Host mRNA

Translation of Viral mRNA. Once viral mRNA has been formed, translation occurs in the host cytoplasm, using host ribosome to synthesize viral proteins. Viral mRNA, which is usually monocistronic (i.e., has a single coding region) can displace host mRNA from ribosome so that viral products are synthesized preferentially. In the early phase, the proteins produced (enzymes, regulatory molecules) are those that will allow subsequent replication of viral nucleic acids in the later phase, the proteins necessary for the formation of capsid are produced. 

About 1.5-2 hours after infection the first viral structural proteins can be detected in cells efficiently infected by SFV (see Kaariainen and S6-derlund, 1978). By 3-4 hours the synthesis of host cell proteins is shut off. The mechanism of host protein shutoff is not yet known, but studies by van Steeg (1982) suggest that it is the viral capsid protein itself which is responsible for the selective inhibition of host protein synthesis. The capsid protein seems to reduce the activity of the initiation factors elF-4B and CAP binding protein below levels necessary for the formation of the 80 S initiation complex from host mRNA. Translation of the viral 26 S RNA is, however, unaffected. More studies are clearly needed to substantiate this interesting possibility. 

The first step in the replication of influenza viruses, which takes place in the cytoplasm, is the synthesis of (+) strands that can serve both as mRNA for synthesis of proteins and as templates for synthesis of new (-) strands. Three of the capsid proteins form the required RNA polymerase. This "transcriptase" is primed preferentially by 5 -capped 10- to 13-nucleotide segments of RNA that have been cut by a viral nuclease from host mRNAs.700 The mRNAs made from viral RNA are polyadenylated and are translated by the host cell s ribosomes. However, some transcripts are used as templates to form viral (-) strands, which... 

Viruses use the host s enzyme system to replicate their DNA and to synthesize their proteins. Since eukaryotic translation systems must synthesize viral protein, the structure of viral mRNAs must mimic that of the host mRNA. 

Most recently Rose et al. (55) have identified an initiation factor that is inactivated after infection of HeLa cells with poliovirus. In their experiments Rose al. (55) took advantage of the finding that translation of YSV mRNA, like host mRNA translation, is inhibited in cells superinfected with poliovirus (52, 56). They prepared extracts from poliovirus-infected and uninfected HeLa cells, and after a preincubation period and RNase treatment to eliminate endogenous mRNA translation, tested the ability of the extracts to translate exogenous poliovirus and 7SV mRNA. Poliovirus mRNA was translated by both extracts, but YSV mRNA was translated only in the extracts from uninfected cells. 

RUSS, D.L., and KOCH, G. Translation of individual host mRNAs in MPC-11 cells is differentially suppressed after infection by vesicular stomatitis virus. J. Virol. (1976), 12., 2 2-2 Q. 

HAGKETT, P.B., EGBERTS, E. and TRAUB, P. Selective translation of mengovirus RRA over host mRNA in homologous, fractionated, cell-free translational systems from Ehrlich-ascites tumor cells. Eur. J. Biochem. (1978), 8, 555-561. 

The currently available evidence (1 5) suggested that the binding of host mRNAs to ribosomes was specifically inhibited in infected cells (2). Furthermore, viral mRNA had been shown to outcompete host mMA at the initiation step of protein synthesis (5), and vitro studies demontrated that picomavirus RNA was preferentially translated over host mRNA when both were present in saturating amoimts (6-7). This competition can be relieved by the addition of a specific initiation factor, eIF-4B, suggesting that the amount of factor available and possibly the higher affinity of viral mRNA for this factor determine the preferential translation of viral templates (8). 

Both of these ideas have their attractions, but they seem unable to account for all virus-host systems, particularly those in which the reduction in host cell protein synthesis occurs soon after infection. The increased permeability of the membrane to monovalent cations is generally thought to occur too late in the infection, and the out-competition by viral mRNA can only cause a significant reduction in host cell protein synthesis when viral mRNA has been produced in sufficient amounts to suppress initiation on host mRNA. As a total explanation, the competition hypothesis seems limited to those systems where the overall rate of protein synthesis remains relatively constant after infection, the rate of host protein synthesis declining progressively as the rate of viral protein synthesis increases. It cannot, for instance, explain the rapid reduction in host protein synthesis which occurs shortly after... 

That the mRNAs of many viruses, including polio and VSV, are preferentially translated in intact, infected cells has been demonstrated ingeniously by their relative resistance to hypertonic shock (NaCl), a treatment that inhibits initiation of translation (Nuss et al., 1975 Nuss and Koch, 1976ft). On the other hand, Lodish and Porter (1980) could find no evidence for preferential translation of VSV mRNAs over typical cellular mRNAs in infected cells. Preferential translation over host mRNAs has been shown for EMC virus RNA in vivo (Jen et al., 1978) and in vitro (Lawrence and Thach, 1974 Golini et al., 1976 Svitkin et al., 1978), as well as for mengovirus RNA in vitro (Abreu and Lucas-Lenard, 1976 Hackett et al., l97Sa,b Rosen et al., 1982). 

One question that deserves attention is the fact that, at least in the case of some virus-cell systems, viral RNA translation is inhibited preferentially over host mRNA translation, for example, in reovirus-infected L cells (Gupta et al., 1974). An interesting possibility was raised by Nilsen and Baglioni (1979). They showed that, in extracts of interferon-treated cells, VSV mRNA hybridized with poly (U) at its poly (A) tail or EMC RNA hybridized with poly (I) at its poly (C) tract are more rapidly degraded than the corresponding control mRNAs. They proposed that, in infected, interferon-treated cells, activation of the endoribonuclease takes place near the replicative intermediate of RNA viruses, because the dsRNA moiety therein promotes the formation of (2 -5 )oligo (A) in its vicinity. As a result, the viral mRNA portion in the replicative intermediate may be more sensitive to degradation than host mRNA. 

Many cytopathogenic viruses induce a decline in the rate of host mRNA translation upon infection. Since this shut-off of host translation is accompanied by extensive synthesis of viral protein, and since the decline in host protein synthesis is not concomitant with degradation or inactivation of host mRNA, it is clear that translational control mechanisms are involved in this phenomenon. A number of explanations have been invoked to explain shut-off by various viruses. Here, a few of these will be examined that are related directly to the material already reviewed above, but for a more extensive treatment, surveys by Koch et al. (1982) and elsewhere in this volume should be consulted. 

A related change occurs during the late stages of replication of reovirus in L cells. The early reovirus mRNA is capped and is translated in competition with host mRNA. Late in infection, however, the viral mRNA is uncapped, and it cannot be translated in extracts of uninfected cells, even though it is an efficient template for translation in extracts of infected cells (Skup et al., 1981). Apparently, reovirus induces a gradual modification in the cap-binding proteins, such that late in infection, translation of host mRNA and early viral mRNA comes to a halt, permitting only the translation of uncapped viral mRNA. 

Several host-virus interactions at the level of translational control may involve eIF-2. The ability of a strong viral RNA template, such as mengovirus RNA, to out-compete host mRNA for eIF-2 (Rosen et al., 1982) will lead to the selective translation of viral mRNA concomitant with a displacement of host mRNA from the ribosomes. 

Even though in mengovirus-infected cells, the physical intactness of host mRNA as a whole does not change perceptibly (Colby et al., 1974), host mRNA, once displaced, may become more prone to limited nuclease attack at sites essential for translation. 

Nilsen, T. W., and Baglioni, C., 1979, Mechanism for discrimination between viral and host mRNA in interferon-treated cells, Proc. Natl. Acad. Sci. USA 76 2600. 

Van Steeg, H., Thomas, A., Verbeck, S., Kasperaitis, M., Voorma, H. O., and Benne, R., 1981a, Shut-off of neuroblastoma cell protein synthesis by Semliki Forest Virus Loss of ability of crude initiation factors to recognize early Semliki Forest Virus and host mRNAs, J. Virol. 38 728. 

Babich, A., Feldman, L. T., Nevins, J. R., Darnell, J. E., and Weinberger, C., 1983, Effects of adenovirus on metabolism of specific host mRNAs Transport control and specific translational discrimination. Mol. Cell. Biol. 3 1212. 

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