IL-10 encoded by viruses: a remarkable example of independent acquisition of a cellular gene by viruses and its subsequent evolution in the viral genome

Many viruses have evolved strategies to deregulate the host immune system. These strategies include mechanisms to subvert or recruit the host cytokine network. IL-10 is a pleiotropic cytokine that has both immunostimulatory and immunosuppressive properties. However, its key features relate mainly to its capacity to exert potent immunosuppressive effects. Several viruses have been shown to upregulate the expression of cellular IL-10 (cIL-10) with, in some cases, enhancement of infection by suppression of immune functions. Other viruses encode functional orthologues of cIL-10, called viral IL-10s (vIL-10s). The present review is devoted to these virokines. To date, vIL-10 orthologues have been reported for 12 members of the family Herpesviridae, two members of the family Alloherpesviridae and seven members of the family Poxviridae. Study of vIL-10s demonstrated several interesting aspects on the origin and the evolution of these viral genes, e.g. the existence of multiple (potentially up to nine) independent gene acquisition events at different times during evolution, viral gene acquisition resulting from recombination with cellular genomic DNA or cDNA derived from cellular mRNA and the evolution of cellular sequence in the viral genome to restrict the biological activities of the viral orthologues to those beneficial for the virus life cycle. Here, various aspects of the vIL-10s described to date are reviewed, including their genetic organization, protein structure, origin, evolution, biological properties and potential in applied research.

Functional replacement of the R region of simian immunodeficiency virus-based vectors by heterologous elements

Substitution of lentiviral cis-acting elements by heterologous sequences might allow the safety of lentiviral vectors to be enhanced by reducing the risk of homologous recombination and vector mobilization. Therefore, a substitution and deletion analysis of the R region of simian immunodeficiency virus (SIV)-based vectors was performed and the effect of the modifications on packaging and transfer by SIV and human immunodeficiency virus type 1 (HIV-1) particles was analysed. Deletion of the first 7 nt of R reduced vector titres by 10- to 20-fold, whilst deletion of the entire R region led to vector titres that were 1500-fold lower. Replacement of the R region of SIV-based vectors by HIV-1 or Moloney murine sarcoma virus R regions partially restored vector titres. A non-retroviral cellular sequence was also functional, although to a lesser extent. In the absence of tat, modification of the R region had only minor effects on cytoplasmic RNA stability, steady-state levels of vector RNA and packaging, consistent with the known primary function of R during reverse transcription. Although the SIV R region of SIV-based vectors could be replaced functionally by heterologous sequences, the same modifications of R led to a severe replication defect in the context of a replication-competent SIV. As SIV-based vectors containing the HIV-1 R region were transferred less efficiently by HIV-1 particles than wild-type SIV vectors, a match between R and cis-acting elements of the vector construct seems to be more important than a match between R and the Gag or Pol proteins of the vector particle.

Relationship among Location of T-Antigen-Induced DNA Distortion, Auxiliary Sequences, and DNA Replication Efficiency

ABSTRACT T-antigen-induced DNA distortion was studied in a series of simian virus 40 (SV40) plasmid constructs whose relative replication efficiency ranges from 0.2 to 36. Bending was detected in the wild-type SV40 regulatory region consisting of three copies of the GC-rich 21-bp repeat but not in constructs with only one or two copies of the 21-bp repeat. In a construct with enhanced replication efficiency, bending occurred in a 69-bp cellular sequence located upstream of a single copy of the 21-bp repeat. Bending occurred both upstream of ori and in the three 21-bp repeats located downstream of ori in a construct with reduced replication efficiency. In a construct with no 21-bp repeats, DNA distortion occurred downstream of ori. The results indicate that SV40 DNA replication is enhanced when the structure of the regulatory region allows the DNA to form a bent structure upstream of the initial movement of the replication fork.

Effect of silencer on polyomavirus DNA replication

We have cloned the cellular sequence termed box DNA from the enhancer region of polyomavirus F9 mutant fPyF9. Box DNA functions as a negative transcriptional element (silencer) in undifferentiated F9 cells but not in differentiated L cells. Plasmid DNAs containing the origin and enhancer of polyomavirus were used to measure simultaneously transcriptional and replication activities in transfected cells. DNA replication activity was significantly reduced under conditions in which the silencer was able to reduce enhancer activity in F9 cells. On the other hand, when the silencer could not repress enhancer activity in MOP-8 cells, which are mouse NIH 3T3 cells producing polyomavirus T antigen constitutively, replication activity was still intact. The silencer itself had no effect on DNA replication or transcription in either type of cells. Furthermore, the insertion of a 6-base oligonucleotide within a consensus sequence of box DNA abolished the repressive effect of the silencer on DNA replication and enhancer activities. These results suggest that enhancer factors, interacting with silencer factors, may be closely associated with the mechanism of replication.