Virus adenovirus pdf

Moreover, several strains have been the subject of intensive research and are used as tools in mammalian molecular biology. More than serologically distinct types of adenovirus have been identified, including 49 types that infect humans. The family Adenoviridae is divided into two Genera, the mammalian adenoviruses mastadenoviruses and the avian adenoviruses aviadenoviruses.

The adenoviruses are named after the human adenoids, from which they were first isolated. Several adenoviruses can cause respiratory and conjunctival diseases. In addition, a few types of human adenoviruses induce undifferentiated sarcomas in newborn hamsters and other rodents and can transform certain rodent and human cell cultures.

There is currently no evidence that adenoviruses are oncogenic in humans, but the possibility remains of interest.

The main target for human adenoviruses is the respiratory tract. Various adenoviruses can also cause acute follicular conjunctivitis, epidemic keratoconjunctivitis, and, less frequently, cystitis and gastroenteritis Fig. In infants, the most common clinical manifestations of adenovirus infections are acute febrile pharyngitis and pharyngeal-conjunctival fever.

In military recruits, acute respiratory disease is the predominant form of adenovirus disease, with adenovirus pneumonia as a not infrequent complication. Except for outbreaks in military groups and occasionally among children, adenovirus infections do not occur epidemically.

The virus is probably transmitted via droplets of respiratory or ocular secretions. The adenovirus particle consists of an icosahedral protein shell surrounding a protein core that contains the linear, double-stranded DNA genome Fig. The shell, which is 70 to nm in diameter, is made up of structural capsomeres. The 12 vertices of the icosahedron are occupied by units called pentons, each of which has a slender projection called a fiber.

The capsomeres that make up the 20 faces and the edges of the isocahedron are called hexons because they form hexagonal arrays. The shell also contains some additional, minor polypeptide elements. Structural model of the adenovirus virion. The Roman numerals refer to the standard designations of the viral structural proteins according to their decreasing molecular masses.

FP stands for fracture plane in freeze etching. From Brown DT, Westphal more Figure shows the genetic map of a prototype adenovirus, adenovirus type 2 Ad2. The genome is divided into early functions E1A, E1B, E2A, E2B, E3, and E4 regions , which are expressed first during viral replication, and late functions L1 to L5 regions , which are usually expressed after the early functions and after the beginning of viral DNA replication.

The late genes encode the viral structural proteins. In the case of Ad2, DNA replication begins 6 to 8 hours after infection of cultured human cells. In , RNA splicing was discovered in adenovirus-infected cells. Both strands of the double-stranded DNA code for specific viral functions Fig.

The termini of the DNA molecule carry inverted repeat sequences so that denatured single strands can form circular DNA molecules. Genetic map of adenovirus type 2. The coding capacities of individual genome segments are indicated by the sizes of polypeptides K represents 1, Dalton or by the designations of the virion structural proteins Roman numerals; see Fig. The double-stranded more At present, 47 types of human adenoviruses have been identified Table five additional candidate types are under investigation.

The genomes of the different adenoviruses are genetically distinct and vary somewhat in size. Host cells differ in permissivity for adenovirus types Table In permissive cells, the virus multiplies productively and kills the host cell. Other cells are semipermissive, allowing replication at low efficiency, whereas in still others replication is blocked and the infection is abortive.

As discussed below, in some abortive infections all or part of the genome may be integrated into the host DNA, resulting in a latent infection, which may lead to oncogenic transformation.

The virion enters host cells either by attaching to the cytoplasmic membrane and then being engulfed into the cytoplasm in a membrane-bound vesicle viropexis or by directly penetrating the cytoplasmic membrane. The viral DNA is gradually uncoated and enters the nucleus of the cell, most probably as a nucleoprotein complex that still contains viral core proteins Fig.

Early events in the interaction of the adenovirion with a host cell. The figure shows a model based on biochemical studies that depicts the major steps in viral penetration and uncoating.

The viral DNA is transcribed and replicates in the nucleus of the host cell. These proteins return to the nucleus, where new virions self-assemble. The mass of newly synthesized virus particles can assume crystal-like arrangements. The bulk of the virions may not be easily released from the nucleus and the cell.

There is evidence that extracellular adenovirus type 12 virions have a considerably higher specific infectivity than intracellular virions. During active viral release, the newly synthesized virions may receive properties conferring high infectivity toward the host cells. Viral DNA replication can proceed bidirectionally and by single-strand displacement from either end of the DNA duplex. Most of the adenovirus genes Fig. This program is regulated by the nucleotide sequences and the structure of the viral promoters and by a host of cell-encoded transcription factors that recognize specific upstream and downstream nucleotide sequence motifs in the promoters.

Genes in the E1A region of the adenovirus genome are the first to be transcribed. One protein product of this gene region is a transactivator that is essential for the activation of all other viral genes. This immediate-early viral function can also activate or inactivate certain cellular genes. Among the E3-encoded functions, one is a 25, 19, -molecular-weight glycoprotein responsible for the interaction with cell membrane-associated proteins major histocompatibility complex.

The E3 region-encoded functions may be unnecessary for viral replication in cell culture, but essential for the interaction with the intact defense system of an organism and for the modulation of host functions. The late viral L1 region can also be transcribed early in the infection cycle, probably to a limited extent. All the late viral functions are under the control of the major late promoter MLP components, which are located at about 17, 20 and 27 map units on the viral genome.

The gene encoding the fiber structural protein can also be controlled by the x, y, and z leaders Fig. The regulation of promoter activity in all biologic systems is dominated by the interaction of promoter sequence motifs with specific factors. These protein factors in turn bind to a host of further proteins, cofactors, that determine the structure of transcription complexes. Viral promoters are conditioned to the factors present in specific host cells.

Enhancers and silencers are quantitative modulators of promoter function. Both act independently of position and orientation and can exert their influence over relatively long distances.

Enhancers strengthen promoter activity, whereas silencers have a negative effect, abrogating or diminishing promoter function.

Enhancer and silencer elements are species specific. It prevents activation of a protein kinase that is responsible for the phosphorylation and ensuing inhibition of the eIF-2 translation factor.

This kinase can be induced by interferon. Virus interaction with a host cell can be blocked at many different steps, thus leading to an incomplete or abortive cycle. Depending on the permissivity of the host cell, different types of adenovirus-host cell interactions can be distinguished Table Many cultured human epithelioid cell lines are productively infected by human adenoviruses. Rat cells are semipermissive e.

The outcome of an adenovirus infection depends on the animal species, cell type, and virus type involved. For example, hamster cells are abortively infected with human Ad The viral DNA is transported to the nucleus, where part of it is integrated into the host cell genome.

Both in productively and in abortively-infected cells, the viral DNA gravitates towards and becomes transiently associated with the host cell chromosomes as demonstrated by fluorescent in situ hybridization. Most of the early viral genes are transcribed, but the late genes remain silent in the host cells. Ad12 DNA replication in hamster cells cannot be detected with the most sensitive techniques.

The major late promoter of Ad12 DNA is inactive in both uninfected and Adinfected hamster cells, whereas it functions in infected human cells. Ad2 cannot replicate in monkey cells; in this case, the translation of some of the late viral mRNAs is amiss. The adenovirus genome persists, perhaps for a very long time, in cells of the human tonsils.

It is not known how adenovirus replication in this human organ is restricted. Adenovirus disease results from localized virus multiplication at the portals of entry Fig. The pathogenesis of localized infections is presented in Chapter Latency and persistence of, as well as oncogenicity by, DNA viruses are frequently associated with integration of all or part of the viral genome into the host cell DNA.

Integration of adenovirus DNA has been demonstrated in abortively infected cells, in adenovirus-transformed cells, and in Adinduced tumor cells. However, it is not known whether this recombination can lead to stable integration, because in the productive infection cycle the host cells are eventually killed. There is evidence that early in productively infected human cells Ad12 DNA becomes preferentially integrated into human chromosome 1. Soon after infection, the viral genome may be inserted into selective sites of the cellular genome.

The initial steps of viral malignant transformation could involve insertional mutagenesis at a certain number of selective cellular sites.

From the viewpoint of the geneticist, this model of viral oncogenesis is still one of the more attractive possibilities. Moreover, after being inserted initially at a limited number of sites and eliciting decisive mutagenic events e. Recently, an interesting alternate mechanism of insertional mutagenesis in adenovirus-transformed or Adinduced tumor cells was discovered.

Insertion of Ad12, plasmid or bacteriophage lambda DNA into established mammalian genomes can lead to extensive changes in patterns of cellular DNA methylation far away from and on chromosomes different from those of the site of viral DNA integration.

Since patterns of DNA methylation are related to expression patterns and genome organization, alterations in patterns of DNA methylation might affect many cellular functions whose altered expression may play a role in insertional mutagenesis and viral oncogenesis. Analyses of several different integration sites in transformed cell lines suggest that transcriptionally active regions of the host cellular genome, which have a characteristic chromatin structure, are most apt to recombine with foreign viral DNA.

In general, considerable variability is observed in the structure of the site of integration. Cellular DNA can be deleted at the insertion site, or the cellular site can be preserved to the last nucleotide. The adenovirus system has also served as a model for studying the function of sequence-specific promoter methylations in mammalian cells.

Upon integration of the adenovirus genome into the host cell genome, a highly specific pattern of methylation is de novo imposed on the integrated viral genome during many cell generations.

This de novo methylation is not primarily dependent on nucleotide sequence. Site of integration, structure of integrate and genetics of the host cell are contributing factors. There is evidence from analyses in many different biologic systems that sequence-specific promoter methylations can cause long-term gene inactivation. Adtransformed hamster cells or Adinduced hamster tumor cells maintained in culture can eventually lose the integrated copies of viral DNA.

Cells from a number of rodent species and humans can be transformed in culture by adenoviruses. The frequency of malignant transformation is extremely low, and this has prohibited quantitative studies in this system. Transformed human cell lines have also been described. Some adenoviruses, such as Ad2 and Ad5, are not oncogenic in animals at all. Tumorigenic potential has been attributed to the capacity of some adenoviruses e. Most of the adenovirus-induced tumors, tumor cell lines, and transformed cell lines carry one or several copies of the viral genome integrated into the chromosomes.

The tumor or transformed state is also associated with the differential expression of the integrated viral genes. The early viral genes are often the predominant genes expressed. It is thought that the E1 region of the viral genome is particularly important in eliciting the transformed state. However, the continued presence of the viral genome, or of parts of it, may not be essential for the maintenance of the transformed state.

The so-called oncogenes represent a set of cellular genes that are involved in many different ways in growth control. Oncogenes in adenovirus-induced tumor or transformed cells have received surprisingly little attention. The few studies on this topic have reported occasional changes of oncogene activity, particularly for the myc gene.

Moreover, E1 proteins can bind tightly to the product of the retinoblastoma RB or the p53 gene, which are considered to be anti-oncogenes. It has been suggested that the fixation of the anti-oncogene products by E1 proteins might contribute to the transformation of cells. The interplay of several viral and cellular factors may eventually alter the cellular growth control and weaken or overcome the host defenses in such a way that an adenovirus-transformed rodent cell can grow into a solid tumor.

Since many human tumors do not contain even traces of adenovirus genes or gene products, the possibility that adenoviruses cause human tumors is low. New, more sensitive techniques are now available. Since even experimentally induced tumors can lose the viral genome and retain oncogenicity, this possible mechanism of transformation of human cells is still being studied. Adenoviruses were first isolated from human adenoids, and the persistence of these viruses or their DNA in the human adenoids has been studied.

It is not known whether adenoviruses or their genomes can persist in other human organ systems. When the adenoids are removed during acute adenovirus infection, intact viral genomes are present. In contrast, when adenoid tissue obtained during a symptom-free interval or from a chronically-infected carrier is analyzed, only a small number of cells seem to harbor the viral genome, which may not be intact. These cells do not produce infectious virus. It is not known to what extent adenovirus virions continue to replicate in the adenoids throughout adult life.

In adolescents and adults a high prevalence of circulating neutralizing antibodies contributes to widespread immunity against adenovirus infections. Cytotoxic T lymphocytes also recognize and destroy adenovirus-infected cells. Interferon is induced by adenoviruses in vitro but fails to inhibit many adenovirus types, perhaps due to the function of VA RNA.

Nevertheless, in a few preliminary studies interferon has been reported to be effective in the treatment of adenovirus conjunctivitis. People with weakened immune systems or existing respiratory or cardiac disease are more likely than others to get very sick from an adenovirus infection….

Adenoviruses are common viruses that typically cause mild cold- or flu-like illness. Adenoviruses can cause illness in people of all ages any time of year.

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