Human herpes virus-8 (HHV-8)

Human Herpes Virus 8 (HHV8) HHV8 user information sheet - Version: 1.0. Index: S - 1568. Printed: 11-Feb-2019 15:48 Human Herpesvirus-8 (HHV-8) is one of the few currently recognised cancer-causing viruses (oncoviruses) in humans. It is still often referred to as Kaposi’s sarcomaassociated herpesvirus (KSHV) since it was originally identified in Kaposi’s Sarcoma (KS) lesions from AIDS patients1. Structure and genome HHV-8 is a virus belonging to the Herpesviridae family, of the Gammaherpesvirinae subfamily and of the Rhadinovirus genus. The 9 herpesviruses infecting humans are classified into 3 subfamilies based on their biological properties and tropism. The alpha subfamily are neurotropic viruses and include herpes simplex viruses (HSV) 1 and 2 (also referred to as HHV-1 and -2), and Varicella zoster virus (VZV or HHV-3). Viruses belonging to the beta family may infect a wider range of tissues and cell types and include human cytomegalovirus (CMV or HHV-5), HHV-6A, HHV-6B and HHV-7. HHV8 and the Epstein Barr Virus (EBV or HHV-4) belong to the gamma subfamily of herpesviruses, based on their tropism for lymphocytes. Like other herpesviruses, HHV-8 has a highly organized icosahedral-shape nucleocapsid containing the linear, double-stranded DNA genome. The nucleocapsid is enclosed in a protein layer (the tegument), itself surrounded by a lipid bilayer containing the glycoproteins necessary for viral attachment and entry into cells. The virion size is 120 nm in diameter, with a genome size of approximately 165kb, encoding about 90 genes. In addition to the conserved herpsevirus genes necessary for its infection and replication functions, HHV-8 is unique amongst herpesviruses in that it possesses a variety of additional genes “pirated” from host cells, such as a DNA polymerase, interleukin-6 (IL-6), BCL-2, a G-protein coupled receptor, complement-binding proteins, thymidine kinase. Pathophysiology HHV-8 has been shown to target mainly human B cells2 as well as monocytes3, endothelial/spindle4 cells and keratinocytes5. Following infection, HHV-8 is endocytosed by macropinocytosis and may remain in a latent state6 where only the HHV8 user information sheet - Version: 1.0. Index: S - 1568. Printed: 11-Feb-2019 15:48 Authorised on: 11-Feb-2019. Authorised by: Nagela Ford. Document . Due for review on: 10-Feb-2020 Author(s): Ronan Calvez Page 1 of 5 viral latency-associated nuclear antigen (LANA) is expressed. LANA suppresses the viral genes required for viral production and assembly, thereby sustaining latency. In this state, the virus remains as a naked piece of circular DNA (episome) within the infected cells. LANA has also been shown to interact with various cellular proteins. Of particular interest is its ability to bind to and inhibit two key cellular tumoursuppressing proteins, p537, 8 and Rb9. Infected cells thereby become protected from apoptosis and may more readily undergo uncontrolled proliferation under certain conditions (eg. immunodeficiency and immunosuppression). HHV8 user information sheet - Version: 1.0. Index: S - 1568. Printed: 11-Feb-2019 15:48 Epidemiology HHV-8 infection and seroprevalence are limited in the general population (from 0-5% in Northern Europe to up to 80% in Central and Eastern Africa). Since most HHV8infected individuals are asymptomatic, the mechanisms of transmission still remain poorly understood. HHV-8 has been found in saliva, nasal secretion and seminal fluid10, 11. The main routes of transmission identified to date are from mother to foetus (through saliva) in endemic population (Africa), and through sexual contacts within the homosexual population in the USA and Europe. Infection (or reactivation) is of particular concern to the immunosuppressed and immunocompromised. Cancer patients receiving chemotherapy, AIDS patients and organ transplant patients are therefore all at a high risk of showing signs of infection. HHV-8 in disease HHV-8 is now accepted as the causative agent in: • all forms of Kaposi’s sarcoma (KS), either AIDS-associated or non AIDSassociated12. KS is a multicentric angioproliferative disorder of endothelial origin which varies in terms of types of lesions, clinical aggressiveness, site of presentation and treatment. HHV-8 is detected in 100% of KS lesions and in 5070% of the peripheral lymphocytes of the same patients. • body cavity lymphoma or primary effusion lymphoma (PEL)13, 14, 15, 16. PEL is a nonHodgkin B-cell lymphoma affecting various body cavities (pleural space, pericardium, peritoneum) and is almost always associated with HIV. HHV-8 genome is always found in the effusion fluid, frequently in association with EBV (70%). • some forms of Castleman’s disease (CD)16. CD is a rare lymphoproliferative (Bcell) disorder resulting from an hypersecretion of IL-6 either of endogenous or viral (HHV-8) origin. CD may affect one (unicentric) or multiple (multicentric) lymph node(s). In unicentric CD, there are usually little or no symptoms and removal of the affected lymph node is usually curative. 50 % of the cases of multicentric CD (MCD) are caused by HHV-8, and where MCD is associated with HIV, HHV-8 is found in 100% of the cases. The other non-HIV-related MCD are of unknown origin. The main complication resulting from MCD is the development HHV8 user information sheet - Version: 1.0. Index: S - 1568. Printed: 11-Feb-2019 15:48 Authorised on: 11-Feb-2019. Authorised by: Nagela Ford. Document . Due for review on: 10-Feb-2020 Author(s): Ronan Calvez Page 2 of 5 of non-Hodgkin’s lymphoma and autoimmune haemolytic anaemia as a result of the proliferating B-cells. In addition, HHV-8 has also been detected but not causally linked to Bowen’s disease, a malignant squamous cell carcinoma, in HIV-negative patients17. In addition, HHV-8 has also been shown to be able to invade and persist in the central nervous system, where it may be linked to some forms of encephalitis, meningitis18, and primary CNS lymphoma19. Although the role of HHV-8 in neuropathology has not been ascertained, early detection of HHV-8 in the CSF might prove helpful for clinical differential diagnosis. HHV8 user information sheet - Version: 1.0. Index: S - 1568. Printed: 11-Feb-2019 15:48 Treatment There is no treatment of HHV-8 infection since primary infection is usually asymptomatic. Once KS has been diagnosed, a local treatment may be applied such as surgical removal of the lesion, radiotherapy or local chemotherapy. Although treatment of HIV-infected individuals with highly active antiretroviral therapy (HAART) has significantly reduced the incidence of KS amongst AIDS patients, efficient and tolerable therapies for MCD and PEL are still lacking. Clinical diagnostics Since HHV-8 cannot be readily cultivated from infected material, primary diagnosis of HHV-8-associated diseases is usually based on cytological examination of biopsies: skin, lung of intestine lesions for KS, effusion fluids for PEL or lymph nodes for CD. This may be associated with immnunofluorescence staining for LANA-1, which will confirm the latent infection by HHV-8. Detection of anti-HHV-8 IgGs have also been described as a means of confirming infection20. HHV-8 viral DNA may also be detected by PCR either from biopsies or from peripheral blood lymphocytes. HHV-8 being predominantly intracellular, it is however rarely detected in plasma, except in immunosuppressed HIV individuals. Various studies have shown that 0-10% of HHV-8-infected individuals without KS and 0-52% of HHV8-infected individuals with KS will present a viraemia at any given time21, 22. In other studies the presence of HHV-8 in the blood predicted the risks of KS development23 and the amount of HHV-8 in PBMCs, not plasma, correlated with clinical staging of KS24. Quantitation of HHV-8 viral load in the blood is therefore a useful mean of assessing response to therapy or survival25. HHV-8 detection may also be of clinical relevance in organ donor screening and monitoring transplant patients with KS resulting either from HHV-8 reactivation or primary infection from the donor26. At Micropathology Ltd, we use a quantitative nested PCR approach, targeting the ORF-26 (minor capsid protein) gene of HHV-8. Although, no international standard is currently available for HHV-8, the quantitation standard used in our assay was calibrated against a CE-IVD control for HHV-8 DNA (#MBC128 from VirCell) and we HHV8 user information sheet - Version: 1.0. Index: S - 1568. Printed: 11-Feb-2019 15:48 Authorised on: 11-Feb-2019. Authorised by: Nagela Ford. Document . Due for review on: 10-Feb-2020 Author(s): Ronan Calvez Page 3 of 5 perform a routine surveillance of public databases to ensure optimal assay performance against newly published and relevant variants. For additional information regarding the HHV8 assay, please contact Dr Ronan Calvez, [email protected]. HHV8 user information sheet - Version: 1.0. Index: S - 1568. Printed: 11-Feb-2019 15:48 References 1. Chang Y. et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 265:1865-1869, 1994. 2. Bechtel J. T., Liang Y., Hvidding J., Ganem D. Host range of kaposi’s sarcoma associated herpesvirus in cultered cells. J. Virol., 77: 6474-6481, 2003. 3. Blasig C, Zietz C, Haar B, Neipel F, Esser S, Brockmeyer NH, Tschachler E, Colombini S, Ensoli B, Stürzl M. Monocytes in Kaposi's sarcoma lesions are productively infected by human herpesvirus 8. J Virol. 71(10):7963-8. 1997. 4. Ensoli B, Sgadari C, Barillari G, Sirianni MC, Stürzl M, Monini P. Biology of Kaposi's sarcoma. Eur J Cancer. 37(10):1251-69, 2001. 5. Cerimele F., Curreli F., Ely E., Friedman-Kien A. E., Cesarman E., Flore O. Kaposi’s sarcoma associated herpesvirus can productively infect primary human keratinocytes and alter their growth properties. J. Virol., 75: 2435-2443, 2001. 6. Antman K, Chang Y. Kaposi's sarcoma. New Engl J Med. 342: 1027–1038, 2000. 7. Friborg J et al. p53 inhibition by the LANA protein of KSHV protects against cell death. Nature 402:889-894, 1999. 8. Chen W. et al. Distinct p53, p53:LANA, and LANA Complexes in Kaposi's SarcomaAssociated Herpesvirus Lymphomas. J. Virol. 84:3898-3908. 2010. 9. Garber AC et al. J Virol. DNA binding and modulation of gene expression by the latencyassociated nuclear antigen of Kaposi's sarcoma-associated herpesvirus. 75(17):788292, 2001. 10. Dukers NH et al. Risk factors for human herpesvirus 8 seropositivity and seroconversion in a cohort of homosexual men. Am J Epidemiol. 151(3):213-24, 2000. 11. Lin JC. et al. Is Kaposi's-sarcoma-associated herpesvirus detectable in semen of HIV-infected homosexual men? Lancet 346:1601-1602, 1996. 12. Hengge UR, Ruzicka T, Tyring SK, Stuschke M, Roggendorf M, Schwartz RA, Seeber S. Update on Kaposi's sarcoma and other HHV8 associated diseases. Part 2: pathogenesis, Castleman's disease, and pleural effusion lymphoma. Lancet Infect Dis. 2(6):344-52. 2002. 13. Chang Y. et al. Kaposi's Sarcoma (KS)-associated herpesvirus and its role in KS. Inf. Agents & Dis. 5:215-222, 1996. 14. Luppi M. et al., The new lymphotropic herpesviruses (HHV-6, HHV-7, HHV-8) and hepatitis C virus (HCV) in human lymphoproliferative diseases: an overview. Haematologica 81:265-281, 1996. 15. Levy JA, Three new human herpesviruses (HHV6, 7, and 8). Lancet 349:558-563, 1997. 16. Edelman DC, Human herpesvirus 8--a novel human pathogen. Virol. J. 2:78-123, 2005. 17. Inagi R. et al. Kaposi's sarcoma-associated herpesvirus (KSHV) sequences in premalignant and malignant skin tumors. Arch. Virology 141:2217-2223, 1997. 18. Chan PK, Ng HK, Cheung JL, Cheng AF. Survey for the presence and distribution of human herpesvirus 8 in healthy brain. J Clin Microbiol. 38(7):2772-3. 2000. 19. Volpi A. Epstein-Barr virus and human herpesvirus type 8 infections of the central nervous system. Herpes. Suppl 2:120A-127A. 2004. 20. Juhász A, Kónya J, Beck Z, Remenyik E, Veress G, Bégány A, Medgyessy I, Hunyadi J, Gergely L. HHV-8 ELISA based on a one-step affinity capture of biotinylated K8.1 antigen. J Virol Methods. 94(1-2):163-72. 2001. HHV8 user information sheet - Version: 1.0. Index: S - 1568. Printed: 11-Feb-2019 15:48 Authorised on: 11-Feb-2019. Authorised by: Nagela Ford. Document . Due for review on: 10-Feb-2020 Author(s): Ronan Calvez Page 4 of 5 HHV8 user information sheet - Version: 1.0. Index: S - 1568. Printed: 11-Feb-2019 15:48 21. Whitby D, Howard MR, Tenant-Flowers M, Brink NS, Copas A, Boshoff C, Hatzioannou T, Suggett FE, Aldam DM, Denton AS. Detection of Kaposi sarcoma associated herpesvirus in peripheral blood of HIV-infected individuals and progression to Kaposi's sarcoma. Lancet. 346(8978):799-802. 1995. 22. Lorenzen T, Albrecht D, Paech V, Meyer T, Hoffmann C, Stoehr A, Degen O, Stellbrink HJ, Meigel WN, Arndt R, Plettenberg A. HHV-8 DNA in blood and the development of HIVassociated Kaposi's sarcoma in the era of HAART--a prospective evaluation. Eur J Med Res. 7(6):283-6. 2002. 23. Engels EA, Biggar RJ, Marshall VA, Walters MA, Gamache CJ, Whitby D, Goedert JJ. Detection and quantification of Kaposi's sarcoma-associated herpesvirus to predict AIDSassociated Kaposi's sarcoma. AIDS. 17(12):1847-51. 2003. 24. Campbell TB, Borok M, Gwanzura , MaWhinney S, White IE, Ndemera B, Gudza I, Fitzpatrick L, Schooley RT. Relationship of human herpesvirus 8 peripheral blood virus load and Kaposi's sarcoma clinical stage. AIDS. 14(14):2109-16. 2000. 25. Tedeschi R, Dillner J, De Paoli P. Laboratory diagnosis of human herpesvirus 8 infection in humans. Eur J Clin Microbiol Infect Dis. 21:831-844. 2002. 26. Luppi M., Barozzi P., Schulz T. F., Trovato R., Donelli A., Narni F., Sheldon J., Marasca R., Torelli G. Molecular evidence of organ-related transmission of Kaposi’s sarcoma-associated herpesvirus or human herpesvirus-8 in transplant patients. Blood, 96: 3279-3281, 2000. HHV8 user information sheet - Version: 1.0. Index: S - 1568. Printed: 11-Feb-2019 15:48 Authorised on: 11-Feb-2019. Authorised by: Nagela Ford. Document . Due for review on: 10-Feb-2020 Author(s): Ronan Calvez Page 5 of 5