Human Herpesvirus 8

Human herpesvirus 8, also known as Kaposi sarcoma–associated herpesvirus, is a double-stranded DNA virus belonging to the Herpesviridae family. This uncommon oncogenic virus causes Kaposi sarcoma (an AIDS-defining condition), primary effusion lymphomas, and multicentric Castleman disease mainly in immunocompromised patients. The process occurs through the induction of cellular growth activity and the inhibition of apoptosis in infected cells.

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Classification

DNA virus classification flowchart

Identification of DNA viruses:
Viruses can be classified in many ways. Most viruses, however, will have a genome formed by either DNA or RNA. Viruses with a DNA genome can be further characterized as single or double stranded. “Enveloped” viruses are covered by a thin coat of cell membrane, which is usually taken from the host cell. If the coat is absent, however, the viruses are called “naked” viruses. Some enveloped viruses translate DNA into RNA before incorporating into the genome of the host cell.

Image by Lecturio. License: CC BY-NC-SA 4.0

General Characteristics and Epidemiology

General features of human herpesvirus 8 (HHV-8)

  • Also known as Kaposi sarcoma–associated herpesvirus
  • Taxonomy:
    • Family: Herpesviridae
    • Subfamily: Gammaherpesvirinae
    • Genus: Rhadinovirus
  • DNA virus:
    • Double-stranded
    • Linear
  • Structure: 
    • DNA core
    • Icosahedral nucleocapsid 
    • Tegument
    • Lipid envelope with glycoprotein spikes

Associated diseases

  • Kaposi sarcoma (vascular malignancy)
  • Multicentric Castleman disease (B-cell lymphoproliferative disease)
  • Primary effusion lymphomas (a non-Hodgkin lymphoma)

Epidemiology

  • Global prevalence: 2%–10%
  • More common in:
    • Mediterranean region
    • Sub-Saharan Africa (endemic)
  • Men > women, particularly men who have sex with men

Pathogenesis

Reservoir

Humans are the only known reservoir.

Transmission

It is not entirely clear how the virus is transmitted.

  • Appears to mainly be through:
    • Saliva
    • Sexual contact
  • Transmission through blood and solid organ transplantation has been documented.

Host risk factors

Human herpesvirus 8 infection is usually asymptomatic. Clinical manifestations can occur in immunocompromised patients:

  • HIV/AIDS (Kaposi sarcoma is an AIDS-defining condition)
  • Transplant patients

Viral replication cycle

  • Process:
    • Virus attaches to host cells with surface glycoproteins → entry
    • Can either lead to:
      • Latency → produce proteins that promote oncogenesis
      • Lytic replication
  • Infects: 
    • Epithelial cells
    • Endothelial cells
    • Lymphocytes
  • Latency occurs in: 
    • B lymphocytes
    • Vascular endothelial cells

Pathophysiology

  • Virus is transmitted through saliva → replicates in epithelial cells in the oropharynx
  • Leads to infection of B cells and endothelial cells → viral latency may occur
  • Infection is kept in check by the immune system.
  • If the patient becomes immunocompromised → reactivation of latent virus → more cells are infected
  • Viral proteins interact with cellular pathways, including:
    • ↑ Cellular growth factor activity → proliferation
    • Inhibition of tumor suppression genes → prevents apoptosis
  • This can lead to:
    • Angiogenesis
    • Oncogenesis

Diseases Caused by HHV-8

Table: Diseases caused by HHV-8
DiseaseClinical presentationDiagnosisManagement
Kaposi sarcomaMalignant vascular lesions of the:
  • Skin
  • Mucosa
  • GI tract
  • Respiratory tract
Biopsy of lesions
  • Optimize antiretroviral therapy
  • Intralesional or systemic chemotherapy
Multicentric Castleman disease
  • Fever
  • Generalized lymphadenopathy
  • Hepatosplenomegaly
  • Lymph node biopsy
  • Immunohistochemical staining
  • PCR for viral DNA
  • Optimize antiretroviral therapy
  • Chemotherapy
  • Immunologic agents
Primary effusion lymphomasManifestations depend on the site of fluid accumulation:
  • Pleural effusion
  • Pericardial effusion
  • Ascites
  • Joint effusion
  • Effusion analysis for malignant cells
  • Immunohistochemical staining
  • Optimize antiretroviral therapy
  • Chemotherapy
Kaposi sarcoma Human herpesvirus 8

Cutaneous lesions of Kaposi sarcoma

Image: “Kaposi’s sarcoma” by OpenStax College. License: CC BY 3.0

Comparison of Herpesviruses

The following table compares the 9 herpesviruses considered endemic in humans; there are 115 different known species of herpesviruses, grouped into 3 families: 

  • Alpha (infect epithelial cells and produce latent infection in postmitotic neurons)
  • Beta (infect and produce latent infection in a variety of cell types)
  • Gamma (produce latent infection, mainly in lymphoid cells)
Table: Comparison of the 9 herpesviruses considered endemic in humans
HHVCommon namePrimary target cellsLatency siteClinical presentation*
1
(alpha group)
HSV-1 Mucoepithelial cells Dorsal root ganglia
  • Gingivostomatitis
  • Keratitis
  • Herpetic whitlow
  • Encephalitis
  • Hepatitis
  • Esophagitis
  • Pneumonitis
2
(alpha group)
HSV-2
  • Genital herpes
  • Meningitis
  • Proctitis
3
(alpha group)
VZV
  • Chickenpox
  • Herpes zoster
4
(gamma group)
EBV
  • Epithelial cells
  • B cells
Memory B cells
  • Infectious mononucleosis
  • Hodgkin lymphoma
  • Burkitt lymphoma
  • Oral hairy leukoplakia
  • EBV-associated gastric cancer
5
(beta group)
CMV
  • Monocytes
  • Lymphocytes
  • Epithelial cells
Hematopoietic progenitor cells in bone marrow
  • CMV mononucleosis
  • CMV retinitis
  • CMV colitis
  • CMV encephalitis
6A, 6B
(beta group)
HHV-6 T cells Monocytes Roseola
7
(beta group)
HHV-7 T cells
8
(gamma group)
Kaposi sarcoma–associated herpesvirus
  • Lymphocytes
  • Epithelial cells
B cellsKaposi sarcoma
* Bold in “clinical presentation” column denotes an AIDS-defining illness.

References

  1. Mui UN, Haley CT, Tyring SK. (2017). Viral oncology: molecular biology and pathogenesis. J Clin Med 6(12). https://pubmed.ncbi.nlm.nih.gov/29186062/
  2. Cesarman E, Damania B, Krown SE, Martin J, Bower M, Whitby D. (2019). Kaposi sarcoma. Nat Rev Dis Primers 5(1):9. https://pubmed.ncbi.nlm.nih.gov/30705286/
  3. Yan L, Majerciak V, Zheng ZM, Lan K. (2019). Towards better understanding of KSHV life cycle: from transcription and posttranscriptional regulations to pathogenesis. Virol Sin; 34(2):135-161. https://pubmed.ncbi.nlm.nih.gov/31025296/
  4. Dittmer DP, Damania B. (2016). Kaposi sarcoma-associated herpesvirus: immunobiology, oncogenesis, and therapy. J Clin Invest 126:3165–3175. https://pubmed.ncbi.nlm.nih.gov/27584730/
  5. Jha HC, Banerjee S, Robertson ES. (2016). The role of gammaherpesviruses in cancer pathogenesis. Pathogens 5(1). https://pubmed.ncbi.nlm.nih.gov/26861404/
  6. Damania B, Münz C. (2019). Immunodeficiencies that predispose to pathologies by human oncogenic γ-herpesviruses. FEMS Microbiol Rev 43:181–192. https://pubmed.ncbi.nlm.nih.gov/30649299/
  7. Purushothaman P, Uppal T, Sarkar R, Verma SC. (2016). KSHV-mediated angiogenesis in tumor progression. Viruses 8(7). https://pubmed.ncbi.nlm.nih.gov/27447661/
  8. Wen KW, Damania B. (2010). Kaposi sarcoma-associated herpesvirus (KSHV): molecular biology and oncogenesis. Cancer Lett 289(2):140-50. https://pubmed.ncbi.nlm.nih.gov/19651473/
  9. Gonçalves PH, Uldrick TS, Yarchoan R. (2017). HIV-associated Kaposi sarcoma and related diseases. AIDS 31:1903–1916. https://pubmed.ncbi.nlm.nih.gov/28609402/
  10. Schneider JW, Dittmer DP. (2017). Diagnosis and treatment of Kaposi sarcoma. Am J Clin Dermatol 18:529–539. https://pubmed.ncbi.nlm.nih.gov/28324233/
  11. Centers for Disease Control and Prevention. (1981). Follow-up on Kaposi’s sarcoma and pneumocystis pneumonia. MMWR 30:409–410.
  12. Rewane A, Tadi P. (2021). Herpes virus type 8. StatPearls. Retrieved June 24, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK556023/
  13. Casper C. (2020). Disease associations of human herpesvirus 8 infection. In Bloom A (Ed.), UpToDate. Retrieved June 24, 2021, from https://www.uptodate.com/contents/disease-associations-of-human-herpesvirus-8-infection
  14. Casper C. (2020). Virology, epidemiology, and transmission of human herpesvirus 8 infection. In Bloom A (Ed.), UpToDate. Retrieved June 24, 2021, from https://www.uptodate.com/contents/virology-epidemiology-and-transmission-of-human-herpesvirus-8-infection

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