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19.3.1: Viruses

Viruses are obligate intracellular parasites. Probably there are no cells in nature that escape infection by one or more kinds of viruses. Viruses that infect bacteria are called bacteriophages. Outside the cell, they consist of particles called virions.

Fig. 19.3.1.1 Poliovirus

Virions range in size from as small as the poliovirus shown above magnified some 450,000 times (courtesy of A. R. Taylor), which is 30 nm in diameter (about the size of a ribosome) to as large as Pithovirus sibericum an amoeba-infecting virus which, at 1,500 nm, is larger than many bacteria.

  • The virion consists of
    • An outer shell, the capsid, made of protein. The capsid is responsible for
      • protecting the contents of the core
      • establishing what kind of cell the virion can attach to infecting that cell
      Some capsids contain other ingredients (e.g., lipids, carbohydrates), but these are derived from their host cells.
    • an interior core containing
      • the genome; either DNA or RNA The genes are few in number (3–100 depending on the species). They encode those proteins needed for viral reproduction that the host cell will not supply.
      • Often, one or more proteins (enzymes) needed to start the process of reproduction within the host cell.

Life Cycle

  • The virion attaches to the surface of the host cell - usually binding to a specific cell surface molecule that accounts for the specificity of the infection. Example: HIV-1, the cause of AIDS, binds to the chemokine receptor CCR5 found on human lymphocytes and macrophages.
  • Once inside the cell, the virions are uncoated.
  • Viral genes begin to be expressed leading to the synthesis of proteins needed for
    • replication of the genome
    • synthesis of new proteins to make new capsids and cores.
  • The details of these processes differ for different types of viruses and are described below for each type.

Viral Genomes

Either DNA or RNA, never both.

DNA viruses can be further divided into

  • those that have their genes on a double-stranded DNA molecule (dsDNA). Example: smallpox
  • those that have their genes on a molecule of single-stranded DNA (ssDNA). Example: Adeno-Associated Virus (AAV)

RNA viruses occur in four distinct groups:

  1. Those with a genome that consists of single-stranded antisense RNA; that is, RNA that is the complement of the message sense. This is also called negative-stranded RNA. Examples: measles, Ebola
  2. Those with a genome that consists of single-stranded sense RNA; that is, the RNA has message sense (can act as a messenger RNA - mRNA). This is also called positive-stranded RNA. Examples: poliovirus
  3. Those with a genome made of several pieces of double-stranded RNA. Example: reovirus.
  4. Retroviruses. Their RNA (also single-stranded) is copied by reverse transcriptase into a DNA genome within the host cell. Example: HIV-1

DNA Viruses

Genome is a molecule of double-stranded DNA

Examples:

  • smallpox (variola)
  • vaccinia (used to immunize against smallpox until the disease was eliminated from the planet)
  • varicella-zoster (causes chicken pox the first time; shingles the second)
  • herpesviruses
    • herpes simplex viruses
      • HSV-1 - usually infects the trigeminal nerves periodically causing "cold sores" on the lips and face
      • HSV-2 - usually infects the genitals
    • KSHV; causes Kaposi's sarcoma in AIDS patients and other people with suppressed immune systems. Also called human herpesvirus 8 (HHV-8).
    • human cytomegalovirus (HCMV); most of us have it; can cause blindness - even death - in people with suppressed immune systems.
    • Epstein-Barr virus (EBV); causes mononucleosis and has been implicated in the development of Burkitt's lymphoma (a cancer) and Hodgkin's disease. Its genome has been completely sequenced: 172,282 base pairs of DNA encoding 80 genes.
  • adenoviruses; some 50 different strains infect humans; responsible for some cases of the common "cold". Two strains have been modified to serve as vectors in gene therapy trials.
  • papilloma viruses; several dozen types infect humans and two of these, HPV-16 and HPV-18, can cause cancer.
  • SV40; a virus that infects primate cells and causes tumors in rodent cells.
  • Some bacteriophages
    • T2 and T4; from which much early information about gene structure and expression was learned.
    • lambda; a popular vector

    Fig. 19.3.1.2 Infective cycle of DNA bacteriophages

The essential elements of the infective cycle of DNA bacteriophages consist of:

  • The virions attach to the surface of their host cell (a).
  • The proteins of the capsid inject the DNA core into the cell (b).
  • Once within the cell, some of the bacteriophage genes (the "early" genes) are transcribed (by the host's RNA polymerase) and translated (by the host's ribosomes, tRNA, etc.) to produce enzymes that will make many copies of the phage DNA and will turn off (even destroy) the host's DNA.
  • As fresh copies of phage DNA accumulate, other genes (the "late" genes) are transcribed and translated to form the proteins of the capsid (c).
  • The stockpile of DNA cores and capsid proteins are assembled into complete virions (d).
  • Another "late" gene is transcribed and translated into molecules of lysozyme. The lysozyme attacks the peptidoglycan wall (from the inside, of course).
  • Eventually the cell ruptures and releases its content of virions ready to spread the infection to new host cells (e).

Hepatitis B

The genome of hepatitis B ("serum hepatitis") is also dsDNA, but its mode of replication is different from the other dsDNA viruses.

  • Once inside its host cell (a liver cell), the virion core enters the nucleus.
  • The viral DNA is transcribed (by the host's Pol II) into molecules of mRNA.
  • These enter the cytoplasm where they are translated (again by host ribosomes, etc.) into the various proteins of the virus, including a viral reverse transcriptase.
  • These components are assembled into new viral cores, and in each
  • one molecule of mRNA is reverse transcribed into a single strand of DNA, which then serves as the template for the synthesis of the second strand.

Genome is single-stranded DNA

Examples:

  • φX174 (phiX174), another famous bacteriophage (infects E. coli) that helped usher in the modern era of molecular genetics. Its single strand of DNA has 5,386 nucleotides and contains 11 protein-encoding genes.
  • Adeno-associated virus (AAV). This virus, which can only grow in cells infected with adenovirus, shows great promise as a safe and effective vector for introducing therapeutic genes into human patients.

RNA Viruses

Negative-stranded RNA viruses:

Genome consists of one or more molecules of single-stranded "antisense" RNA.

Examples:

  • measles
  • mumps
  • respiratory syncytial virus (RSV), parainfluenza viruses (PIV), and human metapneumovirus. (In the U.S., these close relatives account for hundreds of thousands of hospital visits each year, mostly by children.)
  • rabies
  • Ebola
  • influenza

Method of replication

  • In addition to its antisense RNA genome, the core of the virion contains an RNA replicase, which is an RNA-dependent RNA polymerase.
  • Once released in the host cell, this polymerase makes many complementary copies of the genome, which are "sense" and serve as messenger RNAs.
  • These are translated into the proteins needed to assemble fresh virions, e.g., capsid proteins and RNA polymerase.

Note that this strategy

  • provides many copies of mRNA
  • depends on the virion having its own RNA replicase (because the host cell does not) (So, naked RNA molecules of these viruses are not infectious — in contrast to the next group: the positive-stranded RNA viruses)

Positive-stranded RNA

Genome is a molecule of single-stranded "sense" RNA.

Examples:

  • polioviruses
  • rhinoviruses (frequent cause of the common "cold"; 99 different strains are known)
  • noroviruses (frequent cause of outbreaks of gastrointestinal illness — especially in "closed" settings like cruise ships and nursing homes)
  • coronaviruses (includes the agent of Severe Acute Respiratory Syndrome (SARS)
  • rubella (causes "German" measles)
  • yellow fever virus
  • West Nile virus
  • dengue fever viruses
  • equine encephalitis viruses
  • hepatitis A ("infectious hepatitis") and hepatitis C viruses
  • tobacco mosaic virus (TMV)

Method of replication

  • The "sense" RNA encodes an RNA replicase (an RNA-dependent RNA polymerase) that is translated by the host machinery (ribosomes, etc.) into the enzyme, which catalyzes the synthesis of large numbers of "antisense" replicative intermediates.
  • These serve as templates for the synthesis of large numbers of mRNA molecules that
    • are translated by the host cell machinery into the proteins needed to make fresh virions
    • are incorporated into the new virions.

Double-stranded RNA

Examples:

  • reovirus
  • several plant viruses

Method of replication

The virus particle contains enzymatic machinery that transcribes each of the dsRNA molecules into a mRNA (complete with cap) and exports these into the cytosol of the infected cell.

Retroviruses

These viruses contain a reverse transcriptase that copies their RNA genome into DNA.

Examples:

  • The Rous sarcoma virus (RSV)
  • HIV-1 and HIV-2, that cause AIDS
  • HTLV-1 and HTLV-2. 4–5% of the people infected with HTLV-1 develop adult T-cell leukemia/lymphoma (ATL).

Latent Viruses

Most of the infective cycles described for the various viruses end in the death of the host cell. Bacterial cells literally burst, a process called lysis, and similar infective cycles are called lytic cycles.

Lysogeny

In some cases, though, the events of the lytic cycle are not completed. An E. coli cell infected by a DNA bacteriophage may resume its normal existence, including reproducing itself.

Where has the virus gone?

It is still there and, in fact, is present in the descendants of the bacterium. That these cells still harbor the virus can be demonstrated by irradiating the cells with ultraviolet rays or treating them with certain chemicals. Such treatment restores the normal lytic cycle. The phage is said to have been "rescued" — hardly the case for its host!

The stable relationship between a bacteriophage and its host is called lysogeny. The viral DNA actually becomes replicated when the host's DNA is replicated prior to each cell division. During lysogeny, the phage is called a prophage.

Transduction

In some cases, the prophage DNA becomes inserted into the chromosome of its host. In fact, when the phage is "rescued", the released virions may contain some host genes as well as their own. When these virions infect new hosts, they insert these bacterial genes into them. This process of genetic transfer, a virus-mediated transformation, is called transduction.

What does the prophage do while it is a part of its host genome? It can express certain of its genes. For example, the gene that encodes diphtheria toxin is the property of a prophage in the diphtheria bacillus, not of the bacillus itself.

Some animal viruses can also establish latent infections. Simian virus 40 (SV40) is a DNA virus that produces

  • a lytic infection in the kidney cells of the African green monkey (these cells are used to cultivate viruses in the lab)
  • but a latent infection in the cells of humans, mice, rats, and hamsters. Like lysogeny in bacteria, the SV40 genome becomes incorporated as a provirus in the DNA of its host (in chromosome 7 in human cells).

Although a human cell with harboring SV40 shows no outward sign of the provirus, its presence can be detected by:

  • the appearance of viral-encoded antigens in the host cell
  • the ability of these cells to cause a lytic infection in African green monkey cells when fused with them.

Latent infections may also cause the cell to become cancerous. The cell has become transformed. In these cases, the word fulfills both of its biological meanings:

  • "transformed" by the incorporation of new DNA
  • "transformed" as it becomes cancerous.

In humans,

  • lytic infections of plasma cells by the Epstein-Barr virus (EBV) occur in mononucleosis
  • latent infections of B cells by EBV predispose the person to lymphoma.

while

  • lytic infections by human papilloma virus (HPV) cause genital warts;
  • latent infections by some strains of HPV lead to cervical cancer.

and

  • while most CD4+ T cells infected by the retrovirus HIV-1 are killed (causing AIDS),
  • HIV-1 integrates as a provirus into the DNA of a few memory CD4+ T cells where it can persist for years with the potential of creating active disease in the future.

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