Viral Cytokines

For years the large double stranded DNA viruses were thought to contain numerous 'non-essential' genes. These genes are now found to code proteins used by the virus to counteract the host immune response. Genomic mapping of these viruses and the identification of sequence homology to cellular proteins has led to suggested functions for these gene products. These viral genes are thought to have been captured from host cells during viral evolution and modified to confer an advantage in viral replication, survival or transmission.

The myxoma virus, Leporipoxvirus, was one of the first viruses found capable of disruption of the host anti-viral response. This virus produced a soluble IFN-gamma receptor homologue, called M-T7, that can bind rabbit IFN-gamma and inhibit its anti-viral activities.1 Viral IFN-gamma R homologues have been found in several species of poxviruses, and interferon-responsive elements are found in the gamma herpes virus family.2 Interferon-gamma, a primary mediator of host defense against viral and non-viral pathogens, activates macrophages and enhances the expression of major histocompatibility complex (MHC) class I and II glycoproteins in order to aid in viral antigen presentation, and it induces the expression of anti-viral effector proteins in the cell. The production of a soluble cellular homologue to the IFN-gamma R by the virus would prevent triggering of the host cell response by binding to and blocking the host-produced IFN-gamma.

The host defense use of interferon is also targeted by the production of virus-associated RNA genes (VA RNA) in the adenovirus to block the IFN-induced autophosphorylation of double-stranded RNA-activated inhibitor of translation (DAI) and thereby blocking the antiviral effect of interferon. The presentation of viral antigen by the MHC class I molecule also can be disrupted by viral homologues. E3-gp19K from adenovirus binds strongly to class I MHC molecules in the endoplasmic reticulum, preventing their translocation to the surface.3, 4 ML18 from human cytomegalovirus produces a class I homologue that binds beta 2-microglobulin, a subunit of class I MHC molecules required for transport to the cell surface.5

Other soluble cell-receptor homologues include the myxoma virus, M-T2, a cellular TNF-receptor homologue that binds and inhibits TNF.6 Similar TNF-receptor homologues have been detected in cowpox and variola.7 B15R from the vaccinia virus is a secreted IL-1 receptor type II homologue that binds and inhibits the action of IL-1 beta.8, 9 TNF and IL-1 are early promoters of inflammation, and blocking their action stops initiation of inflammatory response. The action of TNF is stopped also by the intracellular inhibitors E3-14.7K, E3-10.4/14.5K, and E1B-19K from adenoviruses by disruption of signal transduction after TNF binds to the cell-surface receptor.3 The cowpox virus gene crmA blocks the IL-1 induced inflammatory response by inhibiting the cleavage of pro-IL-1 beta to the active form.10 CrmA is one member of the serine proteinase inhibitors that have been identified in poxvirus and orthopoxvirus.11 Viruses thus have mechanisms that counteract extracellular and intracellular aspects of the host defense system.

Other inhibitors of host-defense strategies involve blocking the complement pathways by production of viral proteins that bind complement subunits and inhibit the complement-mediated lysis of infected cells.2, 4, 12 Epstein Barr virus encodes BCFR1, an IL-10 homologue,13 produced to suppress the Th1 cellular immune response and turn the response to Th2, which is less effective. Many DNA viruses have genes that encode apoptosis-inhibiting proteins, such as BHRF1 in Epstein Barr virus, a Bcl-2 homologue that blocks the apoptotic response of the host.2, 14-16 Viruses also produce homologues of the human type D cyclin genes that may trigger kinase activity that effectively blocks host regulation of cell proliferation.16-18

Chemokines play a key role in the initial host reaction to infection and injury. Viral genomes have sequences homologous to those of chemokines and chemokine receptors. There are three chemokine receptor homologues, US28, US27 and ML33 in the cytomegalovirus genome. US28-transfected cells can bind a wide range of chemokines, including MCP-1, RANTES, and MIP-1 alpha.19, 20 Although US27 is thought to arise from gene duplication of US28, no ligand has been identified. M33 is the mouse cytomegalovirus equivalent of the human CMV ML33. Mutation of M33 had no effect on infection of mouse fibroblasts in vitro, but in vivo there was much less virus in the salivary glands of mice infected with the mutant than the wild-type virus. It was suggested that M33 is important in the movement of virus through infected cells to the salivary glands to assist in viral transmission to new hosts.5

Human herpesvirus-8 (HHV-8), a gammaherpesvirus, also known as Kaposi's sarcoma-associated herpesvirus (KSHV), is present in almost all AIDS-KS lesions and the rare B-cell primary effusion (body-cavity based) lymphoma associated with KS.2 HHV-8 contains several genes with sequence homology to many cellular proteins such as chemokines (ORF K4, K6 and K4.1), human IL-6 (ORF K2), interferon regulatory factor (ORF K9), Bcl-2 (ORF 16), cyclin D (ORF 72), and an IL-8-like receptor (ORF 74).2, 14, 17, 18, 21 These viral proteins may contribute to mechanisms that block the host defense and contribute to virus-induced neoplasia.HV-8 vIL-6 has been shown to have biological properties similar to human IL-6.21, 22 The chemokine homologues, named vMIP-I and vMIP-II, weakly block HIV infections and induce angiogenesis.21, 23 vMIP-II (also called vMIP-1 beta) binds predominantly to CCR-3, the eotaxin receptor, causing human eosinophil activation as measured by intracellular calcium mobilization and chemotaxis.23 These observations may be significant to the association of HHV-8 with Kaposi's sarcoma, body-cavity-based or pleural effusion lymphoma, and multicentric Castleman's disease, a polyclonal lymphoproliferation associated with increased vascularity.2, 22, 24 It has been hypothesized that HHV-8 plays a role in the development of these diseases.

Understanding the function of viral homologues and the role they play in the establishment of infection and disease may greatly assist in understanding the host response mechanisms involved in reaction to infection and disease. Some specific activities have been demonstrated for some of the viral-encoded proteins, but the actual in vivo functions are uncertain.

Table 1. Viral-Encoded Host Homologues
Virus Family Virus Product Function
Adenovirus3, 4   VA RNA Blocks IFN-induced autophosphorylation of DAI
E3-gp19k Prevents translocation of class I MHC Ag to cell surface
E3-14.7k Interferes with signal transduction of TNF
E3-10.4/14.5k Interferes with signal transduction of TNF
E1B-19k Interferes with signal transduction of TNF
Poxvirus4, 12, 25, 26 Shope fibroma/
Serp-1 Inactivates serine proteinases
MGF EGF/TGF-alpha homologue
T2 Soluble TNF receptor homologue
T7 Soluble IFN-gamma receptor homologue and chemokine binding protein
T1 Chemokine binding protein
Vaccinia VGF EGF/TGF-alpha homologue
VCP C4b complement binding protein
B15R Soluble IL-1 receptor type II homologue
B18R Soluble IFN-alpha/beta receptor homologue
B8R Soluble IFN-gamma receptor homologue
Cowpox SPI-1, 2, 3 Inactivates serine proteinases
crmA Inhibits IL-1 beta converting enzyme
MC148R1 CC chemokine homologue
MC148R2 CC chemokine homologue
Herpesvirus28, 29 Herpes simplex I/II gC-1 C3b complement binding protein
gE-gI IgG-Fc binding protein
Human herpesvirus-630 U83 Chemokine homologue
U12 Serpentine receptor
Human herpesvirus-731 U12 Serpentine receptor
cytomegalovirus5, 32 UL18 Binds beta-2 microglobulin, preventing class I MHC transport to cell surface
US28, US27 Serpentine receptor
UL33/M33 Serpentine receptor
MCK-1/HJ1 Chemokine homologue
Epstein Barr Virus2, 4, 13 BHRF-1 Bcl-2 homologue
BCRF-1 IL-10 homologue
EBER RNA Blocks IFN-induced autophosphorylation of DAI
Human herpesvirus-82 K2 IL-6 homologue
K4/K6 CC chemokine homologue
K9 Interferon responsive factor
ORF 4 Complement binding protein
ORF 16 Bcl-2 homologue
ORF 74 IL-8R-like Serpentine receptor
ORF 72 Cyclin D


  1. Mossman, K. et al. (1995) J. Biol. Chem. 270:3031.
  2. Russo, J. et al. (1996) PNAS USA 93:14862.
  3. Wold, W. and L. Gooding (1991) Virology 184:1.
  4. Gooding, L. (1992) Cell 71:5.
  5. Davis-Poynter, N. et al. (1997) J. Virol. 71:1521.
  6. Upton, C. et al. (1991) Virology 184:370.
  7. Smith, C.A. and R.G. Goodwin, (1995) In Viroceptors, Virokines and Related Modulators Encoded By DNA Viruses, G. McFadden, Ed., R.G. Landes, Austin, TX.
  8. Alcami, A. and G. Smith, (1992) Cell 71:153.
  9. Spriggs, M. et al. (1992) Cell 71:145.
  10. Ray, C.A. et al. Cell (1992) 69:597.
  11. McFadden, G. (1995) J. Leuk. Biol. 57:731.
  12. Alcami, A. and G. Smith (1995) Immunol. Today 16:474.
  13. Hsu, D-H. et al. (1990) Science 250:830.
  14. Sarid, R. et al. (1997) Nature Med. 3:293.
  15. Gregory, C.D. et al. (1991) Nature 349:612.
  16. Nicholas, J. et al. (1992) Nature 355:362.
  17. Godden-Kent, D. et al. (1997) J. Virol. 71:4193.
  18. Cesarman, E. et al. J. Virol. (1996) 70:8218.
  19. Pleskoff, O. et al. (1997) Science, 276:1874.
  20. Gao, J-L. and P. Murphy (1994) J. Biol. Chem. 269:28539.
  21. Moore, P. et al. (1996) Science 274:1739.
  22. Nicholas, J. et al. (1997) Nature Med. 3:287.
  23. Boshoff, C. et al. (1997) Science 278:290.
  24. Neipel, F. et al. (1997) J. Virol. 71:4187.
  25. Lalani, A. and G. McFadden (1997) J. Leuk. Biol. 62:570.
  26. Massung, R. et al. (1993) Nature 366:748.
  27. Krathwohl, M. (1997) PNAS USA 94:9875.
  28. Harris, S.L. et al. (1990) J. Infect. Dis. 162:331.
  29. Bell, S. et al. (1990) J. Virol. 64:2181.
  30. Nicholas, J. and M. Martin (1994) J. Virol. 68:597.
  31. Nicholas, J. (1996) J. Virol. 70:5975.
  32. MacDonald, M. et al. (1997) J. Virol. 71:1671.