Host macromolecular synthesis

Virus infection obviously upsets the regulatory mechanisms of the host, since there is a marked overproduction of nucleic acid and protein in the infected cell. In some cases, virus infection causes a complete shutdown of host macromolecular synthesis while in other cases host synthesis proceeds concurrently with virus synthesis. In either case, the regulation of virus synthesis is under the control of the virus rather than the host. There are several elements of this control which are similar to the host regulatory mechanisms, but there are also some uniquely viral regulatory mechanisms. We discuss various regulatory mechanisms when we consider the individual viruses later in this chapter. 

McSharry, J. J., and Choppin, P. W., 1978, Biological properties of the VSV glycoprotein. I. Effects of the isolated glycoprotein on host macromolecular synthesis, Virology 84 172. 

The most prominent feature of cytocidal virus-cell interaction is the inhibition of host macromolecular synthesis. The understanding of the molecular basis of this inhibition where the host DNA, RNA, and protein synthesis is selectively blocked while virus replication goes on is the central theme of this chapter. The mechanisms by which particular virus-cell combinations accomplish this inhibition appear to be quite variable, and a number of hypotheses have been proposed to explain this phenomenon. It has been suggested that inhibition of host macromolecular synthesis by cytocidal viruses may be initiated by (1) structural components of the input virion, (2) virus-induced products synthesized in the course of infection, (3) viral nucleic acids as either replicative intermediates (double-stranded RNA) or as multiple copies of the viral genome (single-stranded RNA), or (4) the results of perturbations of the cellular membrane which allow for changes in the normal ion concentrations within the cell. 

FIGURE 1.25 The virus life cycle. Viruses are mobile bits of genetic iuformatiou encapsulated in a protein coat. The genetic material can be either DNA or RNA. Once this genetic material gains entry to its host cell, it takes over the host machinery for macromolecular synthesis and subverts it to the synthesis of viral-specific nucleic acids and proteins. These virus components are then assembled into mature virus particles that are released from the cell. Often, this parasitic cycle of virus infection leads to cell death and disease. 

Wengler, G. (1980). Effects of alphaviruses on host cell macromolecular synthesis. In The Togaviruses Biology, Structure, Replication (R. W. Schlesinger, Ed.), pp. 459-472. Academic Press, New York. 

Viruses (from the Latin virus referring to poison) are nonliving obligate intracellular parasites composed of protein and nucleic acid (DNA or RNA) that manipulate the host cell to produce and manufacture more viruses. Viral infection occurs by tire attachment of virus particles to specific cell receptors within the host cell. After fusion of the host cell plasma membrane with the virus outer envelope, the protein-based viral nucleocapsid (containing the viral DNA) is transported to the host cell nucleus, where components of the viral particle inhibit macromolecular synthesis by tire host cell. Herpes viral DNA and new viral nucleocapsid synthesis occurs within the host nucleus, with the acquisition of new viral envelopes via a budding process through the inner membrane of the host nucleus. The mature newly synthesized viral particles are subsequently... 

Because restriction begins soon after infection, both viral RNA and protein synthesis are markedly reduced. The resulting low level of viral macromolecular synthesis delays the inhibition of host functions, impairs virion formation, and prevents physical particle accumulation. Although it is not known which of the three major picornavirus synthetic activities - translation, transcription, or protein processing - is the primary site of restriction, the hypothesis is that at least one of these is impaired. 

Despite the restrictive (abortive) infection described above, macromolecular events that lead to inhibition of host protein synthesis, and ultimately cell death still occur. This would suggest that one might need these specific macromolecules only in catalytic amounts in order to disrupt the cells. Since viral double-stranded RNA is synthesized in such cells, it becomes an ideal candidate as an effector of inhibition of host protein synthesis (see Lucas-Lenard, this volume). 

Inhibition of Host Cell Macromolecular Synthesis following Togavirus Infection... 

Holland, J. J., 1964, Inhibition of host cell macromolecular synthesis by high multiplicities of poliovirus under conditions preventing virus synthesis, J. Mol. Biol. 8 574. 

Most of the research in this field has been done with the prototype vesicular stomatitis virus because of its rapid growth to high titer in a wide variety of cell types and relative ease for purifying large amounts of homogeneous virus particles. VSV rapidly kills many host cells and even more rapidly shuts off cellular macromolecular synthesis (Week and Wagner, 1978). On the other hand, infection of cells with rabies virus results in only a delayed cytopathic effect and dis-... 

The importance of the leader sequence in the shut-off of hostcell macromolecular synthesis will be discussed in detail later. We wish to emphasize here two aspects of the VSV leader RNA pertinent to the shut-off of host cellular macromolecular synthesis. First, the leader sequence contains nucleotide sequences which are essential for controlling VSV transcription, replication, and encapsidation of the virus. Second, there already is some preliminary evidence that VSV contains sequences analogous to other eukaryotic genes. Given the conservation of sequences essential in the transcription of eukaryotic genes, it is tempting to speculate that the VSV leader RNA... 

Gergely, L., Klein, G., and Ernberg, I., 1971, Host cell macromolecular synthesis in cells containing EBV-induced early antigens studied by combined immunofluorescence and autoradiography. Virology 45 22. 

Studies with reoviruses type 2 and 3 have shown that both viruses alter host-cell macromolecular synthesis. Type 1 has not been reported to significantly alter host-cell metabolism. 

The capacity of the S4 gene product to inhibit cellular macro-molecular synthesis may be related to its modulation in persistent non-lytic viral infection of L cells. Ahmed and Fields (1982) have observed that the S4 gene plays a crucial role in the establishment of persistent infections in mouse L cells. The presence of an S4 dsRNA segment that inhibits cellular macromolecular synthesis would be incompatible with a persistent noncytocidal interaction between reovirus and the host cell. Clearly, further studies are needed to provide more detailed insight into the biochemical mechanism, whereby the S4 gene product inhibits protein synthesis. 

Few studies have examined the effects of reovirus type 1 and 2 on host cell macromolecular synthesis. Loh and Soergel (1965) observed that type 2 reovirus inhibits protein and DNA synthesis in human amnion cells but has little effect on RNA synthesis in these cells. Sharpe and Fields (1982) demonstrated that type 2 reovirus produces a decrease in the rate of total RNA synthesis in mouse L cell, whereas, type 3 causes little or no alteration in the rate of RNA... 

The replication of alphaviruses and flaviviruses is supported by both vertebrate and invertebrate cells in tissue culture. Infection by either virus group in permissive vertebrate cells produces infectious viruses and inhibits host cell macromolecular synthesis leading to eventual host cell death, whereas, in permissive arthropod cells, in-... 

The replication of alphaviruses is relatively well understood at the molecular level and extensive review articles on these viruses have recently appeared (Strauss and Strauss, 1977, 1983 Kaariainen and Soderlund, 1978 Schlesinger and Kaariainen, 1980 Garoff et al., 1982). In particular, an excellent review concerning the effects of alphavirus infection on host cell macromolecular synthesis has been written by Wengler (1980), and I will concentrate on recent progress in this field. 

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