Nels and Vincent present ancient hepatitis B virus genome sequences from Bronze Age to Medieval period human remains.
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Show notes at microbe.tv/twievo
Nels joins the TWiV team to talk about his work on genomic accordions in vaccinia virus, hepatitis B virus in a 439 year old mummy, and viral induction of energy synthesis by a long noncoding RNA.
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Show notes at microbe.tv/twiv
A study done in 1985 on a 16th century Italian mummy suggested that the two year old child had smallpox. Recent sequence analysis of tissues from the mummy now reveal the presence of hepatitis B virus, not smallpox virus. The sequence of the viral genome suggests that HBV entered the human population well before 1500.
From Indiana University, Vincent and Kathy speak with Tuli Mukhopadhyay, John Patton, and Adam Zlotnick about their careers and their work on alphaviruses, hepatitis B virus, and rotaviruses.
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In the first of two shows recorded at the University of North Carolina in Chapel Hill, Vincent meets up with faculty members to talk about how they got into science, their research on DNA viruses, and what they would be doing if they were not scientists.
You can find TWiV #407 part one at microbe.tv/twiv. Or watch the video above, or listen below.
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A major new feature of the fourth edition of Principles of Virology is the inclusion of 26 video interviews with leading scientists who have made significant contributions to the field of virology. These in-depth interviews provide the background and thinking that went into the discoveries or observations connected to the concepts being taught in this text. Students will discover the personal stories and twists of fate that led the scientists to work with viruses and make their seminal discoveries.
For the chapter on Infections of Populations, Vincent spoke with Thomas London, MD, of the Fox Chase Cancer Center, about his career and his work on hepatitis B virus.
Satellites are subviral agents that differ from viroids because they depend on the presence of a helper virus for their propagation. Satellite viruses are particles that contain nucleic acid genomes encoding a structural protein that encapsidates the satellite genome. Satellite RNAs do not encode capsid protein, but are packaged by a protein encoded in the helper virus genome. Satellite genomes may be single-stranded RNA or DNA or circular RNA, and are replicated by enzymes provided by the helper virus. The origin of satellites remains obscure, but they are not derived from the helper virus.
Satellite viruses may infect plants, animals, or bacteria. An example of a satellite virus is satellite tobacco necrosis virus, which encodes a capsid protein that forms an icosahedral capsid that packages only the 1,260 nucleotide satellite RNA. The helper virus, tobacco necrosis virus, encodes an RNA polymerase that replicates its genome and that of the satellite.
Satellite RNAs do not encode a capsid protein and therefore require helper virus proteins for both genome encapsidation and replication. Satellite RNA genomes range in length from 220-1500 nucleotides, and have been placed into one of three classes. Class 1 satellite RNAs are 800-1500 nucleotide linear molecules with a single open reading frame encoding at least one non-structural protein. Class 2 satellite RNAs are linear, less than 700 nucleotides long and do not encode protein. Class 3 satellite RNAs are 350-400 nucleotide long circles without an open reading frame.
In plants, satellites and satellite viruses may attenuate or exacerbate disease caused by the helper virus. Examples of disease include necrosis and systemic chlorosis, or reduced chlorophyll production leading to leaves that are pale, yellow, or yellow-white. The symptoms induced by satellite RNAs are thought to be a consequence of silencing of host genes. For example, the Y-satellite RNA of cucumber mosaic virus causes systemic chlorosis in tobacco. This syndrome is caused by production of a small RNA from the Y-satellite RNA that has homology to a gene needed for chlorophyll biosynthesis. Production of this small RNA leads to degradation of the corresponding mRNA, causing the bright yellow leaves.
The giant DNA viruses including Acanthamoeba polyophaga mimivirus, Cafeteria roenbergensis virus, and others are associated with much smaller viruses (sputnik and mavirus, respectively) that depend upon the larger viruses for reproduction. For example, sputnik virus can only replicate in cells infected with mimivirus, and does so within viral factories. Whether these are satellite viruses or something new (they have been called virophages) has been a matter of controversy.
Like satellite viruses, sputnik and others have similar relationships with their helper viruses: they require their helper for their propagation, but their genomes are not derived from the helper, and they negatively impact helper reproduction. Others argue that the definition of satellite viruses as sub-viral agents cannot apply to these very large viruses. For example, sputnik virophage contains a circular dsDNA genome of 18,343 bp encoding 21 proteins encased in a 75 nm t=27 icosahedral capsid. Sputnik is dependent upon mimivirus not for DNA polymerase – it encodes its own – but probably for the transcriptional machinery of the helper virus. Those who favor the name virophage argue that dependence upon the cellular transcriptional machinery is a property of many autonomous viruses – the only difference is that Sputnik depends upon the machinery provided by another virus. It seems likely that a redefinition of what constitutes a satellite virus will be required to solve this disagreement.
Most known satellites are associated with plant viruses, but hepatitis delta satellite virus is associated with a human helper virus, hepatitis B virus. The genome (illustrated) is 1.7 kb – the smallest of any known animal virus – of circular single-stranded RNA that is 70% base paired and folds upon itself in a tight rod-like structure. The RNA molecule is replicated by cellular RNA polymerase II. These properties resemble those of viroid genomes. On the other hand, the genome encodes a protein (delta) that encapsidates the RNA, a property shared with satellite nucleic acids. The hepatitis delta satellite virus particle comprises the satellite nucleocapsid packaged within an envelope that contains the surface protein of the helper, hepatitis B virus.
Infection with hepatitis delta satellite virus only occurs in individuals infected with hepatitis B virus: it is globally distributed, present in about 5% of the 350 million carriers of hepatitis B virus. Acute co-infections of the two viruses can be more severe than infection with hepatitis B virus alone, leading to more cases of liver failure. In chronic hepatitis B virus infections, hepatitis delta satellite virus aggravates pre-existing liver disease, and may lead to more rapid progression to cirrhosis and death than monoinfections. Why co-infection with both viruses leads to more serious outcomes is not known.
Hepatitis B virus (HBV, illustrated) is a substantial human pathogen. WHO estimates that there are now 240,000,000 individuals chronically infected with HBV worldwide, of which 25% will die from chronic liver disease or hepatocellular carcinoma. The hepatitis B virus vaccine is highly effective at preventing infection. Because there are no known animal reservoirs of the virus, it is believed that HBV could be globally eradicated. The recent finding of HBV in bats raises the possibility of zoonotic introduction of the virus.
Serum and liver samples from 3,080 bats from Panama, Brazil, Gabon, Ghana, Germany, Papua New Guinea, and Australia were screened for HBV-like sequences by polymerase chain reaction (PCR). Ten positive specimens were found from three bat species: Uroderma bilobatum from Panama, and Hipposideros cf. ruber and Rhinolophus alcyone from Gabon. The complete viral genome sequence was determined for 9 of the positive specimens. Phylogenetic analysis revealed that the bat viruses form three different lineages, and that each virus differs by at least 35% from known hepadnaviruses.
The virus from Hipposideros cf. ruber has been named roundleaf bat HBV, while those from Rhinolophus and Uroderma have been named horshoe bat HBV, and tent-making bat HBV.
Viral DNA in the liver of Hipposideros bats was found to be higher than in other organs or serum. Some lymphocyte infiltration was observed in the liver of these animals, as well as deposits of viral DNA within hepatocytes. These observations indicate that the bat HBV viruses likely replicate in the bat liver and cause hepatitis.
Serological studies revealed that hepadnaviruses are widespread in Old World bats: antibodies against bat hepadnaviruses were detected in 18% of hipposiderid bats and 6.3% of rhinolophid bats.
An important question is whether these three bat hepadnaviruses can infect human cells. Only tent-making bat HBV could infect primary human hepatocytes, which occurred via the human HBV cell receptor, sodium taurocholate cotransporting polypeptide. However serum from humans that had been immunized with HBV vaccine did not block infection of human hepatocytes with this virus.
These observations show that viruses related to human HBV are replicating in the liver of bats. Earlier this year another hepadnavirus was identified in long-fingered bats (Miniopterus fuliginosus) in Myanmar. The complete genome sequence was obtained and virus particles were observed in bat liver tissues.
The finding of hepadnaviruses in bats raise many interesting questions. The first is whether human HBV originated by infection with bat HBV, either by consumption of bat meat or another mode of transmission. How long ago this occurred is not known. It has been suggested that HBV has been in humans for at least 15,000 years. Some avian species contain avihepadnaviral sequences integrated into their genome, indicating that these viruses originated at least 19 million years ago.
These findings also raise many questions about the pathogenesis of hepadnaviral infection in bats, including the mode of transmission (in humans, the virus is transmitted by exposure to blood, e.g. by injection or during childbirth), and whether chronic infections can occur as they do in humans.
Finally it is interesting to consider the zoonotic potential of tent-making bat HBV, which can infect human cells. Because bat hepadnaviruses are genetically distinct from HBV, current serological and nucleic acid screening programs would not detect human infections. The authors suggest that human and non-human primate sera from areas in which these bat viruses were isolated should be screened using assays that detect the bat hepadnaviruses. Without such information we do not know if these viruses currently infect humans.
Episode #235 of the science show This Week in Virology was recorded before an audience at the 2nd Li Ka Shing Institute of Virology Symposium at the University of Alberta, where they spoke with Dave, Stan, and Lorne about their work on poxvirus vaccines and recombination, an enveloped picornavirus, antivirals against hepatitis B and C viruses, and supporting virology research in Alberta.
You can find TWiV #235 at www.microbe.tv/twiv.
Deans of public health schools in the United States have sent the following letter to President Obama, in which they criticize the use of a vaccination campaign by the Central Intelligence Agency in Pakistan to hunt for Osama bin Laden. I wonder if he will reply.
January 6, 2013
Dear President Obama,
In the first years of the Peace Corps, its director, Sargent Shriver, discovered that the Central Intelligence Agency (CIA) was infiltrating his efforts and programs for covert purposes. Mr. Shriver forcefully expressed the unacceptability of this to the President. His action, and the repeated vigilance and actions of future directors, has preserved the Peace Corps as a vehicle of service for our country’s most idealistic citizens. It also protects our Peace Corps volunteers from unwarranted suspicion, and provides opportunities for the Peace Corps to operate in areas of great need that otherwise would be closed off to them.
In September Save the Children was forced by the Government of Pakistan (GoP) to withdraw all foreign national staff. This action was apparently the result of CIA having used the cover of a fictional vaccination campaign to gather information about the whereabouts of Osama Bin Laden. In fact, Save the Children never employed the Pakistani physician serving the CIA, yet in the eyes of the GoP he was associated with the organization. This past month, eight or more United Nations health workers who were vaccinating Pakistani children against polio were gunned down in unforgivable acts of terrorism. While political and security agendas may by necessity induce collateral damage, we as an open society set boundaries on these damages, and we believe this sham vaccination campaign exceeded those boundaries.
As an example of the gravity of the situation, today we are on the verge of completely eradicating polio. With your leadership, the U.S. is the largest bilateral donor to the Global Polio Eradication Initiative and has provided strong direction and technical assistance as well. Polio particularly threatens young children in the most disadvantaged communities and today has been isolated to just three countries: Afghanistan, Nigeria and Pakistan. Now, because of these assassinations of vaccination workers, the UN has been forced to suspend polio eradication efforts in Pakistan. This is only one example, and illustrates why, as a general principle, public health programs should not be used as cover for covert operations.
Independent of the Geneva Conventions of 1949, contaminating humanitarian and public health programs with covert activities threatens the present participants and future potential of much of what we undertake internationally to improve health and provide humanitarian assistance. As public health academic leaders, we hereby urge you to assure the public that this type of practice will not be repeated.
International public health work builds peace and is one of the most constructive means by which our past, present, and future public health students can pursue a life of fulfillment and service. Please do not allow that outlet of common good to be closed to them because of political and/or security interests that ignore the type of unintended negative public health impacts we are witnessing in Pakistan.
Pierre M. Buekens, M.D., M.P.H., Ph.D.
Dean, Tulane University School of Public Health and Tropical Medicine*
James W. Curran, M.D., M.P.H.
Dean, Rollins School of Public Health, Emory University*
John R. Finnegan Jr., Ph.D.
Professor and Dean, University of Minnesota School of Public Health*
Chair of the Board, Association of Schools of Public Health*
Julio Frenk, M.D., M.P.H., Ph.D.
Dean and T&G Angelopoulos Professor of Public Health and International Development
Harvard School of Public Health*
Linda P. Fried, M.D., M.P.H.
Dean, Mailman School of Public Health, Columbia University*
Howard Frumkin, M.D., Dr.P.H.
Dean, School of Public Health, University of Washington*
Lynn R. Goldman, M.D., M.P.H.
Professor and Dean, School of Public Health and Health Services, George Washington University*
Jody Heymann, M.D., M.P.P., Ph.D.
Dean, UCLA Fielding School of Public Health*
Michael J. Klag, M.D., M.P.H.
Dean, Johns Hopkins Bloomberg School of Public Health*
Martin Philbert, Ph.D.
Dean, School of Public Health, University of Michigan*
Barbara K. Rimer, Dr.P.H.
Dean and Alumni Distinguished Professor
UNC Gillings School of Global Public Health*
Stephen M. Shortell, Ph.D.
Dean, School of Public Health, University of California Berkeley*
*Institutional affiliation is provided for identification only.
Regina M. Benjamin, United States Surgeon General
Hillary Rodham Clinton, Secretary of State
Thomas Frieden, Director, Centers for Disease Control and Prevention
Howard Koh, Assistant Secretary of Health
Michael J. Morell, Acting Director of the Central Intelligence Agency
Janet Napolitano, Secretary of Homeland Security
Kathleen Sibelius, Secretary of Health and Human Services