What Is a Virus? A Brief History of Viruses and Cancer-Causing Viruses

What Is a Virus?

A virus is a small infectious agent that can reproduce only inside living cells of other organisms. Viruses infect all life forms, from animals and plants to bacteria and algae.

In 1892, Dmitri Ivanovsky identified a pathogen infecting tobacco plants that was not bacterial . A paper published by Martinus Beijerinck in 1898 identified it as tobacco mosaic virus, marking the discovery of viruses at the end of the 19th century. Today, viruses are known to have millions of types, occur in almost every ecosystem and are the most diverse biological entities. They are studied in virology, a subspecialty of microbiology.

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When not inside an infected cell or infecting a cell, a virus exists as an independent particle. These viral particles, or virions, consist of two or three parts:

1. DNA or RNA genetic material, long molecules carrying genetic information;
2. a protective protein coat surrounding the genetic material, called the capsid; and
3. in some cases (iii) a lipid envelope around the protein coat.

Viral particles range from simple to highly complex shapes. Most are too small to see with ordinary microscopes. An average virus is approximately one-hundredth the size of an average bacterium. Viral size is measured in nanometers; influenza A, for example, measures 80-120 nanometers. 1 nanometer is one-billionth of a meter. Thus, an average virus's diameter is, relative to 1 meter, one in 10 million.

Viruses' evolutionary origins are unclear: some may have evolved from plasmids, DNA fragments moving between cells, and others from bacteria. Viruses mediate horizontal gene transfer, increasing genetic diversity. Some consider them a life form because they carry genetic material, reproduce and evolve by natural selection, but they lack basic features usually required for life, such as cellular structure. Because of these characteristics, viruses have been described as “organisms at the edge of life” and replicators.

How Do Viruses Spread?

Viruses spread in many ways;

• Plant viruses are often transmitted between plants by feeding insects such as aphids.
• Animal and human viruses may be carried by blood-feeding insects. These disease-carrying organisms are called vectors . Influenza viruses spread through coughing and sneezing. Norovirus and rotavirus, common causes of viral gastroenteritis, spread fecal-orally between people and enter the body through food or water. HIV is among viruses transmitted through sexual contact and body fluids.

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Viral infections usually stimulate immune responses eliminating the infecting virus. Immune responses can also be produced by vaccines that provide artificially acquired immunity against a particular infection. Some viruses causing AIDS and viral hepatitis evade these responses and cause chronic infection. Antibiotics have no effect on viruses, but several antiviral medicines have been developed.

The figure belowdepicts some familiar viruses, showing their structural diversity.

Milestones in Viral History

Louis Pasteur, inventor of the rabies vaccine (1822-1895), could not identify rabies' causal agent despite developing the vaccine and predicted a pathogen too small for microscopy. In 1884, French microbiologist Charles Chamberland invented a filter with pores smaller than bacteria, allowing their complete removal from solutions. In 1892, Russian biologist Dmitri Ivanovsky used this filter to study what is now known as tobacco mosaic virus . Filtering solutions from crushed infected tobacco leaves left the infectious agents in the filtrate. Ivanovsky suggested infection came from a bacterial toxin but did not pursue this. At the time, all infectious agents were thought filterable and able to grow in culture, part of germ theory. In 1898, Dutch microbiologist Martinus Beijerinck repeated the experiments, concluding that the filtrate contained a new infectious agent. It multiplied only in dividing cells, but he could not visualize disease-causing particles and called it contagium vivum fluidum (soluble living germs), later renamed virus . Beijerinck believed viruses existed as fluids in nature; Wendell Stanley, who considered them particles, later overturned this theory.

In the early 20th century, British bacteriologist Frederick Twort discovered viruses infecting bacteria, now called bacteriophages or simply phages. French-Canadian microbiologist Félix d'Herelle described viruses killing bacteria when added to cultures as a suspension. Phages were proposed as treatments for diseases such as typhoid and cholera, but were sidelined by penicillin's development. Phage research supported understanding of gene switching and useful mechanisms for transferring foreign genes into bacteria. Investigations of phage-bacteria relationships even produced one of today's greatest inventions, CRISPR-CAR9 genetic technology through these discoveries.

In 1949, John Franklin Enders, Thomas Weller and Frederick Robbins grew poliovirus in human embryonic cell cultures, producing viruses outside intact animal tissues and embryonated eggs. Jonas Salk used this work to produce an effective polio vaccine.

The first images of viruseswere obtained following the invention in 1931 by German engineers Ernst Ruska and Max Knoll of the electron microscope. Imagine: viruses were visualized only 40 years after their existence was theoretically established.

The latter half of the 20th century was a golden age of discovery, with over 2000 animal, plant and bacterial virus types identified. In 1963, Baruch Blumberg discovered hepatitis B virus; in 1965, Howard Temin identified the first retrovirus. Reverse transcriptase, used by retroviruses to copy DNA from RNA, was independently identified by Howard Martin Temin and David Baltimore in 1970. In 1983, Luc Montagnier's team at France's Pasteur Institute first isolated the retrovirus now called HIV.

The Relationship Between Viruses and Cancer has also been investigated extensively. The most notable concerns HPV and cervical cancer. Of more than 100 known HPV types, approximately 40 infect the genital area, and 15 are high-risk for cervical cancer. Approximately %5 of all cancers are thought HPV-related.

Despite its importance, most knowledge of this link is recent, based on work pioneered by the recipient of the 2008 Nobel Prize for discovering that HPV causes cervical cancer, Harald zur Hausenand his research.

In the 1970s, Harald zur Hausen proposed an idea nobody had previously voiced: “Human papillomavirus (HPV) may cause cervical cancer!”. He believed it integrated its DNA into cervical-cell DNA and used those cells to reproduce. He needed to demonstrate HPV DNA in cancer cells. He pursued this for more than 10 years, studying different types, challenged by only part of viral DNA integrating into the host genome and HPV having over 100 subtypes. Finally, in 1983 he demonstrated HPV DNA in cervical cancer biopsies and showed types 16 and 18 were the principal causes (HPV 16 and 18 occurred in approximately % 70 of biopsies).

This discovery enabled vaccines providing, against high-risk HPV16 and 18 infection, % 95 protection: HPV vaccineswere developed. The preventive vaccine received, in 2006, FDA approval and has already reduced cervical cancer substantially in countries using it routinely; indeed, the country taking vaccination most seriously, Australia, is approaching complete elimination of cervical cancer.

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What Is Viral Structure Like?

All viruses basically consist of nucleic acid (DNA or RNA) and a capsid(protein coat). This structure is called the nucleocapsid . Some viruses also have a surrounding lipid envelope . Structures protruding from the envelope are called glycoprotein units. Glycoproteins allow viral attachment to a target cell's receptor . The space between envelope and capsid, the tegument, contains matrix (M) proteins, which allow enveloped viruses to bud from host cells.

Because viruses cannot produce energy, reproduction requires living cells. They are therefore obligate intracellular microorganisms. Viral reproduction generates thousands of particles.

Structures in infected cells consisting of viral nucleic acid and protein are called inclusion bodies in this context.

Cancer-Causing Viruses — Oncoviruses / Oncogenic Viruses

Viruses are known to cause various cancers in humans and other species. Indeed, %16 of all cancers result from viral and bacterial infections according to estimates. The study of cancer-causing microorganisms is called metagenomics . Nevertheless, viral cancers occur in very few infected people. For example, %70-90 of HPV infections cause no symptoms and resolve spontaneously within 1-2 years, while a small proportion may produce warts.

Cancer viruses come from several families, including RNA and DNA viruses, so there is no single type. Cancer development depends on immunity, DNA repair capacity and virus-induced mutations among various factors.

Which Viruses Cause Cancer in Humans?

Epstein–Barr Virus (EBV): The most widespread human viral infection, thought to affect 95 percent of the world's population. Research links it with lymphoma, stomach and nasopharyngeal cancers. However, the likelihood of EBV-related cancer in infected people is very low. No vaccine against EBV has been developed.

Hepatitis C Virus (HCV): Associated with chronic liver inflammation and liver cancer . Serious liver disease develops in 20 percent of HCV-positive individuals, and HCV-related liver cancer in 4–7 percent. No effective HCV vaccine exists.

Hepatitis B Virus (HBV): Plays a central role in liver cancer, the 5th most common cancer. Persistent infection causes chronic liver inflammation and cancerous transformation. Highly effective vaccines exist.

Human T-Lymphotropic Virus (HTLV): The first discovered retrovirus type. Because retroviruses produce DNA from RNA, they can easily insert genes into cells. Adult T-cell leukemia has occurred in 10 percent of HTLV-infected people. No preventive vaccine exists, but therapeutic medicines have been developed.

Human Papillomavirus (HPV): Among the most studied viruses, with over 100 subgroups identified and linked to cervical cancer. Recent studies show %99 of cervical cancers result from HPV infection. Among infected people, 10- 20 percent have been observed to develop cervical, anal, vulvar, penile, head and neck cancers. Effective vaccines Gardasil and Cervarix are currently available.

Kaposi Sarcoma-Associated Herpesvirus (KSHV): Thought to contain the largest number of oncogenes, genes causing cancerous transformation, among oncoviruses. Kaposi sarcoma is the cancer it causes, occurring mainly in people with AIDS or suppressed immunity.

Merkel Cell Polyomavirus (MCV): A virus only recently discovered to cause cancer. Merkel cell carcinoma is the very rare, aggressive cancer it causes. However, recent research did not detect the virus in 20 percent of patients with this cancer. No vaccine or medicine exists against it. Research into whether it causes cancer continues.

How Do Viruses or Bacteria Cause Cancer?

After entering the body, viruses can attack cells and randomly incorporate their genetic material into nuclear DNA, causing overproduction of oncogenes that contribute to tumor growth, or incorporating these oncogenes into their own genomes and spreading rapidly to promote tumors. At normal production levels, these genes participate in cell proliferation. After mutation, they prevent tumor suppressor genes from functioning, allowing cells that should die to evade death mechanisms and proliferate uncontrollably, contributing to tumors as other microorganisms do. These events provide sufficient evidence explaining how microorganisms cause cancer.

How Does the Immune System Respond to Viral Infection?

1. Interferon response: The host's first immunological response to viral infection. Some viruses, including HIV and EBV, resist interferon.
   Interferons belong to the cytokine family. They do not directly affect viruses; released from infected cells, they stop other cells producing proteins viruses need. Interferons work only against intracellular viruses.
   There are 3 interferon types: alpha, beta and gamma. Alpha interferon is used for HHV-8-associated Kaposi sarcoma, kidney cancer, HPV-related warts and chronic active hepatitis caused by chronic hepatitis B-C viruses.
2. Natural killer (NK) cells and cytotoxic T lymphocytes (Tc): Both kill infected cells rather than viruses themselves. NK cells are nonspecific immune cells, responding before Tc cells. Some cells may change the structure of infected cells to evade immunity, with cancer cells using similar tactics. Effects following some infections, such as measles skin rashes, result from defense cells attacking infected tissues partly indiscriminately.
3. Antibodies: The antibody response has 3 outcomes:
   1. Neutralization through antibody coating: prevents viral interaction with cell receptors and infection of new cells but does not affect intracellular viruses. Vaccine-induced antibodies therefore protect against new infections, not established ones.
   2. Antibody-dependent cellular cytotoxicity: antibody-coated viruses are easier for immune cells to find and kill.
   3. Complement activation: virolysis partially destroys the viral lipid envelope.

Conclusion

We now clearly know that some of these smallest forms of life, viruses with millions of types, cause cancer and understand how they do so. Yet only a small proportion of infected individuals develop virus-related cancer. Many vaccines against cancer-causing viruses have also been developed recently (preventive cancer vaccines).

Scientists discovering the close viral-cancer connection have recently used viruses to develop cancer vaccines. For example, the FDA-approved vaccine for melanoma, Lmlygic, uses herpes virus. Viruses can thus be both disease-causing and therapeutic. Of course, acquiring therapeutic properties requires a series of high-technology procedures.

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