Other Picornaviruses

The observed differences between the results obtained by investigators of protein synthesis regulation by the cardioviruses and those studying poliovirus remained unreconciled for several years, and were largely ignored by each other. This was likely due to a firm belief held by almost all picornavirologists that the basic replication 

The same study drew attention to the differences in kinetics of host cell shut-off in the two virus-infected cells, documenting the rapid inhibition of cellular protein synthesis by polio infection which occurred prior to and during the time that viral protein synthesis was increasing, and which demonstrated the selectivity of the inhibition. EMC protein synthesis, in the same cells, was not preceded by or accompanied by an abrupt inhibition of cellular protein synthesis. Rather, concurrent synthesis of cellular and viral protein was seen throughout the cycle with the ratio of viral to total protein synthesis steadily increasing with time. 

Since extracts of infected and uninfected cells translated both viral and cellular mRNAs with equal efficiencies, other explanations for the preferential synthesis of viral mRNA were sought. Simultaneous addition of viral and cellular mRNAs to either the plasmacytoma (Lawrence and Thach, 1974) or Ehrlich ascites (Abreu and Lucas-Lenard, 1976) cell-free systems resulted in suppression of translation of cellular mRNAs, whereas, viral RNA was translated 

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XIII. Receptors for Other Picornaviruses A. Foot-and-Mouth Disease Vims... 

FKDV particles differ from those of other picornaviruses in being susceptible to the action of proteolytic enzymes. A summary of the effect of trypsin on the virus is given in Table 2. The... 

The above sections have described several different mechanisms which have been proposed and explored during the last decade to explain the selective inhibition of host cell protein synthesis in poliovirus-infected cells. Admittedly, this author s bias has presented each mechanism as a straw man, requiring the reader to await what is perceived at this time to be the correct explanation for this aspect of the regulation of protein synthesis in poliovirus-infected cells. The favored model will be discussed in this and subsequent sections. It is important to state, however, that there is no convincing evidence that other picornaviruses are necessarily similar to poliovirus in the mechanism(s) utilized for host protein synthesis inhibition and that the mechanisms described above, as well as others, cannot all be dismissed in every case of picorna virus-induced protein synthesis inhibition. Thus, the data for other picornaviruses will be reviewed separately. 

Virtually no studies of host cell protein synthesis inhibition have been conducted for other picornaviruses such as rhino virus, foot-and-mouth disease virus, Theiler s virus, coxsackie, echo, or hepatitis A... 

Although the biochemistry of translational initiation is steadily being unraveled, and the block imposed by poliovirus in HeLa cells is simultaneously becoming clarified, other picornaviruses may interact with other cell types in different ways. Infection of at least some cells with the cardioviruses, EMC or mengovirus, does not appear to produce the same initiation factor inactivation as does poliovirus in HeLa cells, and the regulation of protein synthesis in such cells is not well understood. The majority of picornaviruses, in natural host tissue or in cultured cells, have not been studied at all. Thus, despite a long-standing interest in the phenomenon of virus-induced interference with host cell protein synthesis, many questions remain to be answered. 

One of the most striking results that has emerged from the high-resolution crystallographic studies of these icosahedral viruses is that their coat proteins have the same basic core structure, that of a jelly roll barrel, which was discussed in Chapter 5. This is true of plant, insect, and mammalian viruses. In the case of the picornaviruses, VPl, VP2, and VP3 all have the same jelly roll structure as the subunits of satellite tobacco necrosis virus, tomato bushy stunt virus, and the other T = 3 plant viruses. Not every spherical virus has subunit structures of the jelly roll type. As we will see, the subunits of the RNA bacteriophage, MS2, and those of alphavirus cores have quite different structures, although they do form regular icosahedral shells. 

FMDV is the outlier of picornavirus structures (Fry et al, 1990), with capsid proteins that are 20% shorter than in the other viruses. The VPl loops near the 5-fold axis are sheared off, so that there is not the pronounced 5-fold protrusion and canyon of rhinoviruses and polioviruses (Acharya et al, 1989). This leaves a longer VPl GH loop as the prominent surface feature, which is highly antigenic, the site of the RGD receptor attachment sequence, but disordered in structure unless a disulfide is reduced (Acharya et al, 1989 Fox et al, 1989 Lea et al, 1994 Rowlands et al, 1994). FMDV VP2 is more similar to its homologs, except that the GH loop puff is 50 residues shorter than in poliovirus, and its space is occupied pardy by the longer VPl GH loop. 

The togaviruses, which are a little larger than the picornaviruses, have an icosahedral core surrounded by a lipid membrane. Yellow fever and rubella (German measles) are both caused by togaviruses. Other togaviruses, such as Sindbis viras and Semliki Forest virus, have become important in biological research. 

Lipid-enveloped Non-lipid Other, larger viruses picornaviruses non-lipid viruses... 

Hepatitis B virus (HBV) is widespread throughout human populations, specially in Asia and Africa, and it has been estimated that over 200 million carriers exist, some of whom are eventually expected to develop liver carcinoma or cirrhosis. HBV shows a strict tropism for liver hepatocytes in which it displays a protected replication with resultant foci of liver necrosis. The virus is a member of the Hepadnaviridae, along with several other species, and it replicates by a mechanism which appears to be unique to this family. In contrast, hepatitis A virus is a picornavirus and the hepatitis D agent appears to be a viroid-like RNA enclosed within a hepatitis B capsid, and consequently depends upon its association with the HBV for its spread and survival. Control may be effected by passive immunization (with hyperimmune globulin) or by various types of vaccines which are currently being developed and improved. Specific chemotherapy has not been consistently successful, but in some countries (e g., India and China), plant extracts have provided some success. 

In this review I have outlined several theories that have been proposed to explain the mechanism by which picornaviruses inhibit cellular protein synthesis. Some theories seem less likely than others. Inhibition by ds ENA, for example, is no longer thought to be a likely possibility. In cell-free extracts ds ENA inhibits both cellular and viral mRNA translation (61). The inhibitor of cellular protein synthesis would be expected to be selective in its inhibitory activity. It is also apparent that picornavirus infection does not result in the degradation or alteration of cellular mENA (9> 27, 29 51). So,.too, experiments demonstrating that protein synthesis inhibition takes place in the absence of significant viral ENA synthesis (I4) tend to weaken the argument that protein synthesis inhibition results from direct competition of viral mENA with cellular ENA for initiation factor eIE-4D (47) As mentioned earlier, superinfection with poliovirus of cells infected with VSV prevents VSY mENA translation (J2, 56). In lysates from uninfected HeLa cells, however, 7SY mENA translation is favored over poliovirus mENA translation when both mENA species are present in equimolar saturating concentrations (55) If competition were a major cause of cellular protein synthesis inhibition, one would have expected poliovirus mENA to out-compete VSV mENA in cell-free translation, not the contrary. 

Analysis of a second picornavirus was deemed important in light of the conflicting data from two laboratories, to demonstrate that the utilization of two initiation sites for vitro translation was not unique to a particular laboratory virus stock. Consequently, experiments similar to those described above were performed with protein-synthesizing extracts from LSc poliovirus-infected cells. The LSc strain is a multi-step, temperature-sensitive mutant derived from the Mahoney strain of poliovirus type 1. It was selected for these studies because previous work had suggested that initiation of translation of LSc virus proteins vivo showed a greater resistance to hypertonic salt treatment than did translation of Mahoney virus proteins (39)i and other workers have... 

Actiially, the first demonstration that the infectivity of an animal virus resided exclusively in its ENA was provided by Colter al in 1957 (l6)s Experimental evidence was then produced that the MA extracted from mengovirus-infected Ehrlich ascites cells was infectious. This observation was soon extended to poliovirus RNA (17). Retrospectively considered, it was a very happy circumstance indeed that this pioneer work was carried out in the picornavirus system, for we now know that similar experiments performed with other RRA-containing animal viruses (e.g. influenza) would never have produced such a clearcut result. 

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