Human Herpes Viruses

Primary infection occurs through a break in the mucus membranes of the mouth or throat, via the eye or genitals or directly via minor abrasions in the skin. Because of the universal distribution of the virus, most individuals are infected by 1-2 years of age; initial infection is usually asymptomatic, although there may be minor local vesicular lesions. Local multiplication is followed by viraemia and systemic infection; and subsequent life-long latent infection with periodic reactivation.

During primary infection, the virus enters peripheral sensory nerves and migrates along axons to sensory nerve ganglia in the CNS - hence managing to escape the host's immune response. Between reactivations the virus is truly latent - viral DNA is maintained as an episome (not integrated) with limited expression of specific virus genes required for the maintenance of latency. The delicate balance of latency may be upset by various disturbances, physical (injury, U.V light, hormones, menstruation, etc) or psychological (stress, emotional upset etc.). Reactivation of latent virus leads to recurrent disease - virus travels back down sensory nerves to surface of body and replicates, causing tissue damage:

Diagnosis

Rising antibody titres in 1° infection; culture; PCR for fast diagnosis.

Treatment

• Aciclovir or similar antiviral.
• Although painful, most recurrent infections resolve spontaneously, usually to recur later.
• More serious are herpetic keratitis (ulceration of cornea due to repeated infection which can lead to blindness) and encephalitis (very rare but often fatal).
• A number of vaccines are under development - particularly for HSV-2 (a good candidate for post-exposure vaccination). None are currently licensed.
• HSV-1 is under active development as a vector for gene therapy.
• In-vitro trials have suggested that diets high in lysine and low in arginine may help to suppress viral replication, and other trials involving l-lysine supplementation may help in an attack and reduce recurrence rate.^1,2
• There is limited evidence that alternative therapies such as zinc, topical licorice root (Glycyrrhiza glabra) , lemon balm (Melissa officinalis) and Aloe can help - but randomised double blind trials are needed before they can be recommended.

Gives rise to 2 distinct clinical syndromes:

• Varicella (Chicken pox) - Infection normally occurs in childhood (~90%), entering via respiratory tract or conjunctiva. After multiplication at the inoculation sites, virus spreads to bloodstream and reticuloendothelial system. Secondary multiplication involves skin and mucosa, producing vesicles filled with very high titres of infectious virus. Complications are rare, but include pneumonia and CNS infection.
• Zoster (Shingles) - After primary infection, virus persists in sensory ganglia of CNS. It is not clear if this is a latent or a persistent infection, but 'reactivation' after many years leads to infection and tissue damage to dermatosome served by infected ganglia - most serious when cranial nerves are involved, affecting face/head - can lead to blindness.³

Treatment

Aciclovir or similar antiviral.
Complete sequence of VZV genome is known, ~125kbp. Infects a variety of human and animal cell types in vitro.

Epstein-Barr virus (EBV/HHV-4) is widespread in most human populations - ~90% of adults in W.Europe and N. America carry EBV. Infection persists for life with virus regularly shed in saliva which is the usual route of transmission. It can persist for a lifetime in an asymptomatic state. T cells effectively control it. In vitro it is the most potent transforming virus known, and in vivo it affects human B-lymphocytes (generally non-productive infection) and epithelial cells (productive infection). It is linked with several different types of tumour:

Cytomegalovirus is the largest of the Herpesviruses, genome ~240kbp. The kinetics of CMV infection are 'slow' - 7-14 days (compared with 24-48h for HSV). As with some other Herpesviruses, certain parts of the CMV genome have considerable homology with cellular DNA, implying that the virus has acquired cellular genes during evolution. The complete nucleotide sequence is known and expression has been studied in detail.

CMV infection is common; 60% of the UK population have experienced infection by the age of 40. Most infections are asymptomatic. Apart from during pregnancy and newborn infants exposed in utero, active (as opposed to latent) CMV infection only occurs in people with immune defects, specifically T-cell defects, e.g. AIDS patients and immunosuppressed transplant patients.
Transmission is believed to be by oral/respiratory route. Infection produces enlargement of cells and nuclear inclusion bodies in a wide range of tissues - systemic infection. In spite of the widespread distribution, CMV-related illness is rare and occurs only in two groups:

1. Immunocompromised: As the host immune response (particularly cell-mediated) plays a role in latency, AIDS/transplant and other immunocompromised patients may experience frequent and severe infections with multiple organ involvement.
2. Fetal Infections: Particularly a problem when primary infection of the mother occurs, resulting in congenital abnormalities in a proportion of cases.

Treatment

Ganciclovir.

(HBLV/HHV-6) - Isolated in 1986 in lymphocytes (CD4 ) of patients with lymphoreticular disorders. Genome ~160kbp. HHV-6 is now recognised as being a universal human infection. Primary infection in childhood causes a common childhood rash - roseola infantum - "fourth disease". Antibody titres are highest in children and decline with age. Consequences of childhood infection appear to be mild but primary infections of adults (rare) have more severe consequences - mononucleosis and hepatitis, and is a particular problem in immunocompromised patients.

HHV-7 is a recently described T-lymphotropic herpesvirus (first isolated from human CD4 cells in 1990). It infects almost all children by the age of three years and persists lifelong, with the shedding of infectious virus in saliva. It is similar to human herpesvirus 6 (HHV-6) in its genetic content and many of its biological properties, including the ability to cause at least some cases of exanthem subitum (Roseola Infantum).

This is detectable in Kaposi's sarcoma lesions, and may also be associated with body cavity-based lymphomas (BCBLs) of B-cell origin, and a subset of Castleman's disease (a rare non-neoplastic condition where collections of lymph gland tissue (plasma cell type) develop throughout the body), hyperplastic lymphadenopathy.

The herpesvirus particle has a very complex structure: The large double stranded DNA genome assumes a toroidal shape, wound round a proteinaceous core - further surrounded by a complex icosahedral nucleocapsid of about 100 nm in diameter. Outside the capsid is the tegument, a protein-filled region appearing amorphous in electron micrographs. On the outside of the particle is the lipid bilayer envelope, which contains a large number of glycoproteins.

Name comes from the Greek 'Herpein' - 'to creep' = chronic/latent/recurrent infections.