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Herpesviruses


VIRUS:
  • Herpesviruses: Herpes Simplex (HSV-1, HSV-2), Varicella-Zoster virus (VZV), Cytomegalovirus (CMV), Epstein-Barr virus (EBV)


GENERAL CONCEPTS:
  • The Herpesviruses are a large group containing more than 70 members that infect organisms from fungi to humans.
  • The Herpesviruses contain a linear DNA genome and are enveloped (bilayered with surface projections derived from the host cell nuclear membrane). Replication occurs in the host cell nucleus.
  • Herpesviruses cause acute infections but they are also capable of latency. This can lead to recurrent infections, which are important to the mechanism of host to host transmission. HSV-1, HSV-2 and VZV are termed "neurotropic" while CMV and EBV are "lymphotropic", referring to the cell type in which the latent infection is established.
  • Some Herpesviruses have been associated with the production of cancers, providing the best evidence for a viral etiology for these diseases.
  • Humans are the natural host for HSV, VZV, CMV and EBV.


DISTINCTIVE PROPERTIES:
  • The morphology of each the Herpesviruses is similar but unique.
  • At the genome level, HSV-1 and HSV-2 share only about 50% DNA homology; the genome molecular weights, however are similar (96 x 106 daltons). The genome molecular weights of the other viruses are somewhat larger; EBV is about 114 x 106; CMV is about 150 x 106.
  • Except for HSV-1 and HSV-2, the proteins surrounding the genome are immunologically unrelated.
  • Herpes DNA replication involves three coordinately regulated sequential events. Upon entering the host cell, the virus travels to the nucleus. There, a set of genes termed immediate early are transcribed by cellular transcription factors to produce a set of proteins, some of which are new transcription factors. This groups of factors recognize viral promoters preceding the early genes. Some of the resultant proteins are replication enzymes while others are a third set of transcription factors that synthesize mRNAs encoding the late genes. The late gene products, then, are structural proteins that encapsidate the newly formed DNA genome to produce new progeny virions.


PATHOGENESIS:
  • Herpesviruses infect a range of different cell types, causing different disease scenarios. The skin and mucus membranes are common sites of infection for HSV and VZV; CMV and EBV are more internal (EBV infects B lymphocytes).
  • The viruses produce intranuclear inclusions and multinucleated giant cells
  • With the exception of VZV, primary Herpes infections are often asymptomatic. The process of latency is poorly understood but, except for VZV, asymptomatic shedding is common. Recurrence of acute disease results because of emotional stress, surgery, trauma, cold, fever, immune suppression, etc. Recurrence of HSV is common, frequent and localized.
  • More specifically:
    • HSV-1 is responsible for a variety of infections. Most commonly, HSV-1 produces the condition known as gingivostomatitis in which oral cavity vesicles or ulcers form. These lesions may recur frequently as "cold sores" (herpes labialis). Another condition produced by HSV-1 is herpetic keratitis, which may be serious if accompanied by conjunctivitis because this can lead to corneal scarring and blindness. Another condition known as "whitlows" appears as lesions on the fingers.
    • HSV-2 is commonly referred to as genital herpes. This virus produces lesions on the genitals, urethra and bladder. Recurrence may be frequent. In neonates, infection may be local or disseminated and has about 50% mortality if untreated. HSV-2 may also cause meningitis or encephalitis.
    • VZV produces the disease varicella and zoster. Varicella is commonly known as chickenpox. This relatively mild infection in children can be more serious in adults, occasionally progressing to pneumonia. Varicella is characterized by a skin rash appearing first on the head and trunk, and later on the extremities. The skin lesions progress from macules to papules to vesicles to pustules to crusts. These lesions are not prone to scar. Zoster is commonly known as shingles and is a manifestation of varicella infection. Typically occurring in older individuals, the lesions are confined to skin areas innervated by sensory nerves of the dorsal ganglia, primarily in the thoracic and lumbar regions. These nervous tissues are thought to be the sight of latent infection by VZV.
    • CMV infections are often asymptomatic but when infection occurs in utero, cytomegalic inclusion disease may result. This condition is characterized by jaundice, hepatosplenomegaly and central nervous system disorder. CMV may also produce a form of mononucleosis characterized by fever, fatigue and atypical lymphocytes. This form of mononucleosis is different than that produced by EBV (below).
    • EBV is primarily responsible for infectious mononucleosis, characterized by fever, fatigue, malaise and pharyngitis. EBV latently infects B-cells, creating the potential for recurrence. In addition, a strong association between EBV and Burkitt's lymphoma in Africa and nasopharyngeal carcinoma in the Orient and Africa provides evidence for a viral etiology for some human cancers.


HOST DEFENSES:
  • Primary infection by Herpesviruses induces antibody, which is protective, but recurrent infections still occur.
  • The cell-mediated immune response is also important (viral antigens on the cell surface allow detection and killing of infected cells).


EPIDEMIOLOGY:
  • In lower socioeconomic groups, most individuals are infected subclinically by HSV-1, CMV and EBV. In the higher socioeconomic groups, about half are infected. VZV infects both groups equally. HSV-2 is generally transmitted by sexual contact; the others more commonly by saliva. CMV can be spread transplacentally (0.5-2.5% newborns have CMV in the urine).


DIAGNOSIS:
  • Clinical: Generally, the lesions are characteristic and clinical diagnosis is accurate.
  • Laboratory: Smears of lesions show intranuclear inclusions.


CONTROL:
  • Sanitary: Avoidance of contacts reduces the incidence of disease but virus may be transmitted by asymptomatic individuals.
  • Immunological: Vaccines are in development but the problems associated with latency and possible cancers remains. A vaccine for VZV is available. Hyperimmune serum can be used for susceptible or high risk individuals.
  • Chemotherapeutic: Acyclovir (a nucleoside analog) is effective against HSV infections. Acyclovir and other analogs (iododeoxyuridine, trifluorothymidine, adenine arabinoside) have been used to treat other Herpes infections but often show little benefit.

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