Jennifer Louten

The World of Viruses

Virology is the study of viruses. The first viruses were discovered in 1898 and were identified by their ability to pass through filters that were too small to allow the passage of bacteria. Since that time, scientists have been studying viruses to better understand how to prevent epidemics and pandemics, and research on viruses has revealed an abundance of information on how living systems work. Viruses are the most abundant biological entities on Earth and infect all living things, and yet they are not considered to be alive. They share several characteristics with living organisms, but are unable to reproduce independently and maintain metabolic activities. In addition, they do not undergo cell division, like living organisms do, but assemble newly made components from scratch after gaining entry into a cell and its machinery. Viruses appeared around the same time that life began on Earth, but their origin is a much debated issue. The precellular hypothesis proposes that viruses existed before or alongside cells, whereas the escape hypothesis suggests that viruses were once components of living cells. The regressive hypothesis proposes that viruses were once living intracellular parasites that lost their ability to reproduce independently.

The Immune Response to Viruses

The two arms of the immune system, the innate and adaptive immune system, function together to provide long-term immunity against viruses. The innate immune system is activated immediately after infection and consists of nonspecific mechanisms to control viral replication while the adaptive immune system is being activated. Type 1 interferons are important antiviral cytokines produced during this time. Dendritic cells present antigen to cytotoxic T lymphocytes (CTLs) and helper T lymphocytes, which causes their activation. CTLs acquire the ability to kill virally infected cells, while helper T cells induce B cells to produce antibody. Together, the adaptive immune system provides an antigen-specific response that controls infection and creates immunological memory to prevent against reinfection with the same virus. However, many viruses have evolved mechanisms to avoid detection by or interfere with the host immune system.

Vaccines, Antivirals, and the Beneficial Uses of Viruses

Our attempts to prevent and control serious viral illnesses rely upon mass vaccination efforts and the use of antivirals. Live attenuated virus vaccines and inactivated virus vaccines are the most common types of vaccines and have drastically reduced virus-related morbidity and mortality. Recombinant subunit vaccines are also being produced against HBV and HPV, while investigational vaccine formulations use recombinant DNA or live viral vectors. Antivirals inhibit one of the seven stages of viral replication; most antivirals target a viral enzyme or prevent genome replication.

Viruses and Cancer

Cancer is a leading cause of death in developed nations, and viruses contribute to around 15% of cancer cases worldwide. Despite being disparate viruses, seven major human viruses have been associated with oncogenesis: human T lymphotropic virus type I, hepatitis C virus, hepatitis B virus, Merkel cell polyomavirus, human papillomavirus, Epstein–Barr virus, and Kaposis sarcoma–associated herpesvirus. Oncogenesis is a by-product of infection and is not required for viral replication. Oncogenic viruses affect pathways that become dysregulated in human cancers. Viral proteins commonly interfere with the cell cycle, target pRB and p53, prevent apoptosis, and interfere with the immune response. These effects contribute to genomic instability and support a cellular state that is more conducive to becoming oncogenic as additional mutations arise within the cell. Viruses are a leading contributory cause to cervical cancer, liver cancer, and oral cancers, among others.

Virus Structure and Classification

Abstract Viruses have several common characteristics: they are small, have DNA or RNA genomes, and are obligate intracellular parasites. The virus capsid functions to protect the nucleic acid from the environment, and some viruses surround their capsid with a membrane envelope. Most viruses have icosahedral or helical capsid structure, although a few have complex virion architecture. An icosahedron is a geometric shape with 20 sides, each composed of an equilateral triangle, and icosahedral viruses increase the number of structural units in each face to expand capsid size. The classification of viruses is very useful, and the International Committee on Taxonomy of Viruses is the official body that classifies viruses into order, family, genus, and species taxa. There are currently seven orders of viruses.

Virus Transmission and Epidemiology

Abstract For transmission of a virus to occur, a virus must enter a host through a portal of entry, replicate or disseminate within the host, and be transmitted to a new host through a portal of exit. Unless delivered directly into bodily tissues through a bite or needle, most viruses interact with the epithelium at the site of entry. Localized infections replicate at the initial site of infection, while systemic infections spread to additional areas of the body. Viruses are shed into the environment most often through the same route they entered the body. The stability of virions within the environment is dependent upon virion and environmental factors. Epidemiology is the study of how diseases are transmitted through a population. Epidemiologists perform descriptive or analytic studies to characterize the chain of viral infection throughout a population and design control measures to interrupt it.

Detection and Diagnosis of Viral Infections

Abstract Diagnostic tests are paramount in determining the etiology of viral infections. Direct diagnostic methods assay for the presence of the virus, while indirect methods test for effects of the virus. Cell culture is the process of growing cells or tissues in the laboratory. Cell lines can be infected with patient samples to allow viral replication within the cells; observable cytopathic effects can help to identify the identity of the virus. Infected cells can also be used for immunofluorescence assays, which use fluorescently labeled virus-specific antibodies to identify viruses in fixed cells or tissues. A variety of diagnostic immunoassays exist, including enzyme-linked immunosorbent assays/enzyme immunoassays, western blots, lateral flow immunoassays, and agglutination reactions. Assays that detect viral nucleic acids are based upon the principles of PCR or nucleic acid hybridization, are extremely sensitive, and are specific for a particular virus.

Features of Host Cells: Cellular and Molecular Biology Review

Abstract As obligate intracellular parasites, viruses are completely dependent upon a host cell for their replication. They use energy generated by the host cell, and they exploit the hosts machinery to manufacture viral proteins. Many of the cells organelles, as well as the plasma membrane, are involved in viral replication processes. The organelles involved in protein synthesis, processing, and transport—namely the ribosome, rough endoplasmic reticulum, and Golgi complex—are utilized in the manufacture of viral proteins, as well, and viruses use ATP generated by the host cells mitochondria. The plasma membrane, made of a phospholipid bilayer, is the cells primary zone of contact with the extracellular world. As such, it is the first obstacle that a virus must overcome for entry into a cell. The Central Dogma of Molecular Biology states that DNA is replicated to create more DNA, DNA is transcribed into mRNA, and mRNA is translated by ribosomes to create proteins. All viruses are dependent upon the hosts translation machinery, and many viruses will use other portions of the cells replication and transcription mechanisms. DNA polymerase is the major enzyme involved in DNA replication, while RNA polymerase creates messenger RNA. Host ribosomes translate the messenger RNA into proteins, composed of amino acids. Viruses also have many unique strategies to ensure the translation of their proteins over host proteins. As obligate intracellular parasites, viruses are completely dependent upon a host cell for their replication. They use energy generated by the host cell, and they exploit the hosts machinery to manufacture viral proteins. Many of the cells organelles, as well as the plasma membrane, are involved in viral replication processes. The organelles involved in protein synthesis, processing, and transport—namely the ribosome, rough endoplasmic reticulum, and Golgi complex—are utilized in the manufacture of viral proteins, as well, and viruses use ATP generated by the host cells mitochondria. The plasma membrane, made of a phospholipid bilayer, is the cells primary zone of contact with the extracellular world. As such, it is the first obstacle that a virus must overcome for entry into a cell. The Central Dogma of Molecular Biology states that DNA is replicated to create more DNA, DNA is transcribed into mRNA, and mRNA is translated by ribosomes to create proteins. All viruses are dependent upon the hosts translation machinery, and many viruses will use other portions of the cells replication and transcription mechanisms. DNA polymerase is the major enzyme involved in DNA replication, while RNA polymerase creates messenger RNA. Host ribosomes translate the messenger RNA into proteins, composed of amino acids. Viruses also have many unique strategies to ensure the translation of their proteins over host proteins.

Emerging and Reemerging Viral Diseases

Abstract An emerging infectious disease (EID) is defined as a disease caused by a pathogen that has not been observed previously within a population or geographic location. Viruses are a major cause of EIDs, particularly −ssRNA viruses. Many variables are involved in the emergence or reemergence of viruses. These can be classified into human factors, environmental/ecological factors, and viral factors and include urbanization, globalization, weather and climate change, and the genetic composition of the virus. The great majority of emerging viral diseases are zoonoses, notably transmitted by arthropods and nonhuman mammals. Flaviviruses include several notable vector-transmitted viruses, while rodents and bats are thought to be the natural reservoirs of arenaviruses and filoviruses, respectively. This chapter discusses several notable outbreaks of emerging and reemerging viruses, including the 2014–15 outbreak of Ebolavirus in West Africa.

Chapter 14 – Poliovirus

Poliomyelitis (“polio”) is a disease caused by poliovirus, a small, nonenveloped icosahedral virus transmitted through the fecal–oral route. Three poliovirus subtypes exist: type 1, 2, and 3. Following a major viremia, poliovirus replicates within and can cause temporary or permanent damage to the central nervous system, predominantly to the brain stem and motor neurons of the spinal cord. Paralytic poliomyelitis is classified into bulbar, spinal, or bulbospinal poliomyelitis, depending upon the site of the nerves that are damaged. As a +ssRNA virus, translation of the poliovirus genome begins immediately upon entry into the cell, using an internal ribosome entry site in the 5′-region of the genome. A single polyprotein is cleaved sequentially into intermediate precursor and mature proteins responsible for genome replication and virion structure. In 1955, Jonas Salks laboratory developed a formalin-inactivated virus vaccine, known as the inactivated polio vaccine, and Albert Sabin later developed the oral polio vaccine containing live attenuated poliovirus. Permanent eradication of poliovirus through vaccination is theoretically possible because poliovirus infects only humans, has a limited number of serotypes, and does not cause persistent infections. Global Polio Eradication Initiative efforts have currently reduced the number of countries with endemic wild poliovirus to two, Afghanistan and Pakistan.