Herpesvirus Replication and Characteristics

Herpes Viruses Introduction

• The name herpes comes from the Latin word "herpes" (Greek word "herpein"), which means "to creep".
• This reflects the creeping or spreading nature of the skin lesions caused by many herpesviruses
• Herpes viruses are a leading cause of human viral disease, second only to influenza and cold viruses.
• Herpes viruses are characterized by active and latent diseases, such as chickenpox/shingles.

Virology

• Herpes viruses are enveloped viruses and they acquire envelopes during budding from the nuclear membrane.
• The tegument, located between the envelope and the capsid, contains virally-encoded proteins and enzymes involved in the initiation of replication.
• Capsids are doughnut-shaped with icosahedral nucleocapsids.
• Herpes viruses possess double-stranded DNA, with genome sizes differing by virus, cytomegalovirus possesses the largest genome.
• Herpes viruses establish latent infections, persist indefinitely in infected hosts, and frequently reactivate in immunosuppressed hosts
• Some herpes viruses can cause cancer.

Classifications

• Herpes viruses are classified into 3 subfamilies which include alpha(3), beta(3), and gamma(2).
• Alphaherpesviruses are fast-growing, cytolytic viruses that tend to establish latent infections in neurons.
• Examples of alphaherpesviruses include herpes simplex virus-1 (HHSV-1), HHSV-2, and varicella zoster virus.
• Betaherpesviruses are slow-growing and may be cytomegalic (massive enlargements of infected cells) and become latent in secretory glands and kidneys.
• Examples of betaherpesviruses include Cytomegalovirus, human herpesviruses 6 and 7.
• Gammaherpesviruses infect and become latent in lymphoid cells.
• Examples of gammaherpesviruses include Epstein Bar Virus (EBV), and HHSV-8 (kaposi sarcoma-associated herpes virus).
• Herpes simplex virus Type 1 (HSV-1) is an alphaherpesvirus.
• Herpes simplex virus Type 2 (HSV-2) is an alphaherpesvirus.
• Varicella Zoster Virus (VZV) is an alphaherpesvirus.
• Cytomegalovirus (CMV) is a betaherpesvirus.
• Human herpes virus 6 (exanthum subitum or roseola infantum) is a betaherpesvirus.
• Human herpes virus 7 is a betaherpesvirus.
• Epstein Barr virus (EBV) is a gammaherpesvirus.

Replication

• Herpes viruses enter cells by fusion with the cell membrane after binding to specific cellular receptors like heparan sulfate, via envelope glycoproteins.
• After fusion, the capsid enters the nucleus where uncoating occurs and DNA becomes associated with the nucleus.
• Expression of the viral genome is tightly regulated and sequentially ordered in a cascade fashion.
• Immediate-early genes yield "alpha" proteins, translated into "beta" proteins, then viral "DNA" replication and production of late transcripts ("gamma" proteins).
• Alpha and beta proteins are mainly enzymes or DNA-binding proteins, while gamma proteins are structural proteins.
• Maturation occurs by budding through the nuclear membrane, and enveloped virus particles are transported by vesicular movement to the cell surface.
• Cells productively infected are invariably killed, and host molecular synthesis is shut off early in infection.
• Cellular DNA and protein synthesis virtually stop as viral replication begins.

Pathogenesis and Pathology

• HSV is transmitted by contact with someone excreting the virus or droplets via mucosal surfaces or broken skin.
• HSV-1 infections are usually limited to the oropharynx, while HSV-2 spreads via genital routes.
• Viral replication occurs first at the site of infection, then invades local nerve endings and transports by retrograde axonal flow to dorsal.
• Pathologic changes are due to necrosis of infected cells and the inflammatory response because HSV causes cytolytic infections.
• Lesions induced in the skin and mucous membranes by HSV-1 and HSV-2 resemble those of varicella-zoster virus.
• Changes induced by HSV are similar for primary and recurrent infections in degree reflecting the.

Manifestations

• Primary HSV infections may be asymptomatic.
• Rarely, systemic disease may develop, involving multiple organs in immunocompromised hosts.
• Latent infections occur in nonreplicating state (Oropharyngeal HSV-1 in trigeminal ganglia; genital HSV-2 in sacral ganglia).
• Provocative stimuli, such as fever, cause recurrences.
• HSV-1 can cause cold sores on the lip or mouth; HSV-2 can also be responsible.
• HSV-2 can cause genital herpes; HSV -1 can also be responsible.
• Keratoconjunctivitis of HSV-1 infections may occur in the eye, causing keratoconjunctivitis.
• Oropharyngeal disease involves the buccal and gingival mucosa of the mouth in children ages 1-5; Symptoms include fever, sore throat, vesicular and ulcerative lesions, and gingivitis.
• Pharyngitis and tonsillitis may occur in adults.
• Varicella-zoster virus causes chickenpox (varicella) on primary infection and zoster (shingles) on reactivation of latent infection.
• Epstein-Barr virus causes infectious mononucleosis following replication in epithelial cells of the oropharynx and parotid gland and establishes latent infections in lymphocytes.
• Cytomegalic inclusion disease may occur in newborns, and CMV is an important cause of congenital defects and mental retardation.
• Human herpesvirus 6 causes exanthem subitum (roseola infantum) following T lymphocytes infection.

Clinical Manifestations Continued

• Human herpesvirus 7, also a T-lymphotropic virus, has not yet been linked to any specific disease.
• Epstein-Barr virus causes malignancy like Burkitt's lymphoma and nasopharyngeal carcinoma and Human herpesvirus 8 cause Kaposi's sarcoma.
• Severe encephalitis may be caused especially by HSV-1 with a high mortality rate and residual neurologic defects.

Laboratory Diagnosis

• Cytopathology involves staining scrapings obtained from the base of a vesicle with Giemsa's stain.
• The presence of multinucleated giant cells indicates that herpesvirus (HSV-1, HSV-2, or varicella-zoster) is present.
• Virus isolation occurs during primary infection and during asymptomatic periods. Therefore, isolation of HSV insufficient evidence to indicate the virus is the causative agent of a disease under investigation.
• Diagnosis includes polymerase Chain Reaction (PCR).
• Antibodies appear in 4-7 days after infection and reach a peak in 2-4 weeks and persist with minor fluctuations for the life of the host.
• The use of HSV type-specific antibodies, available in some research laboratories, allows more meaningful serologic tests.

Treatment and Prevention

• Antiviral drugs like acyclovir, valacyclovir, and vidarabine inhibit viral DNA synthesis.
• Acyclovir stands as the standard therapy.
• The drugs suppress clinical manifestations, shorten the healing time, and reduce recurrences of genital herpes, however, HSV remains latent in sensory ganglia.
• Newborns and persons with eczema should be protected from exposure to persons with active herpetic lesions.
• Experimental vaccines of various types are developed.

Explore the features of herpesviruses, including replication initiation, latency, subfamily classification based on latency location, and cytomegalic effects. Learn about the characteristics, acquisition of viral envelopes, classification, and the roles of heparan sulfate and alpha proteins in herpesvirus infection.