in neurons.. It include Simplexvirus genus HSV1 &HSV2and varicella-zoster virus (genus Varicellovirus). 2. Betaherpesvirus : slow growing and may be cytomegalic (massive enlargements of infected cell) and become latent in secretory lymphoid glands and kidneys tissue. It includes CMV (Cytomegalovirus genus) and Human herpesvirus 6,Human herpes virus Gammaherpesvirus: they are T lymphotropic (Latent in lymphoid tissue) it includeepstein-barr virus EBV (genus Lymphocryptovirus), infect and become latent in lymphoid cells. Morphology: Virus Spherical in shape, enveloped, large size viruses( )nm in diameter, icosaherdral in symmetry. The nucleocapsid is 100 nm in diameter, surrounded by a glycoprotein envelope. The genome is linear, double-stranded DNA, kbp in size. The most important properties of herpesviruses is their ability to cause different types of infection in the host: a - UPrimary infectionu: Most individuals are clinically asymptomatic. Result in antibody production & followed by establishment of latent infection.

2 b - LUatent infection ULifelong latent infection which Persist indefinitely in infected hosts. Neurons (HSV,VZV) or lymphocytes (EBV, CMV). c- USecondary infection (recurrent infection):uoccur in sero-positive individuals in those exposed to virus previously & have the virus latent in the body. 1.Herpes Simplex Virus (HSV) HSV infection are widespread, able to replicate in many types of cells, the virus grow rapidly. HSV establish latent infections in nerve cells, & recurrence is common. Mode of transmission: HSV1 spread by contact with infected saliva, or by respiratory, or after close contact between the mucous membranes or the space between the skin cracked and mucous membranes, across the skin scars, or secretion containing the virus. HSV2 is transmitted sexually with infected genital secretion or from a maternal genital tract to newborn. Pathogenesis of herpes simplex infection: Spread: Viral replication occurs first at the site of infection (local lesion) epithelial cells, then invades local nerve endings & transported to axonal flow to reach the site of latent infection in neuronal ganglion. HSV latent infection: Site: HSV1 trigeminal ganglia, HSV2 sacral ganglia. State: virus resides in infected ganglia in non-replicating state for lifetime (lifelong latency). Virus cannot be eradicated from the host even by antiviral drugs. Reactivation: Spontaneously or following stimuli (axonal injury, fever, physical stress, emotional stress, exposure to UV, menstrual cycle, immunosuppresion, hormonal changes, hot and cold exposure). Spread after reactivation: Virus follows nerve axons back to the peripheral site and replication proceeds in the skin or mucous membrane (vesiculo-ulcerative lesion).hsv1 to oral mucosa &HSV2 genital mucosa.

3 Clinical disease (HSV1, HSV2): I. Oropharyngeal disease: (fever blister) Symptoms include fever, sore throat. vesiculo-ulcerative lesions of gingival mucosa of the mouth (gingivostomatitis) & submandibular lymphadenopathy. II. Keratoconjunctivitis: (denderitic keratitis) infection With HSV-1 may occur in the eyes producing, sever kerato conjunctivitis (red eye with pain). Recurrent herpetic keratitis cause permanent corneal opacity & blindness. IIIU. Genital herpes Acquired sexually & can be severe lasting for about 3 weeks, Most cases caused by HSV2. Characterized by vesiculo-ulcerative lesions of male genitalia, & female - cervix, vagina & perineum. Lesion is very painful with fever & inguinal lymphadenopathy. UIV. Skin infections: 1. Localized skin infection: Traumatic herpes (whitelow disease). 2. Generalized cutaneous herpes: Sever & life threatening condition, occur in eczema or burns. VU. HSV EncephalitisU: Severe form of encephalitis (mostly HSV1 lesser HSV2), mortality can reach up to 80% without treatment. VI.U Neonatal herpes simplex infection About 75% of neonatal herpes infection caused by HSV-2. The newborn acquire the infection prenatally, natally or postnatally. Neonatal herpes almost always symptomatic. UVII. Infection in immunocompromised patients:

4 Most disease reflects reactivation of latent HSV infection. Treatment: Several antiviral drugs have proved effective against HSV infection e.g. Topical treatment such as Acyclovir cream or ointment 5% (five percent) and placed on the place of infection, Djelkosanol 10% cream and Pensikulovar 1% cream. 2.VARICELLA-ZOSTER VIRUs (VZV) Virus causes two different diseases. I. Varicella (chickenpox) II. Zoster (shingles) Mode of transmission and Source: Respiratory droplet. Patients with varicella or zoster lesion (highly contagious). Pathogenesis: Lesion in target organ: Skin & mucosal lesions initiated by viral infection of capillary endothelial cells & epidermal cells, result in swelling of epithelial cells, ballooning with accumulation of tissue fluid (vesicle formation). Latent: The virus becomes latent in the dorsal root sensory ganglion. Clinical signs and symptoms: UI. Varicella ( chickenpox) Mild disease among children; Severe disease occurs in immunocompromised patients & neonates. Incubation period is days.subclinical varicella is unusual. Characterized by fever, generalized vesicular rash of skin & mucous membranes. The rash is vesicular, generalized on the trunk, then on the face, limbs & pharyngeal mucosa in the mouth. The rash lasts about 5 days. UII. Zoster (shingles) Usually occur in immunocompromised, but occasionally develops in healthy adults. Starts with severe pain in the area of skin or mucosa supplied by one or more groups of sensory nerves & ganglia.

5 Treatment: 1. Varicella in normal children is mild disease & requires no treatment. 2. Antiviral compound shown to be effective including Acyclovir (treatment of choice). Famciclovir, Valacyclovir &Foscarnetcould be also used in severe cases. Laboratory diagnosis : 1- Direct detection: A- Electron microscopy study of vesicle fluid, show virus particles. B-Immunoflouresent stain of swab from the skin lesion.the agent is identified by neutralizationtest or immunofluorescence staining with specific antiserum. C-PCR, used routinely for the diagnosis of herpes simplex PCR amplification ofviral DNA from cerebrospinal fluid has replaced viral isolationfrom brain tissue obtained by biopsy or at postmortem examination as the standard assay for specific diagnosis ofhsv infections of the central nervous system.. 2- Isolation & identification of virus: Samples inoculated onto cell monolayer & monitored for the development of characteristic cytopathic effect.hsv is easy to cultivate, and cytopathic effects usually occurin only 2 3 days. 3-Serology: Antibodies appear in 4 7 days after infection and reach apeak in 2 4 weeks. They persist with minor titer for the life of the host. Detection methods available include neutralization,immunofluorescence, and enzyme-linkedimmunosorbent assay which used to measure the specific antibodies (rising titer of IgG or specific IgM). 3.Cytomegalovirus CMVs are ubiquitous herpesviruses that are common causes of human disease. CMVs are the agents of the most common congenital infection. The name for the classic cytomegalic inclusion disease derives from the propensity for massive enlargement of CMV-infected cells.

6 Properties of the Virus: CMV has the largest genetic content of the human herpesviruses. Its DNA genome (240 kbp) is significantly larger than that of HSV. Human CMV replicates in vitro only in human fibroblasts, although the virus is often isolated from epithelial cells of the host. CMV replicates very slowly in cultured cells, with growth proceeding more slowly than that of HSV or varicella- zoster virus. Mode of transmission: CMV may be transmitted from person to person in several different ways, all requiring close contact with virus-bearing material. There is a 4- to 8- week incubation period in normal older children and adults after viral exposure. The virus can be transmitted in utero with both primary and reactivated maternal infections. About one-third of pregnant women with primary infection transmit the virus. Clinical symptoms:. Most cases of HIV infection cytomegalovirus is clear (not shown symptoms of illness) and can remain in the body for long periods injured. Symptoms of the disease when the immune-impaired elderly often appear. The symptoms are fever, sore throat, inflammation of the liver. Pathogenesis: A. Normal Hosts The virus causes a systemic infection; it has been isolated from lung, liver, esophagus, colon, kidneys, monocytes, and T and B lymphocytes. The disease is an infectious mononucleosis-like syndrome, although most CMV infections are subclinical. Similar to all herpesviruses, CMV establishes lifelong latent infections. Virus can be shed from the pharynx and in the urine for months to years after primary infection. Most cases of HIV infection cytomegalovirus is clear (not shown symptoms of illness) and can remain in the body for long periods injured. B. Immunosuppressed Hosts Primary CMV infections in immunosuppressed hosts are much more severe than in normal hosts. Individuals at greatest risk for CMV disease are those receiving organ transplants,those with malignant tumors who are receiving chemotherapy,and those with AIDS. Viral excretion is

7 increased and prolonged, and the infection is more apt to become disseminated. Pneumonia is the most common complication. C. Congenital and Perinatal Infections Fetal and newborn infections with CMV may be severe. About 1% of live births annually in the United States have congenital CMV infections, and about 5 10% of those will develop cytomegalic inclusion disease. A high percentage of babies with this disease will exhibit developmental defects and mental retardation. CMV can also be acquired by the infant from exposure to virus in the mother s genital tract during delivery and from maternal breast milk. In these cases, the infants usually have received some maternal antibody, and the perinatally acquired CMV infections tend to be subclinical. Laboratory Diagnosis A. Polymerase Chain Reaction and Antigen Direct detection Active infection with CMV can be diagnosed by PCR from blood or urine. PCR assays have replaced virus isolation for routine detection of CMV infections.. B. Isolation of Virus Cell culture methods of viral isolation are too slow to be useful in guiding therapy, particularly in immunosuppressed patients. Human fibroblasts are used for virus isolation attempts. C. Serology Serologic tests that detect CMV antibodies ( IgM and IgG antibody to CMV) are widely available from commercial laboratories. The enzymelinked immunosorbent assay (ELISA) is the most commonly available serologic test for measuring antibody to CMV. Various fluorescence assays and indirect hemagglutination and latex agglutination tests are also available. Treatment: Drug treatments of CMV infections have shown some encouraging results. Ganciclovir has been used successfully to treat life-threatening CMV infections in immunosuppressed patients. Foscarnet, Acyclovir and valacyclovir have shown some benefits in bone marrow and renal transplant patients.