The Human Herpes Viruses

grade 4

Dr. Mohamed Al-Sweify

Objectives:
1) 2) 3) Unique features of Herpes Viruses (HV) Viral Replication Herpes Simplex Virus (HSV)
1) 2) 3) 4) 5) PATHOGENESIS AND IMMUNITY Recurrence of HSV Epidemiology of HSV Genital HSV disease Lab Diagnosis of HSV

Unique features of Herpes Viruses (HV):

HV are ubiquitous in nature. HV have large, enveloped icosadeltahedral capsids containing ds DNA genomes. HV encode many proteins that manipulate the host cell and immune response. HV encode DNA polymerase, good target for antiviral drugs. DNA replication and capsid assembly occurs in the nucleus. Virus is released by exocytosis, cell lysis, and through cell-cell bridges. HV can cause lytic, persistent, latent, and, for EBV, immortalizing infections. Cell-mediated immunity is required for control.

Electron micrograph (A) and general structure (B) of the herpesviruses. (icosadeltahedral capsid)

Viral Replication

The viral genome is transcribed by the cellular DNAdependent ribonucleic acid (RNA) polymerase and is regulated by viral-encoded and cellular nuclear factors. The interplay of these factors determines whether the proteins necessary for a lytic, persistent, or latent infection are produced. Viral-encoded DNA polymerase, replicates the viral genome. Viral-encoded enzymes provide dNTP substrates. Viral enzymes facilitate replication of the virus in nongrowing cells (e.g., neurons)why?

 HSV binds to specific receptors and fuses with the plasma membr.. The nucleocapsid then delivers the DNA genome to the nucleus. Transcription and translation occur in three phases: immediate early, early, and late. The genome is replicated before transcription of the late genes. Capsid proteins migrate into the nucleus, assemble into icosadeltahedral capsids, and are filled with the DNA genome. The capsids filled with genomes bud through the nuclear and endoplasmic reticulum membranes into the cytoplasm, acquire tegument proteins, and then bud through the viral glycoprotein modified membranes of the trans Golgi network.

Immediate early gene products: are DNA-binding proteins, which stimulate DNA synthesis and promote transcription of early viral genes into mRNA, but these RNAs are not translated into protein.
Early proteins: include the DNA-dependent DNA polymerase and catalytic proteins that inhibit the production and initiate the degradation of cellular mRNA and DNA. Late proteins: structural proteins.

Expression of the early and late genes generally leads to cell death. The virus is released by exocytosis or cell lysis. Virus spread between cells through intracellular bridges. Virus-induced syncytia formation also spreads the infection. HSV infection of neurons may result in virus replication or latency, depending on which viral genes is being transcribed.
Transcription

of the LAT (latency-associated transcripts), and no other viral gene will result in latency.

Ttranscription

of immediate early genes lead to viral

replication.

Herpes Simplex Virus (HSV)

The first human herpesvirus to be recognized. The name "herpes" is derived from a Greek word meaning to creep . The two types of herpes simplex virus, HSV-1 and HSV-2, share many characteristics, including DNA homology, antigenic determinants, tissue tropism, and disease symptoms.

PATHOGENESIS AND IMMUNITY

HSV initiates infection through mm or skin breaks . HSV replicates in cells at the base of lesion and infects the innervating neuron, traveling by retrograde transport to its ganglion HSV then returns to the initial site of infection and may be inapparent or may produce vesicular lesions. The vesicle fluid contains infectious virions. Tissue damage is caused by a combination of viral pathology and immunopathology. The lesion generally heals without producing a scar. HSV-2 has a greater potential to cause viremia. HSV is reactivated from latency by stress or.. (see later) Cell-mediated immunity is required for resolution with limited role for antibody. Explaining why HSV diseases!

HSV can cause lytic infections of most cells, persistent infections of lymphocytes and macrophages, and latent infection of neurons.

Cytolysis by HSV results from:

virus-induced inhibition of cellular macromolecular synthesis degradation of host cell DNA membrane permeation cytoskeletal disruption changes in the nuclear structure, margination of the chromatin occur, and Cowdry type A acidophilic intranuclear inclusion bodies are produced.

Immune Response to HSV

Innate protections including IFN and NK cells may be sufficient to limit the initial progression of the infection. The immunopathologic effects of CMI and inflammatory responses are major cause of the symptoms. Antibodies against surface glycoproteins. In the absence of functional CMI, HSV infection is more severe and may disseminate to the vital organs and the brain.

HSV has several ways to escape host protective responses:

Blocks

IFN-induced inhibition of viral protein synthesis. Blocks cell peptides association with MHC-class I, so, prevents CD8 T-cell recognition of infected cells. Direct cell-to-cell spread. Hiding during latent infection of the neuron. The virion and virus-infected cells express Fc and complement receptors that weaken these humoral defenses.

Latent infection occurs in neurons and results in no detectable damage.

Recurrence of HSV infection

Triggers of HSV Recurrence: UV-B radiation (skiing, tanning) Fever (hence the name "fever blister") Emotional stress Physical stress Menstruation Foods: Spicy, acidic, allergies Immunosuppression, and HIV. Chemotherapy, radiotherapy
These events trigger virus replication in an individual nerve cell within the bundle and allow the virus to travel back down the nerve to develop lesions at same dermatome and location each time.

Stress triggers reactivation either by;

Promoting replication of the virus in the nerve, Transiently depressing cell-mediated immunity, or, Inducing both processes.

HSV can be reactivated despite the presence of antibody.

However, recurrent infections are generally less severe, more localized, and of shorter duration than the primary episodes.

Epidemiology of HSV

HSV Virus causes lifelong infection. HSV inactivated by drying, detergents, and GIT juices. Virus may cause asymptomatic shedding. Virus is found worldwide; There is no seasonal incidence. Both types of HSV can cause oral and genital lesions.

2) Transmission Virus is found in saliva, vaginal secretion, lesion fluid. Virus is transmitted orally and sexually and by placement into eyes and breaks in skin. "mixing and matching of mucous membranes Autoinoculation More than 90% of people living in underdeveloped areas have the antibody to HSV-1 by 2 years of age.

HSV-2 is spread mainly by sexual contact or autoinoculation or from an infected mother to her infant at birth. HSV-2 may infect the genitalia, anorectal tissues, or oropharynx. 22% of adults in US are infected with HSV-2, and 1 million newly infected people per year. The incidence of HSV-1 genital infection is approaching that of HSV-2. HSV may cause symptomatic or asymptomatic primary genital infection or recurrences. Neonatal infection usually results from ascending (inutero) infection or descending (at labor). Neonatal infection results in disseminated and neurologic disease with severe consequences.

Who is at Risk of infection ?

What do you think ?

Modes of Control:
What do you think ?

HSV-2 is sero-epidemiologically associated with human cervical cancer, possibly as a cofactor with human papillomavirus or another infectious agent.

Partial inactivation of the HSV-2 genome with ultraviolet light allows the virus to immortalize cells in tissue culture.

Genital herpes is usually caused by HSV-2 but can also be

caused by HSV-1(10%)

In male: lesions typically develop on glans or shaft of penis and occasionally in the urethra. In female: lesions may be seen on the vulva, vagina, cervix, perianal area, or inner thigh and are frequently accompanied by itching and a mucoid vaginal discharge. The lesions are usually painful. primary infection may be accompanied by fever, malaise, myalgia, and inguinal adenitis (transient viremia). HSV proctitis is a painful disease in which the lesions are found in the lower rectum and anus. Unfortunately, any infected person may shed virus asymptomatically. Such individuals may be important vectors for spread of this virus.

Herpes encephalitis is usually caused by HSV-1.

lesions are generally limited to one of the temporal lobes. The viral pathology and immunopathology cause the destruction of the temporal lobe and give rise to erythrocytes in the cerebrospinal fluid, seizures, focal neurologic abnormalities, and other characteristics of viral encephalitis.

HSV is the most common viral cause of sporadic encephalitis and results in significant morbidity and mortality, even in patients who receive appropriate treatment. HSV meningitis is most often a complication of genital HSV-2 infection; symptoms resolve by themselves.

HSV infection in the neonate

a devastating and often fatal disease caused most often by HSV-2. The baby initially appears septic, and vesicular lesions may be present. Because the cell-mediated immune response is not yet developed in the neonate, HSV disseminates to the liver, lung, and other organs, as well as to the central nervous system (CNS). Progression of the infection to the CNS results in death, mental retardation, or neurologic disability, even with treatment.

Lab Diagbnosis of HSV

Direct microscopic examination of cells from base of lesion (see histopathology) Cell culture: detects identifiable cytopathologic effect in most cell cultures. Assay of tissue biopsy, smear, cerebrospinal fluid, or vesicular fluid for HSV antigen or genome by:
1- Enzyme immunoassay, 2- immunofluorescent stain, 3- in situ DNA probe analysis 4- polymerase chain reaction (PCR). HSV type distinction (HSV-1 vs. HSV-2) Type-specific antibody, DNA maps of restriction enzyme fragments, sodium dodecyl sulfate-gel protein patterns, DNA probe analysis, and PCR. Serology: Serology is not useful except for epidemiology.