John Nicholas

Human Herpesvirus-8-Encoded Signalling Ligands and Receptors

Analysis of the genome of human herpesvirus 8 (HHV-8) led to the discovery of several novel genes, unique among the characterized gammaherpesviruses. These include cytokines (interleukin-6 and chemokine homologues), two putative signal-transducing transmembrane proteins encoded by genes K1 and K15 at the genome termini, and an OX-2 (CD200) receptor homologue that had not previously been identified in a gammaherpesvirus. HHV-8 also specifies a diverged version of the gammaherpesvirus-conserved G protein-coupled chemokine receptor (vGCR) and a latently expressed protein unique to HHV-8 specified by open reading frame (ORF) K12. These cytokine and receptor homologues mediate signal transduction or modulate the activities of other endogenous cytokines and receptors to enhance viral productive replication, regulate latent-lytic switching, evade host attack, or mediate cell survival. The viral signalling ligands and receptors are also potential contributors to virus-associated diseases, Kaposis sarcoma, primary effusion lymphoma, and multicentric Castlemans disease, and so represent potentially important targets for therapeutic and antiviral drugs. Understanding these proteins modes of action and functions in viral biology and disease is therefore of considerable importance, and the subject of this review.

Molecular Biology of Human Herpesvirus 8: Novel Functions and Virus–Host Interactions Implicated in Viral Pathogenesis and Replication

Human herpesvirus 8 (HHV-8), also known as Kaposis sarcoma-associated herpesvirus (KSHV), is the second identified human gammaherpesvirus. Like its relative Epstein-Barr virus, HHV-8 is linked to B-cell tumors, specifically primary effusion lymphoma and multicentric Castlemans disease, in addition to endothelial-derived KS. HHV-8 is unusual in its possession of a plethora of accessory genes and encoded proteins in addition to the core, conserved herpesvirus and gammaherpesvirus genes that are necessary for basic biological functions of these viruses. The HHV-8 accessory proteins specify not only activities deducible from their cellular protein homologies but also novel, unsuspected activities that have revealed new mechanisms of virus-host interaction that serve virus replication or latency and may contribute to the development and progression of virus-associated neoplasia. These proteins include viral interleukin-6 (vIL-6), viral chemokines (vCCLs), viral G protein-coupled receptor (vGPCR), viral interferon regulatory factors (vIRFs), and viral antiapoptotic proteins homologous to FLICE (FADD-like IL-1β converting enzyme)-inhibitory protein (FLIP) and survivin. Other HHV-8 proteins, such as signaling membrane receptors encoded by open reading frames K1 and K15, also interact with host mechanisms in unique ways and have been implicated in viral pathogenesis. Additionally, a set of micro-RNAs encoded by HHV-8 appear to modulate expression of multiple host proteins to provide conditions conducive to virus persistence within the host and could also contribute to HHV-8-induced neoplasia. Here, we review the molecular biology underlying these novel virus-host interactions and their potential roles in both virus biology and virus-associated disease.

Identification of Envelope Glycoproteins H and B Homologues of Human Herpesvirus 7

The genes encoding the envelope glycoprotein H (gH) and gB homologues were identified by sequencing genomic clones of human herpesvirus-7 (HHV-7), strain JI. A gB cDNA clone from HHV-7 strain AL was also identified. The deduced primary translation products of the gH and gB genes are a protein of 690 amino acids, with a predicted mass of 80.4 kD, and a protein of 822 amino acids, with a predicted mass of 93.3 kD, respectively. Both the predicted proteins have the characteristics of transmembrane glycoproteins, containing signal and transmembrane sequence motifs and characterized by the presence of 10 (gH) and 11 (gB) potential motifs for N-glycosylation. Comparison of amino acid sequence of HHV-7 gH and gB with the homologous sequences of the other human herpesviruses reveals closest homology with HHV-6 (38.8% identity for gH, 56.2% identity for the gB). In addition, significant sequence similarity was also observed between the gH and gB of HHV-7 and the homologs encoded by human cytomegalovirus (21.6% identity for gH, 37.6% identity for gB). No significant differences existed between the gB sequence of the two different HHV-7 strains analyzed. The products of the HHV-7 gH and gB expressed transiently in eukaryotic cells were specifically recognized by an HHV-7-reactive human serum in immunofluorescence assays.

Molecular biology of human herpesvirus 8 neoplasia.

Human herpesvirus 8 (HHV-8, Kaposi’s-sarcoma-associated herpesvirus) was discovered in 1994, accompanied nby tremendous interest in the field of human viral oncology and rapid development of research

Viral Interleukin-6: Molecular Biology and Pathogenesis

Human herpesvirus 8 (HHV-8, also called Kaposi’s sarcoma-associated herpesvirus) was discovered in 1994, but interleukin-6 (IL-6) had been implicated in Kaposi’s sarcoma and HHV-8-associated multicentric Castleman’s disease (MCD) several years prior to this date. The predicted role of IL-6 in KS and MCD pathogenesis was based on its known pro-angiogenic and B-cell mitogenic properties. Thus, when viral IL-6 (vIL-6) was identified in HHV-8, the first reported viral interleukin-6 homologue, this was immediately recognized as a potential contributor to HHV-8-associated pathogenesis. Indeed, the pro-angiogenic, proliferative, and signaling properties of vIL-6 reflected those of its human counterpart. It is now known that there are significant differences in the precise mechanisms of signaling complex formation and in signal transduction induced by the human and viral IL-6 proteins and also that vIL-6 is able to signal intracellularly, which is likely to be highly relevant to its functions in virus biology and viral pathogenesis. The unique properties of vIL-6 suggest that it may be possible to target the viral cytokine specifically with inhibitory agents, but they also highlight special challenges with respect to appropriate targeting of inhibitory agents to the sites of vIL-6 activity. This review discusses the molecular biology of vIL-6, the means by which it may contribute to virus biology and viral pathogenesis, and possible methods of inhibiting the activity of the viral cytokine.