Friday, 12 July 2013

Microbiology V ; VIRUSES

A. Overview. Viruses are obligate intracellular parasites. They are inert in the extracellular environment and depend on the intracellular machinery of the living host cells for replication. As such, reproduction of viruses occurs by assembly of the individual components rather than by binary fission.
B. Taxonomy and nomenclature. Viruses are classified into families (designated with the -viridae suffix), by genome structure, virion morphology, and means of replication. Further classification and naming of individual members within a family is often based on mode of transmission, associated disease, host range, and tissue or organ tropism.
1. Viral structure
a. The virus particle (virion) consists of a nucleic acid genome packaged into a protein coat (capsid), which may be surrounded by a membrane (envelope). The virion may also contain enzymes, nucleic acid–binding proteins, and other viral accessory proteins necessary for virion structure or initial replication of the virus within the host cell.
b. The genome of the virus consists of either DNA or RNA, but not both. The DNA can be single or double stranded, linear or circular. The RNA can either be positive sense (like mRNA), negative sense, or double stranded. Additionally, RNA genomes may be segmented into pieces, with each piece containing a portion of the total genome.
c. Viral proteins and enzymes. Structural proteins may be part of the capsid or associated with the nucleic acid or envelope. Nonstructural viral proteins are usually enzymes that are necessary to produce viral components important for viral replication (e.g., reversetranscriptase in retroviruses). Smaller viruses tend to be more dependent on host cell machinery than larger viruses, which tend to encode more viral enzymes in the viral genome and have more viral proteins packaged within the virion particle.

2. Naked capsid (nonenveloped) viruses. The capsid is a rigid protein structure and generally determines the overall shape of the virus. The capsid proteins assemble into repeating structural units (capsomeres) that have chemical features to allow them to fit together without complicated assembly processes, often arranging in icosahedral (20-sided) symmetry. The capsid proteins are important for binding of the virion to the receptor on the host cell in order to infect that cell. Naked capsid viruses are generally more environmentally stable and tend to be more resistant to drying, acid, detergents, gastric acid, and bile.

3. Enveloped viruses consist of the nucleocapsid as described earlier (usually icosahedral or helical in shape), surrounded by an envelope, which is a membrane composed of lipids, proteins, and glycoproteins. Virally encoded proteins and glycoproteins associated with the envelope include the matrix proteins, which line the inside of the envelope, and viral attachment proteins that project through the envelope (spikes). The envelope is easily disrupted, which makes most enveloped viruses environmentally labile, such that they typically must remain wet, cannot survive the gastrointestinal tract, and are easily inactivated by detergents, acid, and heat.

4. Atypical virus-like agents
a. Delta agents (e.g., hepatitis D) have viral nucleic acid but require the presence of a helper virus (for hepatitis D, the helper virus is hepatitis B virus) in order to replicate.

b. Prions are small proteinaceous infectious particles that, unlike viruses, do not have a virion structure or genome. Prions are resistant to a wide range of chemical and physical treatments, including disinfectants, formaldehyde, and heat up to 80°C. Human prion diseases tend to affect neural tissue following a long incubation period and are generally described as transmissible spongiform encephalopathies (TSEs) that can manifest as sporadic, genetic, or infectious diseases. The underlying feature of prion diseases appears to be a conversion of a host-encoded protein to a conformationally distinct isoform that is responsible for the consequences of the disease. Prions are transmitted by contact with infected tissue through transplantation, use of contaminated medical devices, or ingestion. Prion diseases of human importance include kuru, Creutzfeldt-Jakob disease (CJD), and variant CJD (vCJD), which is considered to have been transmitted to humans by ingestion of meat prepared from cattle affected by bovine spongiform encephalopathy (BSE).

C. Viral replication. 
The major steps in viral replication are similar for all viruses, although the individual features of each step can vary. The host cell machinery is commandeered to replicate the viral genome and synthesize viral proteins to assemble the progeny viruses; any processes not provided by the host cell must be encoded by the viral genome.
1. Attachment. Viral attachment proteins or glycoproteins (spikes) initiate attachment to the specific receptor on the host cell. The distribution of the host cell receptor determines the viral host range or tissue tropism (e.g., neurotropic, lymphotropic).

2. Penetration and uncoating. The mechanism for internalization (penetration) of the virus depends on the virion structure and cell type. Following attachment, a naked capsid virus enters the cell via endocytosis. An enveloped virus enters the cell either by membrane fusion, which delivers the capsid or nucleic acid directly to the cytoplasm, or by endocytosis followed by vesicle membrane fusion. Once internalized, the nucleic acid must be uncoated to make the viral genome accessible to begin the process of reproduction. The process of uncoating varies with the type of virus.

3. Expression of viral genome and synthesis of viral components. The next steps of viral replication depend on the type of virus.
a. DNA viruses can use host cell transcription machinery to synthesize mRNA directly. For positive sense RNA viruses, the viral genome serves as the initial mRNA transcript. Negative sense RNA viruses need to generate mRNA from the viral RNA genome, which requires a virally encoded RNA polymerase. Upon entry into the host cell, retroviruses create a DNA copy of the RNA genome using the retroviral reverse transcriptase. mRNA is then made from the DNA copy as described earlier.
b. Early protein synthesis by translation of the mRNA makes use of host cell translation processes, including ribosomes, tRNAs, and amino acids.
c. Genome replication, like mRNA synthesis, depends on the type of viral genome.
d. Late protein synthesis includes the synthesis of capsid and other structural proteins necessary for assembly of the progeny virions.

4. Maturation and release. Association of the viral genome with viral proteins (capsid and accessory proteins) to assemble the virion particle typically occurs in the cytoplasm, the nucleus, or at the cytoplasmic membrane. 
Nonenveloped viruses are usually released after the host cell lyses.
Enveloped viruses assemble at a host cell membrane, usually the cytoplasmic membrane, and then exit the host cell by budding through the membrane, which creates the associated membrane envelope.

D. Types of viral infections
1. Infection of a cell by a virus may result in a lytic infection in which the host cell will die, often due to the interference of normal cellular function by the production of progeny virions.
2. Viral infections, such as measles, herpes simplex virus, and respiratory syncytial virus, can lead to fusion of neighboring cells, forming giant multinucleated cells (syncytia).
3. Host cells infected with a virus may also demonstrate changes in appearance that can assist with diagnosis (e.g., Negri bodies in brain tissue due to rabies infection).
4. Persistent infections in which virus persists in the host for a long period may take several forms.
a. A latent infection occurs when the virus persists within the host cell but new virions are
not synthesized. Latent infections may become active to allow viral replication (e.g., herpes simplex virus, varicella-zoster).
b. A chronic infection is a state in which the host cell continues to replicate the virions (e.g.,
chronic hepatitis B infection).
c. Transforming or oncogenic viral infections are persistent infections that stimulate uncontrolled growth or immortalization of the host cell (e.g., human papilloma virus associated with cervical cancer). Different oncogenic viruses have different means of immortalizing the cell.

E. Mechanisms of pathogenicity
1. Host cell damage and altered function can be the source of the symptoms of the viral infection.
2. Immune responses, specifically inflammatory reactions and hypersensitivities initiated by antiviral immunity, can contribute to the symptoms of a viral illness (e.g., interferon release associated with respiratory tract viral infections). Rashes (exanthems) are often due to the immune response directed to viral antigens and thus to infected cells (e.g., measles, parvovirus B19).
3. Some viruses modulate the immune response, resulting in increased susceptibility to secondary infections (e.g., measles virus infections, cytomegalovirus infections).

F. Genetic variation
1. Mutations occur spontaneously in viral genomes, creating new strains with different properties. In the context of an infection, individual viral strains or mutants with advantageous properties have a selective advantage and can quickly become the predominant strain. The high mutation rate of HIV promotes the development of antiretroviral drug-resistant strains after the initiation of treatment. Other changes that can result from genetic variation include changes in virulence, host range specificity, or tissue/cell tropism (tissue tropism is the cells and tissues of a host which support growth of a particular virus or bacteria.).
2. When two segmented RNA viruses infect the same host cell, the resulting progeny virions can be reassorted versions of the original two strains. Antigen shift in the influenza virus is an example of reassortment that leads to major antigenic changes.

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