374 Nature Vol. 269 29 September 1977 action revisited from Paula M. Pitha

INTERFERONS are species-specific cellu­ feron in ~he medium, Vengris et al. VSV or vaccm1a , and measure­ lar glycoproteins synthesised by a wide (Virology 64, 410; 1975) demonstrated ment of virus ydeld. To achieve the variety of animal cells in response to that for the development of the anti­ effect close contact between the two viral infection (or various non-viral viral state interferon had to interact populations was required; the effect stimuli) which induce antiviral resist­ with the external cellular membrane of was not observed in cultures plated at ance in homologous cells. In interferon­ the cell producing interferon. low cell density. Actinomycin D treat­ treated cells, a wide variety of different The results obtained by several ment of the mouse cells blocked both do not replicate well. It was groups (for example F. Ruddle at Yale the antiviral effect in the mouse cells shown with a majority of the viruses University, Connecticut, and F. C. and their ability to transfer resistance studied that the primary effect of inter­ Chany at INSERM, Paris) using to the heterologous cells. It seems, feron is a general inhibition of viral mouse- human cell hybrids demon­ therefore, that the transferred com­ . synthesis. In addition to this strated that the sensitivity to human pound may be a product of interferon block it has also been found that with interferon is governed by human induction rather than interferon itself. some viruses such as VSV and SV40 chromosome 21. Trisomy 21 cells were This conclusion, however, is based the transcription of viral mRNA is markedly more sensitive to human on experiments done in mass cultures decreased in interferon-treated cells. interferon than normal diploid cells or and the challenging viruses replicated Oncornavirus replication seems to be monosomy 21 cells (Tan et at. Science both in homologous and heterologous inhibited by interferon at the level of 186, 61; 1974; Chany et at. Proc. natn. cells. In the future much clearer data virus maturation and assembly. Acad. Sci. U.S.A . 12, 3129; 1975). would be obtained if t-he infecting virus 11he nature of the molecular mech­ Antibodies to hybrid cells containing could not replicate :in the cells homo­ anism ,by which interferon induces the human chromosome 21 were· found to logous to the interferon but only in antiviral state in the cell has not yet inhibit the antiviral effect of human the cells to which the antiviral com­ been clarified. Interferon by itself is interferon in human cells. Revel et al. pound was transferred. It has been not an antiviral agent. The antiviral (Nature 260, 139; 1976) suggested that shown previously that the effect of state does not develop in enucleated chromosome 21 codes for the receptor interferon is an all-or-none pheno­ cells or in cells treated with actino­ for human interferon on the cell menon in L cells and in chick embryo mycin D or cycloheximide. This in­ surface. cells (Chang et a!. J. gen. Viral. 20, dicates that the antiviral effect of inter­ T•he species specificity of 139; 1973; Radke et at. J. Viral. 13, feron requires both transcription and seems to be also determined at the 623; 1974), and thus it should be translation of the cellular genome and receptor level. Recent data indicate possible to measure the transfer of leads to the proposal that t1here is an that in primate-mouse hybrid cells viral resistance from the cell in the interferon-induced antiviral protein containing only one or a few human antiviral state to t·he adjacent neigh­ (Taylor Biochern. biophys. R es. chromosomes interferon specificity is bour. Fluorescent antibody or infec­ Commun. 14, 447; 1964). The situation, due to the interaction with the receptor tious centre techniques could be used however, is not that simple; recent but the antiviral mechanism induced to confirm the requi.rement for cell--cell results from the laboratories of I. Kerr with both mouse and human interferon contact. (MRC, Mill Hill, London), P. Lengyel is of mouse orig.in (Chany, Biomedicine (Yale University, Connecticut) and M. Express 24, 148; 1976). This indicates One of the remarkable properties of Revel (Weizmann Institute of Science, that at least some components of the the interferon system is its high bio­ Rehovot) with cell-f.ree protein syn­ antiviral effect do not have a require­ logical activity. The specific activity of thesising systems, indicate that inter­ ment for species s_pecificity. Samuel both human and mouse interferon is feron treatment induces the synthesis and Joklik (Virology 15, 166; 1976) estimated to be dose to 10" units per mg protein (one unit is the amount of of several translational inhibitors. came to a similar conclusion when they interferon which inhibits vir.us replica­ The first step in the induction of the showed that interferon treatment tion by 50%). It is proba.ble that such a antiviral effect is the interaction of induced a ribosome-associated inhibitor system involves mechanisms which interferon with the cellular membrane of viral mRN A translation in cell-free amplify the initial response. Both the of a sensitive cell, and it has been systems that could be dissociated · from above described transfer of antiviral observed that the interferon binding ribosomes and inhibit the translation of resistance and the mobility of the inter­ involves both cellular ,gangliosides and viral mRNA in a heterologous cell­ feron receptors on the cell surface glycoproteins (Besancon & Ankel free protein synthesising system. (Lebon eta!. Proc Soc. exp. Bioi. Med. Nature 252, 478; 1974; Vengris et at. Tn this issue of Nature (page 422) 149, 108; 1975) may be amplification Virology 12, 486; 1976; Kohn et a!. Blalock and Baron from the University factors in the interferon system. Proc. natn. A cad. Sci. U.S.A . 73, 3695; of Texas at Galveston present another 1976). The cellular uptake of interferon t)-lpe of evidence that vhe interferon­ Currently it seems that the action of is not required for the antiviral effect induced antiviral 'machinery' may not interferon at the cellular surface (Ankel et al. Proc. natn. A cad. Sci. be species specific. The authors also resembles in many respects the action U.S.A . 70, 2360; 1973); the sensitivity suggest that the antiviral compound of the polypeptide hormones. The to interferon seems to be determined induced by interferon treatment of the major task for the future is to answer by a receptor located at the .plasma homologous cells can be transferred to the question of how the impulse from membrane. Using antiserum to inter­ the cell of the heterologous species and the cell membrane is transferred to feron, which neutralised all free inter- elicit in it resistance to viral infection. the nucleus. One possibility which T·he experiments are based on coculti­ remains to be determined is that vation of mouse cells (sensitive to the antiviral effect of interferon is Paula M . Pitha is Associate Professor of mouse interferon) with interferon­ mediated through a second message Oncology in the Cancer Center of the insensitive human cells in the presence such as cyclic AMP (Weber & Stewart Johns Hopkins University School of J. gen. 28, 363; 1975). Medicine. of mouse interferon, infection with Virol 0

© 1977 Nature Publishing Group