Herpes Simplex Viruses and Varicella Zoster Virus PDF

Medical Virology Chapter 8: Herpes Simplex Viruses & Varicella Zoster Virus  HSV - Introduction… The herpesviruses are classified in the family Herpesviridae based on the characteristic large linear double-stranded DNA genome. Members of this family have been identifie...

Medical Virology Chapter 8: Herpes Simplex Viruses & Varicella Zoster Virus  HSV - Introduction… The herpesviruses are classified in the family Herpesviridae based on the characteristic large linear double-stranded DNA genome. Members of this family have been identified in almost all animal species, and the specific herpesviruses are usually restricted to a single species. All these viruses are structurally similar and encode a large number of biosynthetic enzymes involved in the synthesis of viral DNA as well as structure proteins that compose the capsid and tegument, as well as envelope glycoproteins that are required for infection.  …HSV - Introduction… The herpesviridae family is subdivided into 3 subfamilies: 1. The Alphaherpesvirinae includes HSV-1, HSV-2, and VZV, all of which exhibit a relatively short replication cycle in primary human fibroblast cells and the ability to establish latent infections in sensory ganglia. 2. Betaherpesvirinae replicate more slowly and establish latency in secretory glands and myeloid precursor cells and include CMV, HHV-6A, HHV-6B, and HHV-7. 3. The Gammaherpesvirinae, EBV and HHV-8, generally replicate in lymphoblastoid cells and establish latent infections in lymphoid tissue.  …HSV - Introduction… Herpesviruses have a characteristic morphology: 1. The icosahedral protein capsid (average diameter 100 nm) consists of 162 hollow hexagonal and pentagonal capsomeres with an electron-dense core containing the DNA genome. 2. Outside the capsid (in mature virus particles) is an amorphous proteinaceous layer, the tegument, surrounded by a lipid envelope derived from host cell membranes. 3. Projecting from the trilaminar lipid host-derived envelope are spikes of viral glycoproteins.  …HSV - Introduction The herpesvirus genome is linear double-stranded (ds) DNA. The presence of unique long and short (UL, US) regions bounded by repeated and inverted short segments allows recombination and isomeric forms in some cases. Genes coding for viral glycoproteins, major capsid proteins, enzymes involved in DNA replication, and some transcripts associated with latency, have been identified.  Herpes Simplex Virus… Biological Characteristics of HSV: There are two distinct types of HSV: type 1 (HSV 1) and type 2 (HSV 2). Type 1 strains are associated primarily with the mouth, eye and central nervous system (CNS), whereas type 2 strains are found most often in the genital tract. HSV glycoproteins: The envelope of HSV contains at least 11 glycoproteins. Three of the glycoproteins (g) are essential for production of infectious virus: 1. gB and gD, which are involved in adsorption to and penetration into cells.  …Herpes Simplex Virus… 2. gC, and gH (together with gL), involved in fusion at entry and in the release of virus. The replication of both HSV-1 and HSV-2 involves complex interactions with the host cell at the molecular level that drives an efficient replication cycle. The virus then targets sensory ganglia where it establishes and maintains an exquisitely controlled latent infection in which the viral genome remains largely silent and undetected by the host cell.  …Herpes Simplex Virus… Epidemiology: Humans are the only known natural reservoir of HSV. Infections with HSV-1 and HSV-2 are common in both developed and undeveloped countries worldwide. Acquisition of HSV results in lifelong infection with the establishment of latency in sensory neural ganglia followed by periodic clinical or subclinical reactivation of viral replication. The spread of infection since transmission occurs by close contact with infected body fluids such as saliva, mucosal secretions, or vesicle fluid. Surveillance of seroprevalence indicates that earlier acquisition of infection is seen with HSV-1 as compared to HSV-2.  …Herpes Simplex Virus… Clinical significance: Infections due to HSV can result in a wide spectrum of disease, ranging from asymptomatic or uncomplicated mucocutaneous involvement to severe disease involving multisystem dissemination or penetration into the central nervous system (CNS). The most common types of HSV infection are primary and recurrent infections of the orolabial or genital mucosa.  …Herpes Simplex Virus… Primary infection: refers to the patient’s initial acquisition of virus and, thus, occurs in those with no antibody against HSV. It usually involves the mucous membranes of the mouth, but may include the lips, skin of the face, nose or any other site, including the eye and genital tract. They are often asymptomatic.  …Herpes Simplex Virus… Recurrence infection: Symptomatic recurrence is heralded by a prodrome in two- thirds of people, who experience pain or paresthesia (tingling, warmth, itch) at the site followed by erythema and a papule, usually within 24 h. Progression to a vesicle and ulcer, with subsequent crusting, takes 8–12 days before natural healing occurs. Because of their association with febrile illness, the lesions are popularly known as cold sores or fever blisters.  …Herpes Simplex Virus… The most common sites are at the mucocutaneous junction of the lip (seldom inside the mouth), on the chin, or inside the nose. However, recurrent lesions can manifest at any site innervated by the affected neurone, determined by the site of initial infection.  …Herpes Simplex Virus… 1. Oral infection: Classically, primary HSV infection presents as an acute, febrile gingivostomatitis in preschool children. Vesicular lesions ulcerate rapidly and are present in the front of the mouth and on the tongue (stomatitis). Gingivitis is usually present. The child is miserable for 7–10 days in an untreated case before the lesions heal.  …Herpes Simplex Virus… 2. Skin infection: i. Herpetic whitlow: hand infections with HSV are not uncommon, but other sites may be involved [e.g. as a result of sports such as herpes gladiatorum in wrestlers or rugby players. ii. Eczema herpeticum: A severe form of cutaneous herpes may occur in children with atopic eczema. Vesicles resembling those of chickenpox may appear, mainly on already eczematous areas. Herpetic whitlow Eczema herpeticum  …Herpes Simplex Virus… 3. Eye infection: HSV infection of the eye may be initiated during a childhood primary infection, or occur from transfer of virus from a cold sore. There may be periorbital herpetic dermatitis together with conjunctivitis, or keratoconjunctivitis associated with corneal ulceration. The majority of eye infections are with HSV 1, and most patients with recurring eye disease are aged over 50 years. Herpes eye infection  …Herpes Simplex Virus… 4. Central nervous system infection: HSV may reach the brain in several ways. Viraemia has been detected during primary herpetic stomatitis, and infection may be carried within cells into the brain and meninges. i. HSV encephalitis: it is a rare condition, but is the most common sporadic fatal encephalitis recognized in developed countries. The infection has a high mortality rate. ii. HSV meningitis: Aseptic meningitis caused by HSV is much less serious than encephalitis. HSV 2 is the usual cause and it reaches the CSF following radiculitis during genital herpes.  …Herpes Simplex Virus… 5. Genital tract infection: Both types of HSV can infect the genital tract. Although the more common association has been with type 2 virus. Genital infection may be acquired by autoinoculation from lesions elsewhere on the body, but most often results from intimate sexual contact. The lesions are vesicular at first, but rapidly ulcerate: In the male, the glans and shaft of the penis are the most frequent sites of infection. In the female, the labia and vagina, or cervix, may be involved. In both sexes, lesions may spread to surrounding skin sites.  …Herpes Simplex Virus… Diagnosis: Diagnosis of HSV infections is straightforward because the viruses are readily cultured and assays for the detection of antibodies, antigens, and viral DNA are highly sensitive. Swab specimens, mucosal secretions, CSF, and tear specimens among others may be acceptable specimens. Acceptable swabs can be cotton, polyester, or rayon with a plastic shaft since both Dacron swabs and wooden shafts can inhibit some NAAT reactions.  …Herpes Simplex Virus… In most cases, swab specimens are collected from sites such as skin, lip, oral, tongue, throat, nasopharyngeal, genital, eye/conjunctiva, or anal/rectal/perineum. fluid-filled lesions should be disrupted prior to collection and smaller, less-developed lesions are preferable because they contain more infectious virus.  …Herpes Simplex Virus… 1. Culture: Both HSV-1 and HSV-2 replicate well in many cell types, and virus culture remains an established and reliable means to diagnose both oral and genital lesions. HSV replicates with more rapid kinetics than VZV, visual cytopathology at 24 hours following inoculation is often observed with swabs from herpetic lesions.  …Herpes Simplex Virus… 2. Antibody: Serological testing is a proven technology to identify individuals infected with HSV-1 or HSV-2. Commercial assays, such as HerpeSelect-2 (Focus Technologies, Cypress, A), are available and use purified antigens for each virus to diagnose infection and distinguish between the two viruses. Most assays utilize differences in the immune response to glycoprotein G (gG) of the two viruses with sensitivity and specificity reported to be in the range of 90% to 100%.  …Herpes Simplex Virus… Enzyme immuno-assays (EIAs) are much more sensitive and specific than CFTs. Therapy often results in delayed appearance of these type- specific antibodies, and late convalescent samples (at 6 weeks) should be included.  …Herpes Simplex Virus… 3. Nucleic Acid Amplification Tests: With the advent of NAAT methods, detection of HSV DNA rapidly became the diagnostic method of choice for CSF specimens when HSE is suspected. Many commercially available platforms and NAAT assays are available and have FDA-cleared assays for the detection of HSV-1 and HSV-2.  …Herpes Simplex Virus… Treatment and Prevention: Current antiviral therapies for the treatment of both HSV and VZV infections all target the DNA polymerase. Specific pathways that yield active metabolites differ, yet they all ultimately inhibit the viral DNA synthesis by interfering with the viral DNA polymerases. Examples: Acyclovir (ACV) , famciclovir (FCV).  …Herpes Simplex Virus Experimental vaccines are under investigation, but none is licensed for use. Research into subunit vaccines based on the viral glycoproteins, or other significant viral proteins, may lead to an appropriate preparation to elicit the immune responses important in control of HSV. Transmission of herpes simplex can be reduced by: 1. Alleviating over-crowding 2. Simple hygiene measures (e.g. attention to adequate hand hygiene) 3. Education regarding the infectious stages.  Varicella Zoster Virus… Biological Characteristics of VZV: The genomic structure and replication cycle of VZV shares many characteristics with the other alphaherpesviruses, HSV- 1 and HSV-2. One important distinction involves altered replication characteristics in cell culture. First, VZV exhibits a restricted host cell range in cell culture that includes human and simian cells and a modestly extended replication cycle. The typical CPE appears in cell cultures in 3 days to 2–3 weeks.  …Varicella Zoster Virus… The VZV genome is similar to that of HSV and is approximately 125 kb in length with UL and US segments bounded by repeat sequences. The glycoproteins gE, gB and gH are abundant in infected cells, and are present in the viral envelope. Infection with VZV presents in two forms: 1. Primary infection: varicella (or chickenpox) is a generalized eruption. 2. Reactivated infection: zoster (or shingles) is localized to one (or a few) dermatomes.  …Varicella Zoster Virus… Epidemiology: Primary infection with VZV results in the cutaneous manifestation known as varicella or chickenpox. VZV is highly communicable by respiratory droplets as well as by direct contact with skin lesions, as demonstrated by attack rates as high as 30% in classroom settings and 90% in household contacts. After primary infection, VZV establishes lifelong latency in cranial nerves and dorsal root ganglia. Viral reactivation can occur decades later in the form of zoster, or shingles.  …Varicella Zoster Virus… Zoster occurs in as many as 20% of individuals who have been previously infected with VZV. Its incidence increases with age and in individuals with impaired cell-mediated immunity e.g. (old age, HIV patient). Varicella can occur throughout the year but is more common in the late winter and spring, whereas zoster demonstrates no seasonal variability.  …Varicella Zoster Virus… Clinical Significance: Varicella (chickenpox): The incubation period averages 14–15 days but may range from 10 to 21 days. The patient is infectious for 2 days before, and for some days after. VZV infection manifests with prodromal symptoms such as fever, headache, and malaise followed by the onset of a pruritic maculopapular rash that quickly progresses to vesicular lesions. The rash of varicella (chickenpox) is usually centripetal, being most dense on the trunk and head.  …Varicella Zoster Virus… Secondary bacterial infections are the most common complication of varicella mainly in young children. A variety of organs may rarely be affected However, the two most frequent problems are related to the lungs (Pneumonia) and the CNS (Acute encephalitis). Primary varicella acquired during pregnancy can be associated with significant morbidity and mortality in both the mother and the fetus, including maternal pneumonia, spontaneous abortion, preterm labor, congenital varicella.  …Varicella Zoster Virus… Zoster (shingles): Neurocutaneous reactivation of latent VZV and is characterized by a unilateral painful vesicular eruption in a dermatomal distribution. The most common complication of zoster is postherpetic neuralgia, which is the development of chronic pain after the resolution of cutaneous lesions.  …Varicella Zoster Virus… Diagnosis: The laboratory diagnosis of VZV infection is important since it can cause rare life-threatening infections and disease manifestations that can, in some cases, be very similar to those of HSV. Generally, clinical presentation of lesions consistent with varicella or zoster is sufficient to diagnose infection. Acceptable specimen types and maintenance conditions for specimens are generally identical to those described for HSV above.  …Varicella Zoster Virus… 1. Culture: The “gold standard” for the diagnosis of VZV infections is viral culture followed by DFA. A swab specimen in universal transport media or equivalent should preferably be refrigerated (72 hours stable) until it can be cultured in the diagnostic laboratory. Primary human fibroblasts (such as MRC-5 cells), or mixtures of African green monkey kidney cells and primary human fibroblasts are acceptable cell substrates. And then stained with commercially available monoclonal antibodies in a direct fluorescent assay to confirm the presence of VZV.  …Varicella Zoster Virus… 2. Antibody detection: Since most individuals born after 1995 have been vaccinated, serological testing is becoming less informative over time. Antibody testing with VZV antigens can confirm a diagnosis of varicella by demonstration of seroconversion or rising titres of antibody between acute and convalescent serum samples. CFTs are still useful for this purpose but are not widely available any longer. assays need to be based on enzyme or radiolabelled methods, or immunostaining of infected cells.  …Varicella Zoster Virus… Assays need to be based on enzyme or radiolabelled methods, or immunostaining of infected cells. It is increasingly common to test for past infection (and therefore immunity) by measuring IgG antibody to VZV in those who are, or will become, immunocompromised, in women exposed antenatally to VZV, or in healthcare workers (or other adults) who are to be offered VZV immunization.  …Varicella Zoster Virus… 3. Nucleic Acid Amplification Tests: As with HSV, rapid molecular assays for the detection of VZV DNA are increasing in popularity and may be of value in the management of transplant-associated infections. A highly sensitive qualitative assay is commercially available on the LightCycler (Roche, Molecular Biochemicals).  …Varicella Zoster Virus Treatment and Prevention: Acyclovir (ACV) and Penciclovir (PCV) remain the therapy of choice for VZV infections. Vaccination is the best means to protect against disease associated with VZV infection. The Varivax live attenuated vaccine has been proven to be both safe and effective and has been recommended for routine use in children since 1995. Since the recommendation of a second dose of the vaccine at age 12, the effectiveness against varicella has been estimated to be as high as 98%. Questions? Thank you