ReviewHost-related immunomodulators encoded by poxviruses and herpesviruses
Introduction
The voluminous database of genes encoded by large DNA viruses continued to expand over the past year with the publication of the complete DNA sequence for four new poxviruses (myxoma virus, Shope fibroma virus, alastrim variola minor virus and the entomopoxvirus, Melanoplus sanguinipes) and two herpesviruses (Herpesvirus ateles and rhesus rhadinovirus) 1, 2, 3, 4, 5, 6. The ever increasing inventory of host-related immunomodulatory proteins encoded by viruses (reviewed in 7, 8, 9) has provided further support for the hypothesis, first enunciated seven years ago [10], that molecular mimicry by viral proteins in fact contributes to the interspecies diversity of host immune pathways themselves. Here, we consider some of the recent research advances in a few selected examples of host-related viral immunoregulators (for further details on the modulation of host immune responses by human DNA and RNA viruses see the review by C Brander and BD Walker, this issue pp 379–386). Some of these are new and others not, but they all illustrate the theme that cellular immune and inflammatory cascades can be efficiently regulated by viral proteins that are likely to be derived from host genes originally hijacked during ancestral virus infections, and later evolved by Darwinian selection pressures to subserve the needs of the infecting virus. Moreover, there is now evidence that viruses may adapt captured immunoregulatory genes for novel functions unrelated to immunoregulation.
Section snippets
Viral complement control proteins
One of the first identified host-related ‘virokines’ (virus encoded secreted immunoregulator proteins) was a 35 kDa secreted glycoprotein now designated VCP (vaccinia complement control protein) [11]. VCP is encoded by the C3L gene of vaccinia, and contains multiple short consensus repeats (SCRs) each with four characteristic cysteine spacings and certain other conserved motifs indicating membership in a larger family of complement control proteins. VCP was previously shown to inhibit
Viral TNF-receptor homologs
Following the cloning and sequencing of the two major human tumor necrosis factor (TNF) receptors in the early 1990s, related secreted receptor species expressed by poxviruses provided the first example of ‘viroceptors’, or virus encoded receptor homologs (reviewed in 18, 19, 20). In the past year, the first example of a cell surface variant of a viral TNF-receptor (designated A53R, or crmC) was documented in certain strains of vaccinia [21]. In fact, these authors noted surprising variability
Poxvirus IL-18-binding proteins
A new class of viral immunomodulatory protein was discovered in 1999 following the identification and sequencing of cellular interleukin (IL)-18 binding proteins [24••]. IL-18 is an important pro-inflammatory cytokine that, like IL-1β, exists as an inactive precursor that can be activated by caspase-1 and then rapidly secreted from monocytic cells, whereupon it has a profound ability to assist in the activation of Th1 lymphocytes and natural killer (NK) cells, as well as the induction of other
Viral IL-6 and IL-10
A viral homolog of IL-10 was first found in the genome of Epstein-Barr virus (EBV) a decade ago; closely related homologs were then identified in equine herpesvirus in 1993 and the parapoxvirus orf virus in 1997. Compared to these, an HCMV IL-10 homolog (cmvIL-10, the product of ORF UL111a), which was identified this year, has unusual features [31••]. It is only 27% identical in amino acid sequence to any other known mammalian or viral IL-10. Moreover, the ORF is interrupted by two introns,
Viral chemokines
Genomic analysis of large DNA viruses has revealed eight chemokine homologues among herpesviruses and poxviruses (reviewed in 37, 38), including five agonists (HHV6 U83; HHV8 vMIP-I and vMIP-III; mouse CMV [MCMV] m131/129; and HCMV vCXC-1), two antagonists (HHV8 vMIP-II and MCV MC148R), and one molecule whose function is not yet defined (HCMV vCXC-2). All except vCXC-1 and-2 are CC chemokines (Table 1).
Viral chemokine scavengers
Large DNA viruses can also block chemokine signaling by secreting soluble chemokine-binding proteins [38]. To date three structurally unique classes have been identified: the 35 kDa CC chemokine scavengers of diverse ortho and leporipoviruses; the mixed CC chemokine and interferon-γ scavenger of myxoma virus, a rabbit poxvirus [38]; and the recently discovered M3 protein of γ-herpesvirus 68. M3 binds a broad spectrum of CC and CXC chemokines and blocks chemokine signaling [49••]. Its relevance
Viral chemokine receptors
Six 7-transmembrane domain viral chemokine receptor homologues have been identified so far: ECRF3 of Herpesvirus saimiri, US28 of HCMV, U12 and U51 of HHV6, KSHV GPCR of HHV8, and, most recently, E1 of equine herpesvirus 2 37, 53. Additional candidates are known in these and other herpesviruses, and poxviruses (reviewed in 37, 38). These receptors have diverse but broad chemokine specificities, including CXC restriction (ECRF3), CC restriction (U12, U51 and E1), CC/CX3C restriction (US28) and
Conclusions
The pace of discovery in the area of host-related immunomodulators of viruses continues to quicken. As the human genome sequencing project approaches completion, it is anticipated that some of the newer ‘orphan’ virus genes that regulate host immune molecules, such as the GIF gene product of orf virus that inhibits both GM-CSF and IL-2 [57], may turn out to have host counterparts. Indeed, the viral ‘anti-immune’ system is approaching the complexity of the host immune system with which it has
Update
Recently, it was demonstrated [58••] that a viral broad-spectrum chemokine-binding protein from myxoma virus can reduce inflammatory cell infiltration into sites of vascular trauma, thereby reducing subsequent vessel occlusion following angioplasty injury in two animal model systems. This further supports the notion that immunomodulatory viral proteins can be exploited as clinical therapeutic reagents.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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