HHV-4

Human pathogenic, enveloped, double-stranded DNA virus of the Herpesviridae family (HHV-4) and causative agent of infectious mononucleosis. HHV-4 plays an important role in the development of malignant tumours, for example in various lymphoproliferative diseases such as Burkitt's lymphoma, a tumour endemic in Equatorial Africa, transplantation-associated B-cell lymphomas and nasopharyngeal carcinoma, which occurs in southern China with an incidence of 98/1200,000 inhabitants.

Mode of transmission: Like all herpes viruses, HHV 4 is ubiquitously distributed and infects humans persistently. It is excreted in saliva and is also transmitted. The main mode of transmission is droplet infection, which is why the mononucleosis occurring with the primary infection has been given the name "kissing disease".

In industrialized countries, the infection reaches about 40% by the age of 15, and then rises steeply with puberty to 80-90% in adulthood. In the developing countries, due to the lower hygiene standards, the infestation is practically 100 % already among the under 3-year-olds. Iatrogenic transmission in transplants has been reported. Especially HHV-4-seronegative recipients are at risk (Schnitzler P et al. 2020).

Target cell - B lymphocytes: After entering the oral cavity, the virus initially infects undifferentiated cells of the pharynx and tongue margin. Here it is also passed on to tissue infiltrating B-lymphocytes, which are immortalized immediately after infection. Apparently, these indefinitely growing B lymphocytes provide an excellent target for virus-specific host cytotoxic T lymphocytes (CTL), so that in immunocompetent individuals the vast majority of EBV-infected lymphocytes are eliminated.

Latency of the virus: Apparently, however, in a few cells the virus succeeds in establishing a latent state. Such cells are apparently not eliminated by CTL. They constitute the reservoir for reactivation and re-infection of epithelial cells.

Abrogation of latency: If such latently infected B lymphocytes in lymphoid tissues are exposed to stimulatory signals by T lymphocytes, the latency of the virus can initially be partially abrogated by amplifying the episomal DNA genome. Depending on further signaling (cytokines, interaction with T cell ligands), this may lead to a lyticproductive replication cycle and/or back into latency in resting memory cells .

EBV-induced immunosuppression: In EBV infection, immunosuppression occurs so that, for example, antibody titers to infectious agents drop. Heterophilic antibodies are also produced, e.g. against mutton erythrocytes, which are used in the Paul Bunnell test (Schnitzler P et al. 2020).

The virus is the causative agent of infectious mononucleosis (glandular fever) and other EBV-associated diseases:

Infectious mononucleosis: In adolescents or in adult infected individuals, the onset of infectious mononucleosis occurs in 30-60% of all cases.

Virus-drug interactions: in about 1/3 (Chovel-Sella et al. 2013, studies in 173 children) of all children treated with aminopenicillins for acute tonsillitis, but who actually have infectious mononucleosis, a rump-accentuated small-spot exanthema occurs. The cause is unclear (EBV-induced polyclonal B-cell activation?). After resolution of the infection, aminopenicillins are largely tolerated again.
In older age, 95% of people are infected with EBV. Even after infectious mononucleosis has cleared, Epstein-Barr virus remains in the body. Like all herpes viruses, it can reactivate (see also organ transplants, skin lesions).

EBV-associated malignancies:

• As a rare complication: EBV-associated Burkitt's lymphoma.
• EBV-associated B-cell lymphoma in AIDS patients.
• Post-transplant lymphoproliferative disorder (PTLD).
• Patients with a history of infectious mononucleosis have a threefold increased risk of developing Hodgkin's disease.
• In the Asian region, EBV infection is considered a risk factor for tumors of the nose or larynx (EBV-associated nasopharyngeal carcinoma-NPC). Incidence in the population of southern China: 98/100,000 population.
• EBV also seems to play a role in breast carcinoma and leiomyosarcoma(Aida N et al. 2019).

Furthermore, EB viruses act as cofactors in:

• the rare X-linked recessively inherited lymphoproliferative syndromes(Purtilo syndrome/ Duncan syndrome).
• oral hairy leukoplakia
• EBV-associated Burkitt's lymphoma
• see below EBV virus infections

Clinic, Serology!

VCA (Virus Capsid Antigen): Formation of antibodies in the early phase of the disease. IgM-antibodies: detectable for 4-12 weeks; IgG-antibodies: detectable for life

EA ("early antigen"): Already a few days after infection antibodies can be detected, but 10-20 % of all patients do not produce antibodies against EA. Antibodies against EA are no longer detectable about 12 months after infection.

EBNA (Epstein-Barr nuclear antigen): late formation of IgG antibodies approx. 6-8 weeks after infection, then lifelong persistence

1. Aida N et al (2019) A Case of Epstein-Barr Virus-Associated Leiomyosarcoma Concurrently With Posttransplant Lymphoproliferative Disorders After Renal Transplantation. Clin Med Insights Case Rep 12:1179547619867330.
2. Chovel-Sella A et al (2013) Incidence of rash after amoxicillin treatment in children with infectious mononucleosis.Pediatrics 131:e1424-1427.
3. Epstein MA (1964) Viral particles in cultured lymphoblasts from Burkitt's lymphoma. Lancet 1: 702-703
4. Hof H et al (2019): Special virology. In: Hof H, Schlüter D, Dörries R, eds Duale Reihe Medizinische Mikrobiologie. 7th, completely revised and expanded edition. Stuttgart: Thieme S 259
5. Schnitzler P et al (2020) Virology. In: Hof H et al. (eds) Medical Microbiology Thieme Verlag pp 256-260.
6. Trappe, R et al. (2006) Pathogenic, Clinical, Diagnostic and Therapeutic Aspects of Posttransplantation Lymphoproliferative Disorders. Dtsch Arztebl 103: A-3259 / B-2836 / C-2718