Review
Host-related immunomodulators encoded by poxviruses and herpesviruses

https://doi.org/10.1016/S1369-5274(00)00107-7Get rights and content

Abstract

In the past year, important advances have been made in the area of host-related immunomodulatory genes encoded by the larger DNA viruses, particularly for the poxviruses and herpesviruses. Not only has the repertoire of viral immunomodulator homologs expanded as a result of sequencing the complete genome of another six large DNA viruses, but also new concepts of how they work have been proposed and in some cases supported by in vivo evidence. Recent developments have been made in understanding a spectrum of host-related viral modulators, including complement control proteins, TNF-receptor homologs, IL-18 binding proteins, viral interleukins (vIL-6 and vIL-10), chemokine mimics and chemokine receptor homologs.

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

References (58)

  • K.D. Jones et al.

    Involvement of interleukin-10 (IL-10) and viral IL-6 in the spontaneous growth of Kaposi’s sarcoma herpesvirus-associated infected primary effusion lymphoma cells

    Blood

    (1999)
  • Y. Aoki et al.

    Angiogenesis and hematopoiesis induced by Kaposi’s sarcoma-associated herpesvirus-encoded interleukin-6

    Blood

    (1999)
  • A.S. Lalani et al.

    Evasion and exploitation of chemokines by viruses

    Cyt Growth Fact Rev

    (1999)
  • J.T. Stine et al.

    263KSHV-encoded CC chemokine vMIP-III is a CCR4 agonist, stimulates angiogenesis, and selectively chemoattracts TH2 cells

    Blood

    (2000)
  • M.C. Sirianni et al.

    Gamma-Interferon production in peripheral blood mononuclear cells and tumor infiltrating lymphocytes from Kaposi’s sarcoma patients: correlation with the presence of human herpesvirus-8 in peripheral blood mononuclear cells and lesional macrophages

    Blood

    (1998)
  • D.J. Dairaghi et al.

    HHV8-encoded vMIP-I selectively engages chemokine receptor CCR8: agonist and antagonist profiles of viral chemokines

    J Biol Chem

    (1999)
  • A.S. Lalani et al.

    Role of the myxoma virus soluble CC-chemokine inhibitor glycoprotein, M-T1, during myxoma virus pathogenesis

    Virology

    (1999)
  • D.N. Streblow et al.

    The human cytomegalovirus chemokine receptor US28 mediates vascular smooth muscle cell migration

    Cell

    (1999)
  • C.L. Afonso et al.

    The genome of Melanoplus sanguinipes entomopoxvirus

    J Virol

    (1999)
  • J.C. Albrecht

    Primary structure of the Herpesvirus ateles genome

    J Virol

    (2000)
  • R.P. Searles et al.

    Sequence and genomic analysis of a rhesus macaque rhadinovirus with similarity to Kaposi’s sarcoma-associated herpesvirus/human herpesvirus 8

    J Virol

    (1999)
  • M.K. Spriggs

    One step ahead of the game: viral immunomodulatory molecules

    Annu Rev Immunol

    (1996)
  • H.L. Ploegh

    Viral strategies of immune evasion

    Science

    (1998)
  • G.L. Smith

    Secreted poxvirus proteins that interact with the immune system

  • G.J. Kotwal et al.

    Vaccinia virus encodes a secretory polypeptide structurally related to complement control proteins

    Nature

    (1988)
  • J. Howard et al.

    Molecular mimicry of the inflammation modulatory proteins (IMPs) of poxviruses: evasion of the inflammatory response to preserve viral habitat

    J Leuk Biol

    (1998)
  • S.B. Kapadia et al.

    Murine gammaherpesvirus 68 encodes a functional regulator of complement activation

    J Virol

    (1999)
  • A.A. Johnson et al.

    The structural basis for complement receptor type 2 (CCR, CD21)-mediated alternative pathway activation of complement: studies with CR2 deletion mutants and vaccinia virus complement-control protein-CR2 chimeras

    Eur J Immunol

    (1999)
  • M.D. Kirkitadze et al.

    Central modules of the vaccinia virus complement control protein are not in extensive contact

    Biochem J

    (1999)
  • Cited by (0)

    View full text