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Human Herpes virus 8

By Jill D. Henning ** Ph.D and Heather R. Hensler Ph.D *

Human herpesvirus 8 (HHV-8), is the causative agent of Kaposi’s sarcoma and is the most recently discovered human herpesvirus. This article discusses the virus pathway and implications of disease.

  1. Introduction
  2. HHV-8-associated Cancers
  3. Genome, structure and viral replication
  4. Viral proteins of interest
  5. Summary
  6. References

1.   Introduction

Human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus (KSHV), is the causative agent of Kaposi’s sarcoma (KS), as well as the rarer primary effusion lymphoma (PEL) and a subset of Multicentric Castleman’s disease (MCD)44,45. HHV-8 is the most recently discovered human herpesvirus and was first identified in AIDS-KS tissue in 199415. It is a member of the lymphotrophic (gamma) herpesviruses, specifically, a gamma-2 herpesvirus or rhadinovirus44. HHV-8 has been found in B cells, endothelial cells, CD34+, and monocytic cells in vivo 7,8,28,58. DC-SIGN has been shown to serve as an entry receptor in B cells, macrophages and dendritic cells55,56, xCT plays a role in viral fusion 30, and integrins a3ß1 and avß3 act as post-binding entry factors 2,26. Transmission of HHV-8 can occur through sexual contact33,41, as well as, non-sexual routes 3,6,52. Seroprevalence in the United States in the general population is between 5-10%1, but is higher in select groups, such as homosexual men1,4,25,41,49,57, or other geographic regions such as the Mediterranean, South America and Africa12,13,16,17,21,35,43,63,65.

2.   HHV-8-associated cancers

Kaposi’s sarcoma (KS) was first described by as a disease of elderly men late in the 19th century in Europe31. Kaposi’s sarcoma is characterized by the classic spindle cell shape (Figure 1), neo-angiogenesis, inflammation, and edema 60,68.  Four types of Kaposi’s sarcoma have been described: classic, endemic, iatrogenic, and epidemic67. Classic KS is also referred to as European, sporadic, or chronic KS, and affects primarily elderly men of Mediterranean decent67. Endemic KS is mainly seen in Africa and is divided into two subtypes: the first seen in adults, ages 25-50 localized primarily to sub-Saharan Africa, and the second seen in young children under the age of 10, primarily of Bantu decent45. Iatrogenic KS, or post-transplant KS, arises in the context of therapeutic immunosupression53. Epidemic KS, also known as AIDS-associated KS, is a more aggressive tumor than classic KS and can disseminate into the viscera with a greater likelihood of death62. 

Karposi sarcoma lession

Karposi sarcoma lession Nov 08
Legend - This is a Hematoxylin & Eosin (H & E) staining of a KS lesion. The picture was taken at 400x.  The uniform small spindle cells adjacent to the vessel wall are denoted by an arrow.

Primary effusion lymphoma (PEL) was first identified as a subset of body-cavity-based lymphomas and has been shown to contain HHV-8 DNA sequences14. PEL is a rare lymphoma which accounts for only 4.0% of all AIDS malignancies in AIDS patients in the USA and occurs even more rarely post-transplant or in patients with no other obvious risk factors11. While HHV-8 is always associated with PELs, Epstein-Barr virus co-infection is variable20. PELs characteristically lack a solid component and morphologically show immunoblastic and anaplastic, large-cell lymphomas with some plasma cell differentiation10.

HHV-8 is also linked to another B cell lymphoproliferative disorder called Multicentric Castleman’s Disease (MCD), which is described as generalized lymphadenopathy with polyclonal hyperimmunoglobulinemia and high levels of serum IL-664,73. MCD presents as B-cells with large size and large vesicular nucleus with one or two prominent nucleoli19.  It occurs in two forms (a vascular hyline variant and a plasma cell variant), though HHV-8 is only associated with the plasma cell variant50.

3.   Genome, structure and viral replication

The HHV-8 genome is  double–stranded linear DNA of 165 to 170 kilobases (kb)44,59. The genome contains a central unique region of 145 kb, which includes all of the viral open reading frames, flanked by a series of highly GC-rich direct terminal repeats59.  HHV-8 has four major subtypes: A and C are present in the USA, Asia, Europe, and Middle East,  B is found in sub-Saharan Africa, and D is found in South Asia, Australia, and the Pacific Islands75. Like other herpesviruses, HHV-8 virions are composed of an electron dense nucleocapsid composed of major (ORF25) and minor capsid (ORF 62, ORF26, ORF65) subunits, surrounded by a protein-dense tegument, and a lipid bilayer envelope44,74.   

As is characteristic of herpesviruses, HHV-8 can establish either a latent, non-replicating, or a lytic, actively replicating infection.  During latency, the viral genome is maintained as a circular episome tethered to the cellular chromosome, and its replication is coupled to cellular replication. No infectious virus is produced during latency, but there is a clonal expansion of the infected population due to viral episomal replication being coupled to cellular replication71. Only five HHV-8 genes have been shown to be associated with latency:  LANA-1 (Latency-associated nuclear antigen-1, ORF 73), viral cyclin D (ORF72), kaposin (ORF K12), vIRF-2 (viral Interferon Regulatory Factor-2, LANA-2, ORFK11.1) and vFLIP (ORF K13)9,18,32,34,46,54. LANA-1 appears to function in tethering the viral episome to the host chromatin, maintenance of latency, regulation of host cellular pathways, cellular transcriptional repression by of binding MLF1 interacting protein, and immune evasion51,70. vCyclin is a viral homologue of the cellular cyclin-D protein, and functions as a surrogate in cellular cyclin cascades for cell cycle regulation36. Kaposin is thought to function in transformation46 and has recently been shown to have a role in the stabilization of cellular cytokine mRNAs42. vIRF-2, also known as LANA-2, functions to regulate early immuno-responsive genes via suppression of interferon induced PKR9,23. Lastly, vFLIP, is a viral FLICE (FAS-associated death-domain-like IL-1beta-converting enzyme) inhibitory protein which acts to inhibit apoptosis through activation of IKB kinase37.        

Latently infected cells have the potential to shift to lytic replication once the replication transactivator (Rta, ORF50) is activated24. Rta induces a multitude of viral genes and various studies have shown that expression of Rta alone is sufficient for reactivation of latently infected cell lines27,39,40. Various studies have investigated the genes involved in phorbol ester-induced reactivation of primary effusion lymphoma (PEL) lines, giving a preliminary outline to alpha, beta and gamma-designated genes29,34,38, however it has yet to be determined whether this outline will match up with the gene cascade of natural infection.                       

4.   Viral proteins of interest

In addition to genes required for the formation of virions and the process of infection and egress, HHV-8 contains many genes used in subversion of cellular processes, many of which are homologues to cellular genes. Several genes act in cell cycle regulation and anti-apoptosis, such as the previously mentioned, vFLIP, vCyclin, and LANA-1. Additionally, the K1 gene product blocks Fas-mediated apoptosis72, ORF16 encodes a viral Bcl-2 homologue61, ORFK7 encodes a  viral inhibitor of apoptosis protein (vIAP)71, and ORF74 encodes a vGPCR capable of constitutive signaling with anti-apoptotic effects5. HHV-8 also encodes a variety of genes involved in immune evasion, such as the vIL-6 homologue (ORFK2)48, the viral Macrophage Inflammatory Proteins (vMIPs, ORFK4, K4.1 and K6)47,66, the viral Interferon Regulatory Factors (vIRFs, ORFK9, K10.5/6, K11.1), and the K3 and K5 (MIR-1 and MIR-2) gene products which act in degradation of immune-related surface molecules22,69.

5.   Summary           

The oncogenic potential of HHV-8 makes it an important public health issue and an attractive target for therapy design. As HHV-8 is the most recently discovered human herpesvirus, many aspects of this virus remain unstudied or poorly understood. Additional studies are needed to completely characterize the mechanisms of HHV-8 transformation and latency to assist in design of treatment therapies. Furthermore, investigation into the viral strategies for immune evasion may lead not only to treatment options, but also assist in designs of new immunosuppressive drugs.  Finally, as new methods for in vitro infection that more closely mimic in vivo infection have recently become available55, studies on entry and cellular responses to infection may be performed.  Furthermore, reagents for HHV-8 research are becoming more readily available, poising the field for major discoveries in the near future.

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** UPCI, Bovbjerg Lab, University of Pittsburg, USA * Longnecker lab, Northwestern University, USA

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