The viral genomes and mRNAs have been completely sequenced, viral mutants that are unable to induce transformation have been isolated, and the transforming potentials of individual viral genes have been determined by gene transfer assays. Transformation by these viruses has thus been found to result from expression of the same viral genes that function in early stages of lytic infection. The genomes of SV40 and polyomavirus are divided into early and late regions. The early region is expressed immediately after infection and is required for synthesis of viral DNA.
The late region is not expressed until after viral DNA replication has begun, and includes genes encoding structural components of the virus particle. The early region of SV40 encodes two proteins , called small and large T antigens, of about 17 kd and 94 kd, respectively Figure Their mRNAs are generated by alternative splicing of a single early-region primary transcript.
Polyomavirus likewise encodes small and large T antigens, as well as a third early-region protein of about 55 kd, designated middle T. Transfection of cells with cDNAs for individual early-region proteins has shown that SV40 large T is sufficient to induce transformation, whereas middle T is primarily responsible for transformation by polyomavirus.
The SV40 genome. The genome is divided into early and late regions. Large and small T antigens are produced by alternative splicing of early-region pre-mRNA. During lytic infection, these early-region proteins fulfill multiple functions required for virus replication. In addition, the early-region proteins of SV40 and polyomavirus stimulate host cell gene expression and DNA synthesis.
Since virus replication is dependent on host cell enzymes e. Most cells in an animal are nonproliferating, and therefore must be stimulated to divide in order to induce the enzymes needed for viral DNA replication.
This stimulation of cell proliferation by the early gene products can lead to transformation if the viral DNA becomes stably integrated and expressed in a nonpermissive cell. As discussed later in this chapter, both SV40 and polyomavirus early-region proteins induce transformation by interacting with host proteins that regulate cell proliferation. For example, SV40 T antigen binds to and inactivates the host cell tumor suppressor proteins Rb and p53 , which are key regulators of cell proliferation and cell cycle progression see Figures The papillomaviruses are small DNA viruses genomes of approximately 8 kb that induce both benign and malignant tumors in humans and a variety of other animal species.
Approximately 60 different types of human papillomaviruses, which infect epithelial cells of several tissues, have been identified.
Some of these viruses cause only benign tumors such as warts , whereas others are causative agents of malignant carcinomas, particularly cervical and other anogenital cancers. The mortality from cervical cancer is relatively low in the United States, in large part as a result of early detection and curative treatment made possible by the Pap smear. Cell transformation by human papillomaviruses results from expression of two early-region genes, E6 and E7 Figure The E6 and E7 proteins act analogously to SV40 T antigen by interfering with the function of the cellular Rb and p53 proteins.
In particular, E7 binds to Rb, and E6 stimulates the degradation of p53 by ubiquitin -mediated proteolysis. Herpesvirus ateles is a closely related virus of spider monkeys Ateles spp. Similar to other rhadinoviruses, the genome of Herpesvirus saimiri harbours a series of virus genes with pronounced homology to cellular counterparts including a D-type cyclin, a G-protein-coupled receptor, an interleukin, a superantigen homologue, and several inhibitors of the complement cascade and of different apoptosis pathways.
Preserved function has been demonstrated for most of the homologues of cellular proteins. These viral functions are mostly dispensable for the transforming and pathogenic capability of the virus. However, they are considered relevant for the apathogenic persistence of Herpesvirus saimiri in its natural host.
Ability to produce temporary or permanent damage in the host via:. Induction of formation of substances which are not specified by the viral genome, but are apparently cellular products normally not produced by the cell. Induction of structural alterations in the host cel l. Some viruses enter host tissues directly by trauma or insect bite, but most infections start on the mucous membranes of the respiratory and alimentary tracts. To initiate infection, virus particles must first survive on these mucous-covered membranes in the presence of viral and non-viral commensals.
Subsequently, to replicate, the virus must enter host cells either in the mucous membrane itself or in tissues farther afield after penetration through the surface membrane. Replication in mucous membrane cells can produce the disease effects directly as in respiratory diseases, but sometimes it provides a staging post for subsequent damaging replication in another site, e.
The host anti-viral defense mechanisms include:. Non-specific host defense mechanisms. How virulent viruses overcome these non-specific and specific virus inhibitors is unknown. They do bypass these inhibitors and infect the mucosal cells in certain diseases influenza, common cold.
Other viruses pass through the mucosa without establishing infection in the membrane itself, but infect other body tissues. Although ability to replicate in host tissues is not the only factor in virus virulence, it is essential, and the more rapid the rate of replication, the more likely the success of the virus in producing its disease syndrome. Ability to proliferate in vivo depends on an inherent ability to replicate in the biochemical conditions of the host tissues, coupled with a capacity to resist or not to stimulate host defense mechanisms which would otherwise kill or remove them.
The ability of a virus to replicate in a particular cell depends on inherent features of the cell as well as the virus. These features can be involved in one or more stages of replication:.
Provision of energy and precursors of low-molecular-weight compounds. Assuming that a virus can enter a cell and complete its normal replication cycle, what are some specific temporary or permanent damages incurred by the cell? The most obvious is cell lysis. This may occur due to a physical internal pressure exerted by the multiplying virus. The cell becomes filled with virus and merely bursts.
This is common with bacterial viruses, but not with animal viruses. With animal viruses, cell lysis is usually the result of one of four types of allergic reactions:. Type I. IgE antibodies fixed to mast cells react with the complete virus or with viral components, triggering release of histamine and activation of slow reacting substance SRS-A and eosinophil chemotactic factor ECF-A.
These act on blood vessels, smooth muscle and secreting glands to give the typical anaphylactic type reaction. Allergy to viruses usually results in a very localized anaphylactic reaction. Furthermore this viral-mediated reaction is limited to a few virus species. Type II. Try out PMC Labs and tell us what you think. Learn More. Simian virus 40 SV40 infection of human skin fibroblast and human tumor cells resulted in the expression of T-antigen and transformed foci.
By examining various conditions of input virus multiplicity and initial cell density, the systematic variation of T-antigen determination was minimized. Volume of virus inoculum was critical for some cell lines, but not for others.
Cell passage level had no general effect on T-antigen expression, although specific cell lines demonstrated increased or decreased levels of T-antigen expression with serial passage for no apparent reason. T-antigen expression correlated with virus-induced cell transformation focus formation at two different multiplicities.
In addition, T-antigen assays at 3 days gave consistently more reproducible results than transformation assays at 21 days in seven cell lines tested at two multiplicities of infection. These results defined input multiplicity as the major source of systematic variability and will permit development of a more reproducible tool in the evaluation of individuals at high risk of cancer.
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