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Retroviruses and Immunity

Posted in Cell Biology, Clinical Genomics, Curation, Human Immune System in Health and in Disease, Immunology, Virology, tagged evolution and endogenous retrovirus, Evolutionary Biology, human evolution, immunity, Immunology, innate immunity, retrovirus on March 4, 2016| Leave a Comment »

Retroviruses and Immunity

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Viral Remnants Help Regulate Human Immunity

Endogenous retroviruses in the human genome can regulate genes involved in innate immune responses.

By Jyoti Madhusoodanan | March 3, 2016
http://www.the-scientist.com//?articles.view/articleNo/45503/title/Viral-Remnants-Help-Regulate-Human-Immunity/

http://www.the-scientist.com/images/News/March2016/310ERVs.png

Dendrogram of various classes of endogenous retroviruses WIKIMEDIA, FGRAMMEN

Remnants of retroviruses that entered the human genome millions of years ago can regulate some innate immune responses. These viral sequences have previously been linked to controlling early mammalian development and formation of the placenta, among other things. A study published today (March 3) in Science establishes that one such endogenous retrovirus in human cells can also regulate the interferon response, which helps organisms quickly respond to infections. The work is one of the first reports to show that human cells could have adopted retroviral sequences to regulate their genes.

“Before we started this project . . . we knew our genomes were full of these elements and many of them are activated during normal development in cells,” said study coauthor Edward Chuong, a postdoc at the University of Utah in Salt Lake City. “Our motivation was: How can we take the next step and figure out their potential biological consequences?”

Chuong and his University of Utah mentors Nels Eldeand Cédric Feschotte began by scanning the sequences around interferon-induced genes, finding at least 27 transposable elements that likely originated from the long repeats at the ends of retroviral sequences. One such element, known as MER41, comes from a virus that invaded the genome approximately 45 million to 60 million years ago; the team found that its sequence in present-day human cells contained interferon-inducible binding sites.

The group then focused on a MER41 sequence that occurs 220 base pairs upstream of an interferon-induced gene called AIM2, which activates an inflammatory response in cells. When the researchers deleted this MER41 element in a cell line using CRISPR/Cas9 gene editing, interferon treatment could not trigger the AIM2 gene. Without the interferon-mediated response, these cells were more susceptible to viral infections, the team found.

“This is a really strong paper,” said Dixie Mager of the University of British Columbia who was not involved with the study. Although previous studies have considered the regulatory functions of endogenous retroviruses, most have been genome-wide correlations, Mager added. “[Here] they go in and delete the specific endogenous retroviruses and show an effect. That’s one of the things that sets this study apart.”

In addition to AIM2, the group found MER41 elements helped regulate at least three other interferon-inducible genes involved in human immunity. Looking across the genomes of other mammals, the researchers also found MER41-like regulatory elements in lemurs, bats, and other species.

The work is “simple and elegant,” said Todd Macfarlan of the Eunice Kennedy Shriver National Institute of Child Health and Human Development who was not involved with the study. “The novelty here is that it extends this idea that retroviruses are continually being coopted for things—not just for placental or early development, but also for other types of gene regulatory pathways. In the future the question might be: Are there any pathways where retroviruses don’t play a role?”

Whether host cells coopted the viral sequences for their regulatory needs or if ancient viruses used their regulatory abilities to control host immunity during invasion is still unknown, according to Feschotte. “We can only speculate why ancient viruses might have carried these regulatory switches to begin with, but data suggest they had these systems built into their sequence already,” he told The Scientist.

Endogenous retroviral elements make up about 8 percent of the human genome, and similar regulatory effects might be found on other mammalian gene functions, said Mager. “What’s cool about endogenous retroviruses is that their ends, known as LTRs, are optimized to have all these regulatory sequences in just 300 to 400 base pairs of DNA,” she said. “These units are powerhouses of regulatory potential.”

Future studies are needed to establish that these regulatory mechanisms are functional in animals, said Macfarlan. In subsequent work, Feschotte and his colleagues aim to extend their studies to a mouse model and immune cell lines.

To Feschotte’s mind, understanding how these sequences regulate human genes could shed light on previously unknown mechanisms of many diseases. While studies of cancer, autoimmune diseases, and other conditions have reported that endogenous retroviruses are reactivated in disease, the reasons for reactivation— and its consequences—are still unclear.

“What has plagued this field is that we don’t the consequences or molecular mechanisms by which these endogenous retroviruses contribute to disease,” he said.

E.B. Chuong et al., “Regulatory evolution of innate immunity through co-option of endogenous retroviruses,” Science, doi:10.1126/science.aad5497, 2016.

Regulatory evolution of innate immunity through co-option of endogenous retroviruses

Edward B. Chuong, Nels C. Elde*,†, Cédric Feschotte*,†
Science 2016;Vol. 351, Issue 6277, pp. 1083-1087 http://dx.doi.org:/10.1126/science.aad5497

Regulatory use of endogenous retroviruses

Mammalian genomes contain many endogenous retroviruses (ERVs), which have a range of evolutionary ages. The propagation and maintenance of these genetic elements have been attributed to their ability to contribute to gene regulation. Chuong et al. demonstrate that some ERV families are enriched in regulatory elements, so that they act as independently evolved enhancers for immune genes in both humans and mice (see the Perspective by Lynch). The analysis revealed a primate-specific element that orchestrates the transcriptional response to interferons. Selection can therefore act on selfish genetic elements to generate novel gene networks.

Science, this issue p. 1083 see also p. 1029

Endogenous retroviruses (ERVs) are abundant in mammalian genomes and contain sequences modulating transcription. The impact of ERV propagation on the evolution of gene regulation remains poorly understood. We found that ERVs have shaped the evolution of a transcriptional network underlying the interferon (IFN) response, a major branch of innate immunity, and that lineage-specific ERVs have dispersed numerous IFN-inducible enhancers independently in diverse mammalian genomes. CRISPR-Cas9 deletion of a subset of these ERV elements in the human genome impaired expression of adjacent IFN-induced genes and revealed their involvement in the regulation of essential immune functions, including activation of the AIM2 inflammasome. Although these regulatory sequences likely arose in ancient viruses, they now constitute a dynamic reservoir of IFN-inducible enhancers fueling genetic innovation in mammalian immune defenses.

Researchers Trace Spread of Ancient Viruses

Wed, 03/09/2016 Greg Watry, Digital Reporter http://www.dddmag.com/articles/2016/03/researchers-trace-spread-ancient-viruses

Viruses have been present for billions of years, affecting the gamut of life from single celled to multicellular organisms. But these diminutive infectious agents don’t leave behind fossils. Therefore, understanding their origin and evolution has proven difficult.

However, researchers from Boston College have traced the spread of an ancient group of retroviruses—known as ERV-Fc—that affected 28 of 50 studied mammalian ancestors between 15 and 30 million years ago.

“Over the course of millions of years, genetic sequences from the viruses accumulate in the DNA genomes of living organisms (including humans),” the researchers wrote in their paper appearing in eLife. “These sequences can serve as molecular ‘fossils’ for exploring the natural history of viruses and their hosts.”

Retroviruses affect various populations, and included in that group are immunodeficiency viruses, such as HIV-1 and HIV-2, and T-cell leukemia viruses.

The ancient viruses studied “affected a diverse range of hosts, including carnivores, rodents and primates,” the researchers wrote. “The distribution of ERV-Fc among different mammals indicates that the viruses spread to every continent except Antarctica and Australia, and that they jumped between species more than 20 times.”

The ERV-Fc virus was traced to the beginning of the Oligocene Epoch, which was marked by the first appearance of elephants with trunks, early horses, and extensive grasslands, according to the Univ. of California Museum of Paleontology.

In order to trace the virus group, the researchers searched mammalian genome sequence databases for ERV-Fc loci, and then “reconstructed the sequences of proteins representing the virus that colonized the ancestors of that particular species,” according to eLife.

The researchers also followed the changing patterns in the ERV-Fc viruses’ genes as it adapted to various hosts.

“As part of this process, the viruses often exchanged genes with each other and with other types of viruses,” the researchers wrote. “Such genetic recombination is likely to have played a significant role in the evolutionary success of the ERV-Fc viruses.”

According to study co-author William E. Diehl, the research may help humanity predict the long-term effects of viral infections, and the future evolution of such organisms.

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Heroes in Medical Research: Dr. Robert Ting, Ph.D. and Retrovirus in AIDS and Cancer

Posted in Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Prevention: Research & Programs, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Health Economics and Outcomes Research, Human Immune System in Health and in Disease, Infectious Disease & New Antibiotic Targets, Interviews with Scientific Leaders, Molecular Genetics & Pharmaceutical, Scientist: Career considerations, Systemic Inflammatory Response Related Disorders, tagged AIDS, autobiography, Aviva Lev-Ari, Biology, Cancer - General, Cell Biology, Conditions and Diseases, DNA, DNA virus, history of science, HIV, National Institutes of Health, NCI, retroviral, retrovirus, RNA, RNA virus, sarcoma, Science and Medicine, Scientific method on April 17, 2013| 3 Comments »

Heroes in Medical Research: Dr. Robert Ting, Ph.D. and Retrovirus in AIDS and Cancer

Curator and Reporter: Stephen J. Williams, PhD

This is the second posting in this series in which I highlight the basic research which led to seminal breakthroughs in the medical field, brought on by the result of basic inquiry, thorough and detailed investigation, meticulously following the scientific method, and eventually leading to development of important medical therapies.

In his autobiography, Virus Hunting: AIDS, Cancer & the Human Retrovirus: A Story of Scientific Discovery, Dr. Robert Gallo, M.D. describes a wonderful story of the history behind, scientific biographies, and chronology of the discoveries which led he and his colleagues (including co-discoverer Dr. Luke Montagnier) to recognize retroviruses (in particular HIV) as the leading culprit for the cause of AIDS and in the etiology of Kaposi’s sarcoma. For anyone who appreciates the history behind scientific discoveries and appreciates learning about the multitude of individual efforts which are the crux of seminal research, this book is a must read.

Recommendations from the back cover include:

“Virus Hunting will be read and reread, for years to come.” —New York Newsday

“Provides a human, revealing look into the arcane, usually secret confines of laboratory science.”

— Martin Delany, Project Inform

..as well as others.

While a fascinating aspect of this book is the description, like fitting pieces of a puzzle, of the important discoveries throughout history which are the necessary foundations for further investigations and discoveries, more important is a telling, personal narrative of the people involved in those initial and subsequent discoveries. In fact, the book has over 396 colleagues, mentors, technicians, students, and even critiques who are given credit, in one form or another, for the ultimate discovery of HIV as a causative agent for the development of AIDS. The book is a literal Who’s Who in Science and shows how important personal collaboration and friendships are in the process of scientific discovery.

In 1972, Dr. Seymour Perry had appointed the young Dr. Robert Gallo as head of a new department, the Human Tumor Cell Biology Branch, renamed the Laboratory of Tumor Cell Biology. The lab was carrying on the work on tRNA that Dr. Gallo had performed in Dr. Sid Perska’s group at NIH. However, with the help of new lab members Dr. David Gillespie, Dr. Flossie Wong-Staal, and Dr. Marjorie Robert-Guroff the lab focused on the search for disease-causing retroviruses, especially in human leukemias. This was, in part, due to conversations with Dr. Robert Huebner and Todaro, who insisted that

“within the genetic makeup of this endogenous retroviral material was, they suggested, a special gene, the oncogene, that was the parent of the cancer-causing protein”

which may explain some of the early work by Rous concerning the Rous sarcoma virus.

Enter in Gallo’s good friend Dr. Bob Ting. Dr. Gallo had known Dr. Ting socially since 1966, shortly after Gallo had arrived at NIH. Dr. Bob Ting was a well-established NCI investigator, who was doing work on DNA and RNA oncogenic viruses of animals. Originally from a large and wealthy family in Hong Kong, Dr. Ting had worked with Nobel Prize winners Salvatore Luria (who worked on phages) and Renato Dulbecco, who, along with his well-known cell culture media, had made the seminal discoveries that led to our knowledge how some DNA viruses can transform normal animal cells into neoplastic-like cells in culture.

Bob Ting gave a talk on these oncogenic viruses and Gallo was very interested in his observations that oncogenic viruses like Rous and Maloney, could transform cells in vitro in a matter of days.

A friendship developed between the two over tennis matches and Chinese food. During this time, Dr. Ting made the important suggestion that they both collaborate and use the viral systems developed by Dulbecco. Ting also introduced him to RNA viruses, Dr. Robert Huebner, and Dr. Howard Temin. It was, in part, due to these associations that Gallo started looking, in earnest, at the possibility of RNA retroviruses in leukemias. Thus, just like the internet today, connections and networking provided new insights into current research, and helped lead the advent of new discoveries, therapies, and scientific disciplines.

Therefore, “after some late-night discussion with Bob Ting, I decided to enter the fray. My own laboratory, … would immediately be set up to compare the properties of reverse transcriptase enzymes from many different animal retroviruses”.

Although the rest is more history, this early friendship, collaboration, and mentoring by Bob Ting had “transformed” Gallo’s research efforts to set him up to make some of the important discoveries eventually leading to the discovery of the role of HIV in AIDS.

A video interviewing Dr. Gallo can be found here:

VIEW VIDEO

https://www.youtube.com/watch?v=ELRlXLGWu4I

A very nice writeup/obituary for Dr. Ting was written by Patricia Sullivan of the Washington Post and is included below.

Robert Ting, 77; Biotech Pioneer

Dr. Robert Ting’s biotech company in Rockville developed the first FDA-approved diagnostic test kits to test for HIV antibodies. (By Gerald Martineau — The Washington Post)

By Patricia Sullivan

Washington Post Staff Writer
Friday, September 22, 2006

Robert C.Y. Ting, 77, a research scientist who started one of the early biotechnology companies in the Washington area, died Sept. 11 of complications after cardiac surgery at the Cleveland Clinic in Cleveland.

Dr. Ting founded Biotech Research Laboratories Inc. in Rockville in 1973, producing cells for government scientists to use in research. Eleven years later, his firm obtained a federal license to develop and produce the first FDA-approved diagnostic test kits for HIV antibody confirmation.

Robert C. Gallo, who co-discovered the HIV virus as the cause of AIDS, called Dr. Ting a pioneer in the field who popularized the term “biotechnology” when he moved from research to entrepreneurship.

“He introduced me to virology, and he did it twice,” said Gallo, director of the Institute of Human Virology in Baltimore. The men had known each other since the 1960s, and while playing tennis one day, Dr. Ting advised the cancer researcher to look at new research in viruses. Later, when Gallo was studying leukemia, Dr. Ting directed him to animal research in leukemia. “First he showed me how viruses change cells. Then he introduced me to retrovirology. . . . I went into retrovirology solely because of those discussions with Bob Ting on tennis courts,” Gallo said.

Dr. Ting, whom Gallo described as a quiet, modest man, was born in Shanghai, the son of a physician to Gen. Chiang Kai-Shek. His family fled the country during the Japanese invasion of China during World War II and moved to Hong Kong. Soon after, he moved to the United States, where he received a bachelor’s degree and in 1956 a master’s degree in genetics from Amherst College.

He received a doctoral degree in microbiology and biochemistry from the University of Illinois in 1960 under Salvador E. Luria, who later won the 1969 Nobel Prize in Medicine and Physiology. Dr. Ting spent the next two years on a postdoctoral fellowship at the California Institute of Technology, working with Renato Dulbecco, who later won the 1975 Nobel Prize in Medicine and Physiology. Their work focused on how viruses cause tumors.

“A lot of molecular biology developed from this,” Dr. Ting told The Washington Post in 1984 from his Rockville office, cluttered with scientific journals, awards and a large blackboard. “There was so much evidence in animal systems [that viruses cause tumors], that the next question was obvious — can you find the equivalent in humans.”

Dr. Ting joined the National Institutes of Health in 1962 as a visiting fellow and then a senior research scientist at the National Cancer Institute. From 1966 to 1968, he was an associate editor for the Journal of the National Cancer Institute.

In 1969, he joined Litton Bionetics Inc. in Rockville as director of experimental oncology, leading a project funded by the institute to search for viruses in human leukemia patients. He became scientific director of the cancer research branch the next year.

With academic, government and private business experience under his belt, Dr. Ting decided to go into business on his own and in 1973 started Biotech Research Laboratories in Rockville. It was a profitable supplier of research services and supplies until 1981, when it went public and produced the HIV diagnostic test kits. It became one of the most successful public biotech companies in the area in the mid-1980s.

The Economic Development Board of Singapore invited him to return to Asia to start a biotech company, which he did in 1985, forming Diagnostic Biotechnology Ltd. He also joined the Institute of Molecular and Cell Biology at the National University of Singapore, which Gallo called “the most prominent Asian academic biotechnology center.”

He returned to the United States in 1998 to join the board of Cell Works Inc. in Baltimore, and became chair and chief executive of a joint venture, Cell Works Asia Limited, in 2000.

Most recently, Dr. Ting was the founding president and chief executive of Profectus Biosciences Inc. of Baltimore, previously known as Maryland BioTherapeutics Inc.

Dr. Ting was past chairman of the F.F. Fraternity, one of the oldest Chinese fraternities in the United States. He was also a member of the Organization of Chinese Americans in the D.C. area since its inception in the early 1970s. He enjoyed tennis, golf, ballroom dancing and international travel. He also was a wine connoisseur.

Survivors include his wife of 44 years, Sylvia Han Ting of Potomac; three children, Anthony Ting of Shaker Heights, Ohio, Andrew Ting of Beverly, Mass., and Jennifer Chow of Potomac; seven sisters; and seven grandchildren.

An obituary written from his son Anthony can be found here:

https://www.amherst.edu/aboutamherst/magazine/in_memory/1953/robertting

Sources:

http://www.amazon.com/Virus-Hunting-Retrovirus-Scientific-Discovery/dp/0465098150

http://www.washingtonpost.com/wp-dyn/content/article/2006/09/21/AR2006092101936.html