Human Herpes Viruses

There are 8 currently identified members of the human herpes virus family. They are ubiquitous and extremely well adapted pathogens. The name comes from the Greek 'Herpein' - 'to creep', describing the chronic, latent or recurrent nature of infections.

The herpesvirus particle has a very complex structure:

• The large double stranded DNA genome assumes a toroidal shape, wound round a protein core, further surrounded by a complex icosahedral nucleocapsid, 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.

• 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.
• Most individuals are infected with HSV-1 by 1-2 years of age; HSV-2 infection tends to be with the onset of sexual activity.
• 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 (e.g. injury, UV light, hormones, menstruation) or psychological (e.g. stress, emotional upset).
• 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
• Viral 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).
• Suppressive antiviral therapy may be used for individuals with frequent and/or particularly severe relapses.
• 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.³

Prevention

• HSV is widespread and avoiding contact with often asymptomatic virus shedders is difficult. Barrier protection with condoms is recommended to minimise exposure to genital HSV infection, but may not prevent infection completely.
• Health care workers should always wear gloves when examining the mouth of patients to avoid herpetic whitlow.
• A number of vaccines are under development - particularly for HSV-2 (a good candidate for post-exposure vaccination).⁴

The complete sequence of VZV genome is known, ~125kbp. It infects a variety of human and animal cell types in vitro and gives rise to 2 distinct clinical syndromes in vivo:

• Varicella (Chickenpox):
  • 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.
  • It is highly contagious. Approximately 95% of unimmunised 20-29 year olds and over 99% of those aged over 40 have evidence of previous VZV 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' takes place after many years and leads to infection and tissue damage in the dermatosome served by the infected ganglia.
  • This is most serious when cranial nerves are involved, affecting the face/head. Where the eye is involved, blindness can result.⁵
  • Post-herpetic neuralgia may also occur.
  • Shingles affects about 30% of individuals over a lifetime.

Treatment

Aciclovir or similar antiviral.

Prevention

• Immunosuppressed individuals (or others e.g. neonates, at risk of severe or complicated disease) who have been in contact with infective individuals within the last 3 days should be given zoster immunoglobulin for passive immunity. Antivirals should also be considered for prophylaxis.
• The VZV vaccine was originally developed and licensed as the "chickenpox vaccine" to prevent varicella. It is a live attenuated vaccine that is effective in preventing primary infection with wild-type VZV. It has been part of the childhood immunisation programme in the USA for some time but there are no plans for take up in the NHS at the current time.
• Immunisation with a VZV vaccine appears to be an effective strategy for boosting waning cell-mediated immunity in older adults, reducing the risk of zoster or zoster related complications.⁶ Since May 2006, the FDA in the States has licensed the zoster vaccine for the prevention of herpes zoster in persons older than 60 years.

• Epstein-Barr virus (EBV/HHV-4) is widespread in most human populations - approximately 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 with T cells effectively controlling it.
• In vitro, it is the most potent transforming virus known, and in vivo it infects human B-lymphocytes (generally non-productive infection) and epithelial cells (productive infection). It is linked with several different types of tumour.
• Classic, acute infectious mononucleosis resolves in 2 to 6 weeks, but relapses can occur in the first 6 to 12 months following infection, and it may be linked, in the short term, to a prolonged fatigue syndrome and depression.
• Understanding normal immune control of EBV in the healthy host and increasingly the molecular basis to its involvement in oncogenesis is allowing the development of rational therapies for the management of EBV-related malignancies.

Investigation

Laboratory criteria for the confirmation of acute infectious mononucleosis include:

• Leukocytosis with a moderately raised white cell count.
• >10% atypical lymphocytes on peripheral smear
• Positive serologic test result (e.g. Paul Burnell-heterophile antibody or Monospot assay)

LFTs are also temporarily elevated in the majority of acute EBV infections.

Treatment

• Infectious mononucleosis is a self-limiting illness that does not usually require specific treatment.
• Nonsteroidal anti-inflammatories may be used for symptomatic relief and corticosteroids are sometimes used to treat complicated disease e.g. thrombocytopaenia or significant upper airway obstruction due to enlarged tonsils or lymph nodes, but do not alter the course of the disease.
• The risk of rare complications such as splenic rupture should not be forgotten.

Prevention

Vaccine development, mainly based on preventing primary infection, is underway. One vaccine strategy is to generate neutralizing antibody to the viral envelope glycoprotein (gp-350) that binds to B cells in infection.⁹

Cytomegalovirus is the largest of the Herpesviruses with a 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 but most infections are asymptomatic.
• 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. Typical clinical presentations include pyrexia of unknown origin, pneumonia, hepatitis, encephalitis, myelitis, colitis, uveitis, retinitis, and neuropathy.
  2. Fetal Infections: Particularly a problem when primary infection of the mother occurs, resulting in congenital abnormalities in a proportion of cases. Congenital CMV infection is suggested by clinical findings such as petechiae, jaundice, splenomegaly, microcephaly and small size for gestational age. Sequelae include developmental delay, hearing and visual loss.

Investigation

Traditionally, paired sera show a peak in antibody titre 4-6 weeks following infection. Now antibody tests are sensitive enough to pick up IgM early in infection or reactivation. Other tests include those based on detection of antigens or PCR.
Histology shows intranuclear inclusions, which may be confirmed as CMV using insitu hybridisation or direct or indirect staining using CMV-specific antibodies linked to an indicator system such as fluorescein.

Treatment

Ganciclovir is the most effective treatment agent known against CMV to date. Ganciclovir and other antivirals have also been used for prophylaxis/pre-emptive treatment in those receiving transplants.¹¹

HBLV/HHV-6 was first isolated in 1986 in lymphocytes (CD4 ) of patients with lymphoreticular disorders. Its genome is ~160kbp.

HHV-6 is now recognised as being a universal human infection.
Primary infection in childhood causes a common childhood rash - roseola infantum or "sixth disease":

• A minority of HHV-6 infections in children manifest as roseola, with an abrupt onset of high fever lasting 3-5 days, followed by an erythematous maculopapular rash that appears as temperature subsides.¹³ The rash is initially on the trunk, then spreads centrifugally to the face and limbs.
• The rest of infections either present as acute nonspecific febrile illness or are asymptomatic.
• Complications of childhood infection include febrile convulsions and rarely encephalitis.¹⁴
• Antibody titres are highest in children and decline with age.

Primary infections of adults is rare but tends to have more severe consequences:

• In immunocompetent adults, a mononucleosis-type illness occurs with negative EBV test results.
• Infection/reactivation is a particular problem in immunocompromised patients - for example, in HIV+ patients, it upregulates HIV replication and speeds progression towards AIDS and is also implicated in AIDS dementia complex.
• HHV-6 has been found in tissues, cells and fluid associated with different conditions such as sarcoidosis, epilepsy, Sjogren's syndrome, multiple sclerosis (MS), SLE, Guillain-Barré syndrome and chronic fatigue syndrome, although no causality has been established.

HHV-7 is a recently described T-lymphotropic herpesvirus, first isolated from human CD4 cells in 1990.¹⁵ 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.

HHV-8 rates vary around the world : high in central Africa, low in the United States and Western Europe with intermediate rates in Mediterranean countries.¹⁷HHV-8 is detectable in Kaposi's sarcoma (KS) lesions. KS in its classic or Mediterranean form is typically benign whilst in transplant recipients or AIDS patients, it may be life-threatening. Localised KS lesions often appear as discrete red or blueish patches, these tend to enlarge and elevate into dome-shaped nodules and plaques. The disease may be locally aggressive, and generalised involving visceral organs. HHV-8 has been shown to be necessary but not sufficient for the development of KS.
HHV-8 may also be associated with:

• Body cavity-based lymphomas (BCBLs) of B-cell origin
• Castleman's disease (a rare, non-neoplastic condition where collections of lymph gland tissue develop throughout the body)
• Hyperplastic lymphadenopathy