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ADENOVIRUS Properties of Adenoviruses

and fibers constitute the major adenovirus antigens important in viral classification and disease diagnosis

Structure & Composition Adenoviruses are 7090 nm in diameter and display icosahedral symmetry, with capsids composed of 252 capsomeres. There is no envelope. Adenoviruses contain 13% DNA and 80% protein. The particle has an estimated molecular weight of 150180 x 106. Adenoviruses are unique among icosahedral viruses in that they have a structure called a "fiber" projecting from each of the 12 vertices, or penton bases. The rest of the capsid is composed of 240 hexon capsomeres. The hexons, pentons,

The DNA is linear and double-stranded. There are an estimated 11 virion proteins;. Hexon and penton capsomeres are the major components on the surface of the virus particle. There are group- and typespecific epitopes on both the hexon and fiber polypeptides. All human adenoviruses display this common hexon antigenicity. Pentons occur at the 12 vertices of the capsid and have fibers protruding from them. The penton base carries a toxin-like activity that causes rapid appearance of cytopathic effects and detachment of cells from the surface on which they are growing. Another group-reactive antigen is exhibited by the penton base. The fibers contain typespecific antigens that are important in serotyping. Fibers are associated with hemagglutinating activity. Because the hemagglutinin is type-specific, HI tests are commonly used for typing isolates. It is possible, however, to recover isolates that are recombinants and give discordant reactions in Nt and HI assays.

Classification Adenoviruses have been recovered from a wide variety of species and grouped into two genera: one that infects birds (Aviadenovirus) and another that infects mammals (Mastadenovirus). At least 51 distinct antigenic types have been isolated from humans and many other types from various animals. Human adenoviruses are divided into six groups (AF) on the basis of their physical, chemical, and biologic properties

Adenoviruses of a given group have fibers of a characteristic length, display considerable DNA homology (> 85%, as compared to < 20% with members of other groups), and exhibit similar capacities to agglutinate erythrocytes from either monkeys or rats. Members of a given adenovirus group resemble one another in the guanine-plus-cytosine content of their DNA and in their potential to produce tumors in newborn rodents. Importantly, viruses within a group tend to behave similarly with respect to epidemiologic spread and disease association.

of the endosome. Microtubules are probably involved in the transport of virus particles across the cytoplasm to the nucleus. Uncoating commences in the cytoplasm and is completed in the nucleus, with release of the DNA perhaps occurring at the nuclear membrane. Uncoating is an organized, sequential process that systematically breaks down the stabilizing interactions that were established during maturation of the virus particle. Early Events The goals of the early events are to induce the host cell to enter the S phase of the cell cycle to create conditions conducive to viral replication, to express viral functions that protect the infected cell from host defense mechanisms, and to synthesize viral gene products needed for viral DNA replication. Replication of Viral DNA and Late Events Viral DNA replication takes place in the nucleus. The virus-encoded, covalently linked terminal protein functions as a primer for initiation of viral DNA synthesis. Late events begin concomitantly with the onset of viral DNA synthesis. The major late promoter controls the expression of the late ("L") genes coding for viral structural proteins. There is a single large primary transcript ( 29,000 nucleotides in length) that is processed by splicing to generate at least 18 different late mRNAs. These mRNAs are grouped (L1 to L5) based on the utilization of common poly(A) addition sites. The processed transcripts are transported to the cytoplasm, where the viral proteins are synthesized. Although host genes continue to be transcribed in the nucleus late in the course of infection, few host genetic sequences are

Cycle Virus Attachment, Penetration, and Uncoating The virus attaches to cells via the fiber structures. The host cell receptor for some serotypes is CAR (coxsackie-adenovirus receptor), a member of the immunoglobulin gene superfamily. The interaction of the penton base with cellular integrins following attachment promotes the internalization step. Adsorption and internalization are separate steps in the adenovirus infection process, requiring the interaction of fiber and penton proteins with different cellular target proteins. Adsorbed virus is internalized into endosomes; the majority of particles ( 90%) move rapidly from endosomes into the cytosol (half-life 5 minutes) by a process triggered by the acidic pH

transported to the cytoplasm. A complex involving the E1B 55-kDa polypeptide and the E4 34-kDa polypeptide inhibits the cytoplasmic accumulation of cellular mRNAs and facilitates accumulation of viral mRNAs, perhaps by relocalizing a putative cellular factor required for mRNA transport. Very large amounts of viral structural proteins are made. It is noteworthy that studies with adenovirus hexon mRNA led to the profound discovery that eukaryotic mRNAs are usually not colinear with their genes but are spliced products of separated coding regions in the genomic DNA. Viral Assembly and Maturation Virion morphogenesis occurs in the nucleus. Each hexon capsomere is a trimer of identical polypeptides. The penton is composed of five penton base polypeptides and three fiber polypeptides. A late L4encoded "scaffold protein" assists in the aggregation of hexon polypeptides but is not part of the final structure. Capsomeres self-assemble into empty-shell capsids in the nucleus. Naked DNA then enters the preformed capsid. A cis-acting DNA element near the left-hand end of the viral chromosome serves as a packaging signal, necessary for the DNA-capsid recognition event. Another viral scaffolding protein, encoded in the L1 group, facilitates DNA encapsidation. Finally, precursor core proteins are cleaved, which allows the particle to tighten its configuration, and the pentons are added. A virus-encoded cysteine proteinase functions in some cleavages of precursor proteins. The mature particle is then stable, infectious, and resistant to nucleases. The adenovirus infectious cycle takes about 24 hours. The assembly process is inefficient; about 80% of hexon capsomeres and 90% of viral DNA are not used. Nevertheless, about 100,000 virus particles

are produced per cell. Structural proteins associated with mature virus particles are catalogued in Figure 322B. Virus Effects on Host Defense Mechanisms Adenoviruses encode several gene products that counter antiviral host defense mechanisms. The small, abundant VA RNAs afford protection from the antiviral effect of interferon by preventing activation of an interferon-inducible kinase that phosphorylates and inactivates eukaryotic initiation factor 2. Adenovirus E3 region proteins, which are nonessential for viral growth in tissue culture, inhibit cytolysis of infected cells by host responses. The E3 gp19-kDa protein blocks movement of the MHC class I antigen to the cell surface, thereby protecting the infected cell from cytotoxic T lymphocyte (CTL)-mediated lysis. Other E3-encoded proteins block induction of cytolysis by the cytokine TNFVirus Effects on Cells Adenoviruses are cytopathic for human cell cultures, particularly primary kidney and continuous epithelial cells. The cytopathic effect usually consists of marked rounding, enlargement, and aggregation of affected cells into grape-like clusters. The infected cells do not lyse even though they round up and leave the glass surface on which they have been grown. In cells infected with some adenovirus types, rounded intranuclear inclusions containing DNA are seen. Such nuclear inclusions may be mistaken for those of cytomegalovirus, but adenovirus infections do not induce syncytia or multinucleated giant cells. Although the cytologic changes are not pathognomonic for adenoviruses, they are helpful for diagnostic purposes in tissue culture and biopsy specimens .

Adenovirus Infections in Humans Respiratory Diseases Typical symptoms include cough, nasal congestion, fever, and sore throat. This syndrome is most commonly manifested in infants and children and usually involves group C viruses. These cases are difficult to distinguish from other mild viral respiratory infections that may exhibit similar symptoms. Adenovirusesparticularly types 3, 7, and 21are thought to be responsible for about 1020% of pneumonias in childhood. Adenoviral pneumonia has been reported to have an 810% mortality rate in the very young. Adenoviruses are the cause of an acute respiratory disease syndrome among military recruits. This syndrome is characterized by fever, sore throat, nasal congestion, cough, and malaise, sometimes leading to pneumonia. It occurs in epidemic form among young military recruits under conditions of fatigue, stress, and crowding soon after induction. This disease is caused by types 4 and 7 and occasionally by type 3. Because of vaccine unavailability, the United States military stopped vaccinating against adenoviruses (types 4 and 7) in the 1990s; this was followed by large epidemics affecting thousands of trainees.