We have demonstrated the existence of human cytokine synthesis inhibitory factor (CSIF) [interleukin 10 (IL-10)]. cDNA clones encoding human IL-10 (hIL-10) were isolated from a tetanus toxin-specific human T-cell clone. Like mouse IL-10, hIL-10 exhibits strong DNA and amino acid sequence homology to an open reading frame in the EpsteinBarr virus, BCRFI. hIL-lO and the BCRFI product inhibit cytokine synthesis by activated human peripheral blood mononuclear cells and by a mouse Thl clone. Both hIL-10 and mouse IL-1O sustain the viability of a mouse mast cell line in culture, but BCRFI lacks comparable activity in this assay, suggesting that BCRFI may have conserved only a subset of hIL-10 activities.
Cytokine synthesis inhibitory factor (CSIF; interleukin-10), a product of mouse TH2 T cell clones that inhibits synthesis of cytokines by mouse TH1 T cell clones, exhibits extensive sequence similarity to an uncharacterized open reading frame in the Epstein-Barr virus BCRF1. Recombinant BCRF1 protein mimics the activity of interleukin-10, suggesting that BCRF1 may have a role in the interaction of the virus with the host's immune system.
The complete gene 4 nucleotide sequence was determined for rhesus rotavirus and each of 11 viral variants selected by neutralizing monoclonal antibodies. Gene 4 is 2362 bases in length and encodes a protein, VP3, of 776 amino acids with a calculated Mr of 86,500. A conserved trypsin cleavage site, located at amino acid 247, divides VP3 into VP8 and VP5. Neutralizing monoclonal antibodies directed at VP3 were used to select variants that escaped neutralization. Each variant contains a single gene 4 mutation that permits viral growth in the presence of the antibody. Variant mutations were identified in six distinct neutralization regions in VP8 and VP5. Five of the six neutralization regions were found in VP8. The VP8 regions were primarily associated with strain-specific or limited heterotypic rotavirus neutralization. One region was identified in VP5 by three monoclonal antibodies that neutralize a broad range of rotavirus serotypes. The VP5 neutralization region is largely hydrophobic and is similar to putative fusion sequences of Sindbis and Semliki Forest viruses.Rotavirus is a 70-nm icosahedral virus comprised of two capsid layers. The inner capsid, composed of proteins VP1, VP2, and VP6, contains an endogenous RNA-dependent RNA polymerase and 11 double-stranded RNA segments (1). Gene segments 4 and 9 encode the outer capsid proteins VP3 and VP7, respectively, of rhesus rotavirus (RRV) (2). VP7 (37 kDa) is a glycoprotein, and antibodies directed against VP7 neutralize the virus and specify the viral serotype (3-8). The other viral surface protein, VP3, is an 84-to 88-kDa nonglycosylated protein containing the viral hemagglutinin (9). In the presence of trypsin, VP3 is cleaved to VP5 (60 kDa) and VP8 (28 kDa), which results in enhancement of viral infectivity (10). Preliminary studies indicate that cleavage of VP3 mediates penetration of the virion into the cell (11). VP3 is also associated with restriction of virulence of certain rotavirus strains in mice (12) and humans (13). Antibodies directed at VP3 inhibit viral hemagglutination (14), neutralize the virus in vitro (14), and passively protect mice against heterologous rotavirus challenge in vivo (15). Further studies have demonstrated that VP3 effectively induces protective immunity in animals (16) and is immunogenic in young children (17).We have studied VP3 neutralization sites of the rhesus strain of simian rotavirus. RRV is serotypically identical to type 3 human rotavirus strains (18). Previously, we described a library of monoclonal antibodies (mAbs) directed against the RRV VP3 protein, which defines its functional and antigenic topography (22). mAbs directed at VP3 were used to delineate distinct neutralization domains and to demonstrate that VP3 contains both heterotypic and homotypic neutralizing epitopes. Neutralizing mAbs (N-mAbs) selecting these distinct domains were characterized by competitive binding studies and by their ability to recognize mutants that grew in the presence of N-mAbs.In this study, we have determined the full-len...
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