MicrobiologyBytes: Virology: HHV-8 Updated: March 4, 2009 Search

Human Herpesvirus 8 (HHV-8/KSHV)

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KSHV

Sequences of an unique herpesvirus were identified in 100% of amplifiable samples from AIDS patients with Kaposi's sarcoma (KS) and 15% of non-KS tissue samples from AIDS patients. In addition to KS, HHV-8 may also cause other tumours such as primary effusion lymohoma (PEL) and multicentric Castleman's disease (MCD). Although there is no truly permissive tissue culture system for HHV-8, the virus can be maintained in cell lines derived from BCBLs and induced into lytic replication using phorbol esters or sodium butyrate.

The complete HHV-8 genome sequence shows that it has sequence similarities to other gammaherpesviruses including, herpesvirus saimiri (HVS), murine gammaherpesvirus 68 (MHV68) and Epstein-Barr Virus (HHV-4). The ~165 kb genome contains over 80 open reading frames arranged in a long unique region flanked by multiple 801bp terminal repeat units of high G+C content. The long unique region contains blocks of conserved genes found in most herpesviruses, interspersed with blocks of non-homologous genes that are specific for HHV-8 and related viruses. HHV-8 proteins with recognizable homology to cellular proteins include:


  • complement binding protein (ORF 4)
  • IL6-like cytokine (ORF K2)
  • three chemokines (ORF K4, ORF K4.1 and ORF K6)
  • Bcl-2 (ORF 16) anti-apoptotic factor
  • interferon regulatory factor (ORF K9)
  • D-type cyclin (ORF 72)
  • FLICE inhibitory protein (ORF K13)
  • cell adhesion-like molecule (ORF K14)
  • G-protein coupled receptor (ORF 74)

In addition, HHV-8 has a number of genes such as ORF K12 (encodes the highly expressed transcript, kaposin), and ORF K1, a transmembrane protein that interacts with immunoreceptor kinases, which are likely to play a role in tumorigenesis. Functional studies suggest that these pirated genes may help the virus to evade immune responses, prevent cell cycle shutdown and interrupt activation of apoptotic pathways. This strategy has been referred to as "molecular piracy" of host cell genes. Like many complex DNA viruses, HHV-8 encodes a number of immunomodulatory factors:

v-FLIP Fas signalling in (virus-infected) target cells is triggered by Fas receptor multimerization on binding with membrane-bound Fas-L. Subsequent recruitment of the adaptor molecule Fas-activated death domain (FADD) leads to upstream caspase (caspase 8) autoactivation and release, leading to downstream effector capsase activation (caspase-3, -6, -7) & apoptosis. Death-receptor triggered apoptosis can be inhibited at several points: at the initiator stage by FLIP or in the amplification loop by bcl-2. HHV-8 v-FLIP block apoptosis in virus-infected cells. In addition, the vius also encodes a decoy (non-signalling) Fas receptor.
(Rezaee SA, et al. Kaposi's sarcoma-associated herpesvirus immune modulation: an overview. J Gen Virol. 2006 87: 1781)

Evidence suggests that one of the genes of HHV-8, vGPCR (viral G-protein coupled receptor) acts as a vascular switch, turning on synthesis of a powerful angoigenic agent, vascular endothelial growth factor (VEGF), which is responsible for the development of KS. However, HHV-8 also contains a considerable number of other 'pirated' cellular genes in an 'oncogenic cluster' within the virus genome which may also be involved in the development of malignancy (see Boshoff, C. Nature 391: 24-25, 1998), e.g. the K1 gene (Nature Med. 4:435 1998).

The seroprevalence rates for HHV-8 vary from < 5% in normal blood donors in the UK or USA up to 35% in HIV-positive homosexual men. Antibodies to HHV-8 are more common in African and Mediterranean populations. At least 85% of patients with Kaposi's sarcoma have antibodies to HHV-8.

PCR studies have suggested that HHV-8 may be sexually-transmitted through semen, and that infection, in low titer and in a latent form, may be more prevalent in healthy subjects than initially thought and may be reactivated to replicate upon immunosuppression or other stimuli. The virus may also occasionally be transmitted vertically from mother to child. HHV-8 has been transmitted by renal allografts, and two kidney transplant recipients have subsequently developed Kaposi's sarcoma.

HHV-8 resembles HHV-4 in that:

Epidemiological evidence now points to concurrent epidemics of HIV-1 and HHV-8 present among US homosexual men during the early 1980s and that the incidence of HHV-8 subsequently slowed dramatically in parallel with the incidence of HIV-1. In other groups, HHV-8 infection rates are low compared to other human herpesviruses:

Incidence of HHV infection

The situation with HHV-8 and prostate cancer is presently unclear. Although some studies have linked HHV-8 seropositivity with prostate cancer, it is far from clear that the virus causes the tumour. HHV-8 might serve as a co-factor for the initial development of prostate cancer or for the advancement to higher-grade lesions, or it might simply represent a marker for some other infectious agent or behavior that causes the cancer.

Herpesvirus infections of the nervous system. Nat Clin Pract Neurol. 2007 3: 82-94


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