HERPES VIRUSES

The herpes virus family contains six important human pathogens:

• Herpes simplex virus type 1
• Herpes simplex virus type 2
• Varicella zoster virus
• Cytomegalovirus
• Epstein-barr virus
• Human herpes virus 8 (the cause of kaposi’s sarcoma)

They replicate in the nucleus, form intranuclear inclusions, and are the only viruses that obtain their envelope by budding from the nuclear membrane. The virions of herpesviruses possess a tegument located between the nucleocapsid and the envelope. This structure contains regulatory proteins, such as transcription and translation factors, which play a role in viral replication.

Herpesviruses are noted for their ability to cause latent infections. In these infections, the acute disease is followed by an asymptomatic period during which the virus remains in a quiescent (latent) state. When the patient is exposed to an inciting agent or immunosuppression occurs, reactivation of virus replication and disease can occur

Three of the herpesviruses, herpes simplex virus types 1 and 2 and varicella-zoster virus, cause a vesicular rash, both in primary infections and in reactivations.  The other two herpesviruses, cytomegalovirus and Epstein-Barr virus, do not cause a vesicular rash.

Certain herpesviruses are suspected of causing cancer in humans (e.g., Epstein-Barr virus is associated with Burkitt’s lymphoma and nasopharyngeal carcinoma, and human herpesvirus 8 is associated with Kaposi’s sarcoma).

	HSV	VZV
Incubation	3-6 days	2 weeks
Prodromal symptoms	Burning, itching	Fatigue, hyperesthesia
Pain	Moderate	Severe
Distribution	Localized	Dermatomes
Disease course	Rapid healing	Post herpetic neuralgia in 15%
Recurrence	Frequent	Rare
Trigger	– Pyrexia – Menstruation – UV/Sunlight – Stress – Malignancy – Old age – Immunosuppression	– Cytotoxics – Dental treatment – Radiation – Alcohol abuse – Malignancy – Old age – Immunosuppression
Management	– Acyclovir and analogs – Systemic treatment	– Calamine lotion – Symptomatic

HERPES SIMPLEX VIRUSES – HSV

Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are distinguished by two main criteria:

– Lesions caused by HSV-1 (primary herpetic gingivostomatitis) are, in general, above the waist, whereas those caused by HSV-2 (genital herpes)are below the waist.

Characteristics—Cross-reaction with HSV-1/2 occurs. No herpes group–specific antigen.

Summary of Replicative Cycle (same for others)

• The HSV has a large double stranded DNA genome, a protein capsid and phospholipid membrane with glycoproteins on the surface
• Viral envelope incorporates into the host cell membrane, the nucleocapsid uncoats and releases the DNA into the nucleus
• In the nucleus, the DNA circularizes and the host enzymes begin to transcribe the first set of viral genes, early genes. The early mRNA molecules enter the cytoplasm, and are translated into early proteins.
• Early proteins enter nucleus where they are required for Viral DNA replication
• Late mRNA transcribed, enters cytoplasm for translation into late proteins aka capsid structural proteins which enter the nucleus
• The late proteins also include envelope proteins which are produced in the ER and become incorporated in the nuclear membrane
• Viral DNA continues to replicate with end to end copies, which are cut into individual genome and packaged into capsids
• Nucleocapsids bud off at nuclear membrane (which has enveloped proteins incorporated in it), through ER and buds off from ER in a vesicle. Migrates to the plasma membrane, fusion of membranes and virus released

http://www.sumanasinc.com/webcontent/animations/content/herpessimplex.html

In latently infected cells, such as HSV-infected neurons, circular HSV DNA resides in the nucleus and is not integrated into cellular DNA. Transcription of HSV DNA is limited to a few latency-associated transcripts (LATS). These noncoding, regulatory RNAs suppress viral replication.

Etiology—Direct contact (contagious)

Pathogenesis & Immunity

Spreads by direct contact, incubation few days to a week, systemic symptoms are fever and malaise. Primary disease course runs for 7-10 days and heals with out scarring.

Secondary disease reactivated by sunlight, stress, immunosuppression. Prodromal symptoms are tingling and burning. Vesicles form superficial ulcer. Heals in 1-2 weeks without scarring.

The virus replicates in the skin or mucous membrane at the initial site of infection

Then migrates up the neuron by retrograde axonal flow and becomes latent in the sensory ganglion cells.

In general, HSV-1 becomes latent in the trigeminal ganglia, whereas HSV-2 becomes latent in the lumbar and sacral ganglia.

During latency, most viral DNA is located in the cytoplasm rather than integrated into nuclear DNA. The virus can be reactivated from the latent state by a variety of inducers (e.g., sunlight, hormonal changes, trauma, stress, and fever), at which time it migrates down the neuron and replicates in the skin, causing lesions.

The typical skin lesion is a vesicle that contains serous fluid filled with virus particles and cell debris. When the vesicle ruptures, virus is liberated and can be transmitted to other individuals. Multinucleated giant cells are typically found at the base of herpesvirus lesions.

Histology—Superficial smear – stain with PAP/Giemsa stain

• Virus infected multinucleated cells
• Intranuclear inclusions (Cowdry type A)
• Intracellular inclusions (Lipschutz bodies)
• Tzanck cells (ballooning degeneration)

Complications:

• Herpetic whitlow – inoculation of virus into finger – pain, redness and vesiculobullous eruptions
• Immunocompromised patient – more chronic and destructive lesions

VARICELLA ZOSTER VIRUS – VZV

Primary disease—Varicella, chicken pox Picture

• Children
• Self limiting
• Clinical:
  • Vesicular eruptions of trunk, head and neck – occurs in crops
  • Fever, malaise

Secondary disease—Zoster, shingles Picture

• Adults
• Self limiting
• AIDS defining illness
• Clinical:
  • Unilateral rash/vesicles along a dermatome
  • Post herpetic pain – severe and in 15%

NB: Ramsay Hunt Syndrome – Zoster infection of geniculate ganglion

Pathogenesis—Varicella: Droplet/direct infection. 2 weeks incubation. Initial infection is in the oropharynx. It spreads via the blood to the internal organs such as the liver and then to the skin. Vesicular eruptions on head, neck and trunk – pustular and ulcerate. Fever and malaise. Self limiting with recovery. After the acute episode of varicella, the virus remains latent in the sensory ganglia and VZV DNA is located in the nucleus and is not integrated into cellular DNA. Zoster: Later in life, frequently at times of reduced cell-mediated immunity or local trauma, the virus is reactivated and causes the vesicular skin lesions and nerve pain of zoster. Precipitating factors include leukemia, lymphoma, trauma, radiation. Prodromal symptoms are pain and paresthesia. Vesicular skin eruptions – pustular, ulcerates, dermatomal, unilateral. 15% post herpetic neuralgia

CYTOMEGALOVIRUS – CMV

Pathogenesis—Initial infection usually in the oropharynx. In fetal infections, the virus spreads to many organs (e.g., central nervous system and kidneys). In adults, lymphocytes are frequently involved. A latent state occurs in monocytes. Disseminated infection in immunocompromised patients can result from either a primary infection or reactivation of a latent infection.

Transmitted as:

• IU
• Perinatal
• Breast milk
• Respiratory droplets
• Sexually
• Parentally

 

EPSTEIN–BARR VIRUS – EBV

Important Properties — The most important antigen is the viral capsid antigen (VCA), because it is used most often in diagnostic tests. EBV enters B lymphocytes at the site of the receptor for the C3 component of complement. Selective binding to CD21 on epithelium and B cells.

Pathogenesis—Infection begins in the pharyngeal epithelium, spreads to the cervical lymph nodes, then travels via the blood to the liver and spleen. EBV establishes latency in B lymphocytes.

Associated with Burkitt’s lymphoma and hairy leukoplakia.

HUMAN HERPESVIRUS 8 – KAPOSI’S SARCOMA–ASSOCIATED HERPESVIRUS

HHV-8, or Kaposi’s sarcoma–associated herpesvirus (KSHV), may be the cause of Kaposi’s sarcoma (KS), the most common cancer in patients with AIDS.

POXVIRUSES

SMALLPOX VIRUS

Important Properties – DNA-dependent RNA polymerase in virion. This enzyme is required because the virus replicates in the cytoplasm and does not have access to the cellular RNA polymerase, which is located in the nucleus.

 Summary of Replicative Cycle

• After penetration of the cell and uncoating
• The virion DNA-dependent RNA polymerase synthesizes early mRNA, which is translated into early, nonstructural proteins, mainly enzymes required for subsequent steps in viral replication.
• The viral DNA then is replicated, after which late, structural proteins are synthesized that will form the progeny virions.
• The virions are assembled and acquire their envelopes by budding from the cell membrane as they are released from the cell.
• Note that all steps in replication occur in the cytoplasm, which is unusual for a DNA virus.

Pathogenesis  – Smallpox begins when the virus infects the upper respiratory tract and local lymph nodes and then enters the blood (primary viremia). Internal organs are infected; then the virus reenters the blood (secondary viremia) and spreads to the skin. These events occur during the incubation period, when the patient is still well. The rash is the result of virus replication in the skin, followed by damage caused by cytotoxic T cells attacking virus-infected cells.

Immunity following smallpox disease is lifelong; immunity following vaccination lasts about 10 years.