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Viruses

Description
Viruses are a very common type of infectious disease. Many of the most common human diseases are viral. Viruses are the smallest life-form existing, since they are not even a single cell. It is almost like they are not alive at all. They are small strands of DNA-like cell material. A virus consists mostly of RNA and cannot survive without host cells. A virus can enter the body in many ways besides food, fluids, and bites from insects or animals. The infectious secretions from viruses are passed on to others by coming in contact with them. They can be inhaled from airborne particles from coughs and sneezes. Touching or holding hands with an infected person and then rubbing the eyes or nose is a common way to "catch" a virus. There are approximately 200 known viruses that cause disease in humans. Over 100 of these cause "colds." Viral diseases include: HIV/AIDS, the common cold, flu, measles, rubella, chicken pox, mumps, polio, mononucleosis, ebola, West Nile fever, chickenpox, smallbox, hepatitis, meningitis, encephalitis, pneumonia, and SARS. Many viruses are hard to destroy without damaging or killing the living cells they infect; this is why drugs are not used to control them. Many viral diseases can be prevented by immunization.

Who is at Risk?
Young children are highly sensitive to viruses because their immune system is still developing.

Sources: CureResearch.com, University of Iowa Health Care

Hope for AIDS Vaccine Rises after Scripps Research Scientists Discover Antibody
The search for an AIDS vaccine has taken a step forward with TSRI scientists determining the structure of an antibody that can neutralize the virus. The antibody, called 2G12, was first isolated from an AIDS patient a decade ago, and binds to HIV to prevent it from infecting human cells. TSRI professors Ian A. Wilson, D. Phil., and Dennis R. Burton, Ph.D. found an unusual configuration of the 2G12 antibody that had never been seen before. This discovery provides the opportunity to design new vaccine candidates to stimulate the body to make 2G12-like antibodies and destroy HIV before it can establish an infection. HIV has generally proven to be remarkably resistant to neutralization by antibodies so that detailed understanding of how such an antibody works is considered a significant advance.

HIV/AIDS affects about 42 million people worldwide and results in more than 4 million deaths annually. It is generally accepted that the best way to halt the pandemic is through the development of an effective vaccine. The current work will likely take several years to come to fruition but raises hope that such a vaccine may be feasible.

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A Simple Strategy for Blocking HIV Transmission Proves Effective in Pre-clinical Trials
An international team of researchers recently announced the promising results of a preclinical study on a chemical called PSC-RANTES to block male-to-female sexual transmission of human immunodeficiency virus (HIV). In a recent issue of Science, the team reports how a topical microbicide with a high enough concentration of PSC-RANTES prevented HIV transmission to female rhesus macaques that were challenged with high doses of a modified form of HIV. Donald Mosier, M.D., Ph.D., a professor of immunology at TSRI is a member of the research team. PSC-RANTES works by targeting a protein in the body called C-C chemokine receptor 5 (CCR5) - the receptor on human cells to which HIV binds. HIV needs CCR5 in order to achieve infection of any given cell.

In order for the virus to be transmitted during heterosexual intercourse - the number one way the virus is spread in many parts of the world - the virus must attach to CCR5 in cells within the vaginal mucosa. When these cells are protected with PSC-RANTES, however, the virus cannot attach to them. To date, more than 20 million people have died from HIV. In the United States, 40,000 people are infected with HIV each year - more than one person every 15 minutes. If, in the future, a topical mibrobicide containing PSC-RANTES proves to be effective in humans in the context of clinical trials, it would be a boon to worldwide efforts to contain and curtail the global HIV epidemic because such a microbicide would be broadly efficacious against the many HIV strains that exist in the world. Virtually all HIV strains use the CCR5 receptor. Completely blocking CCR5 would block 99 percent of HIV transmission worldwide.

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FIV a Good Model for Studying HIV-type Infections
TSRI Professor John Elder, Ph.D., has studied feline immunodeficiency virus (FIV) since the mid-1980s. FIV was discovered in California in 1986. Elder and his colleagues extract DNA from infected blood lymphocytes, chop it up with enzymes, insert the DNA pieces into a phage (a virus that infects bacteria), and then infects the bacteria with the phage. Elder and his colleagues found one piece of DNA that contained what looked to be the whole virus. They then took that piece of DNA and used it to transfect cells. When they observed those cells, they found that they were productively replicating the virus, which they then isolated so they could sequence it.

Building on this initial work, Elder and his colleagues have been able to characterize the genomic organization of FIV and, significantly, to compare it to that of its cousin HIV. FIV and HIV have a lot in common, which makes FIV a good model for studying an HIV-type infection. Both are members of the lenti (slow) virus family and they contain many of the same characteristic genes and proteins. FIV, much like its human cousin HIV, has an RNA genome of around 10,000 bases that is packaged in a protein and lipid capsid and coat. HIV and FIV both code for a number of structural genes, which encapsulate the RNA and are produced by a gene called gag. Elder and his collaborators are trying to make more broad-based inhibitors of the two viruses, and also look at the development of vaccines in HIV and FIV.

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Possible Antibody Isolated for Ebola Virus
Ebola hemorrhagic fever is one of the most virulent diseases known to humankind. Very few pathogens are more dangerous than Ebola virus once a person is infected. There is no cure, and with a case-fatality rate of between 50 and 90 percent, depending on which strain is involved, it is one of the deadliest viruses on the planet. The virus acts quickly. It kills people in two weeks or less. Antibodies to Ebola virus appear 10 days to two weeks after the infection, which is bad timing for the infected person as the virus has more often than not run its lethal course by then. TSRI Professor Dennis Burton, Ph.D. thinks an antibody he has made might prove to provide a technology that would help.

Burton got bone marrow from two survivors and made phage display libraries from that bone marrow. Phage display is a method for selecting from billions of protein variants those that bind to a particular target. The virus is allowed to reproduce in culture, where it copiously makes new copies of itself and the antibody library. In effect, Burton reconstituted the antibody response the survivors made in Africa six months later in the laboratory.; Tests carried out by Burton's collaborators in BioSafety Level 4 laboratories have shown the antibody to be reactive against live Ebola virus in cell culture and in live models - promising results so far. Burton and his colleagues are interested in looking at the possibility of using the antibody derived from this patient as a serum that might be used to treat patients, particularly as a first-line defense for laboratory workers who accidentally receive a needle prick injury.

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A Lesson For Lassa
An acute viral illness named after the Nigerian village where it was first discovered in 1969, Lassa fever is an extraordinarily deadly disease caused by a single-stranded RNA virus. Hundreds of thousands of people a year contract Lassa fever when they come into contact with the virus, which is shed by a small rodent common to West Africa. Lassa infections can be severe, causing hemorrhagic fever and killing up to a third to a half of those infected in some outbreaks. Each year, thousands die from Lassa fever infections, but hundreds of thousands may suffer some form of deafness as a result. TSRI Professor Michael B.A. Oldstone, M.D., and his colleagues are reporting a possible mechanism for how Lassa fever virus causes hearing loss.

Oldstone has made a career of studying host-virus interactions and his work has been recognized with numerous prizes, including the J. Allyn Taylor International Prize in Medicine. A few years ago while studying a similar virus to Lassa called Lymphocytic choriomeningitis virus, or LCMV, Oldstone discovered that the receptor for Lassa fever virus and LCMV is the protein a-dystroglycan. If scientists prevent binding of the virus to that receptor, they can prevent infection from occurring. Oldstone and his colleagues report that the hearing loss that often accompanies infections with Lassa fever virus is likely related to the virus glycoprotein binding to a-dystroglycan receptors on Schwann cells in the peripheral nervous system. Lassa fever virus uses these a-dystroglycans to gain entry and then suppresses the function of the Schwann cells.

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TSRI Team Makes First Culture System
for Hepatitis C
TSRI Professor Frank Chisari, M.D. and his colleagues have developed a way to produce the hepatitis C virus (HCV) in tissue culture. Their system will make it possible for the first time to understand all aspects of the life cycle of the virus, which in turn will lead to the development of antiviral drugs and vaccines. Until now, the inability to grow the pathogen in laboratories has delayed the development of more effective drugs and a vaccine. A liver-destroying pathogen, HCV infects 170 million people around the world and represents a growing public health burden. There are six major genetic families of HCV, and current treatments work better against some so-called genotypes than others. But a fundamental roadblock has stymied scientific progress: HCV has stubbornly refused to grow in laboratory cell cultures until now.

Chisari's advance will finally enable researchers to study critical aspects of the pathogen"s life cycle, such as cell entry, replication, and packaging into new virus particles, each of which represents a novel drug target that has not been previously approachable. More precise targets, in turn, may yield drugs that are more effective than currently available agents, which are toxic and expensive, require a year of injections, and fail in some patients. Chisari"s other projects involve the discovery of how interferon cures hepatitis B infection by activating hepatocellular mechanisms that prevent the formation of replication competent HBV capsids and inhibit HBV replication; and how commonly used drugs that control serum cholesterol levels can also control hepatitis C virus replication by illustrating a complex cellular regulatory network that controls HCV RNA replication, presumably by modulating the trafficking and association of cellular and/or viral proteins with cellular membranes.

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Turning a Page on Protein Dynamics
TSRI Professor Jack Johnson, Ph.D., has been using x-ray crystallography to solve the structures of intact complex virus particles for over a decade. Johnson and his colleagues have reported the individual steps of the maturation of a virus called bacteriophage HK97, which they elucidated with a highly unusual application of a routine laboratory technique called SDS PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis). The bacteriophage HK97 is a double stranded DNA virus that infects Escherichia coli cells. It was first isolated from pig dung by a rice geneticist in Hong Kong. Proteins link together to form a "chain mail" that is extremely durable and makes the virus more chemically and mechanically stable. It helps protect the DNA during transport from one host to another. Once the DNA is inside and all the linkages are in place, the tail is attached and the virus is mature and ready to infect another E. coli cell.

Since the subunits of the HK97 virus link covalently as the viral head expands into its final form, SDS PAGE gave Johnson and his colleagues a perfect way to resolve the individual pieces of the capsid as the reaction proceeded and to read how many of the linkages were in place at various points in the reaction. In addition to shedding light on basic questions such as how protein assemblies change their shape, interact with other proteins, and assemble themselves, the work is important because the HK97 virus has properties similar to some animal viruses, particularly herpes viruses. In fact, the vast majority of complex viruses change their morphology and shape as they mature. Like HK97, the herpes procapsid morphology is round, while the capsid is angular. Herpes also packages its DNA similarly. This work may lead to better understanding of the maturation mechanisms of herpesvirus and other human viruses and may lead to ways to address the diseases they cause.

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Viral Pathogenesis and Antiviral Immunity
Antiviral vaccines are a landmark in medical care and have led to the eradication of smallpox; the approaching eradication of poliomyelitis; and the dimunition, at least in developed countries of a variety of microbial diseases. Nevertheless, new challenges (e.g., HIV disease) have arisen, and old foes (e.g., tuberculosis and measles) threaten to reappear. One approach to immunization is the direct inoculation of plasmid DNA. This approach shows great promise but, surprisingly, the precise mechanism that underlies this technology remains unclear.

TSRI Professor Lindsay Whitton, M.D., Ph.D., and his colleagues attempt to enhance DNA immunization by rationally exploiting antigen-processing pathways. DNA immunization can be improved by covalently attaching the viral protein ubiquitin, a cellular protein that "marks" other proteins for degradation. Whitton and his colleagues are developing and testing a DNA vaccine against Lassa virus, which causes a severe, often fatal, hemorrhagic fever. They are also evaluating the usefulness of DNA immunization in altering the course of autoimmune disease.

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Viral Particles - Pathogen Inhibitors and Biomolecular Sensors
The goal of nanotechnology in biomedical science is to design tiny nanomachines with multiple functions that can be used to detect, target, and treat human diseases in vivo, thereby eliminating the need for invasive diagnostic or therapeutic procedures. TSRI Associate Professor Mari Manchester, Ph.D., and her colleagues use cowpea mosaic virus (CPMV) as a nanoparticle platform for antivirals, antitoxins, vaccines, and tumor-targeting agents. CPMV is an icosahedral, 31-nm particle that can be produced easily and inexpensively in black-eyed pea plants. Manchester and her colleagues began working on viral nanoparticles by developing a CPMV-based antiviral that can inhibit the interaction between measles virus and CD46, the cellular receptor for measles virus. Their work with antivirals based on viral nanoparticles led them to hypothesize that nanoparticle inhibitors could also function as vaccines, by inhibiting a pathogen-receptor interaction and simultaneously inducing antipathogen immunity to protect against further exposures.

Surprisingly, Manchester and her colleagues also found that viral nanoparticles traffic from the gastrointestinal tract into the bloodstream and reach a variety of tissues in vivo, including the spleen, liver, kidney, lymph nodes, lung, and bone marrow. Viral nanoparticles pass through the gut endothelial lining, possibly via M cells that sample particulate matter in the gastrointestinal tract. Interestingly, high concentrations of plant viruses are commonly found in food sources. Although these plant viruses are not infectious for mammalian cells, their results suggest that systemic exposure to plant pathogens via ingestion of infected leaves most likely is common and might have pathogenic or immunologic consequences in certain individuals. Upon discovering that viral nanoparticles were orally bioavailable, Manchester and her colleagues also investigated the usefulness of the particles as biomolecular sensors for tumor targeting and imaging in vivo. Their goal is to develop viral nanoparticles that can be delivered in a noninvasive manner, home to a tumor in vivo, act as an image-contrast agent for detection by magnetic resonance imaging or other noninvasive imaging techniques, and deliver an antitumor therapeutic or tumoricidal gene. They are developing targeted viral nanoparticles that are designed to detect, image, and treat tumors in vivo.

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Two Viruses Provide Open Doorway To Complex Threats - And New Ways To Fight Them
The viruses that Juan C. de la Torre, Ph.D., has been studying in one form or another since he joined The Scripps Research Institute in 1989 have the acronmyms LCMV and BDV, potentially lethal bits of stray RNA. The archetypal arenavirus lymphocytic choriomeningitis virus, or LCMV, is a rodent-borne virus, first isolated during a 1933 epidemic of St. Louis encephalitis; since then, LCMV has become a primary workhorse in the fields of viral immunology and pathogenesis. Arenaviruses also include important human pathogens such as Lassa fever virus and other causative agents of hemorrhagic fever disease. Moreover, evidence indicates that LCMV is likely a neglected human pathogen, especially in cases of congenital infections. The neurotropic Borna disease virus (BDV) is named for Borna in Saxony, Germany, where an epidemic of "head disease" in horses was first described in the late 1880s. Naturally occurring infections with BDV were thought to be limited to horses and sheep within certain endemic areas of central Europe, but more recent data indicate that BDV is more widespread, both geographically and in terms of types of hosts, than originally thought. Now there's evidence that BDV can infect humans, as well as a proposal - still highly controversial and not yet proven - that BDV might be associated with certain neuropsychiatric disorders. Taken together, like a viral yin and yang, these two viruses provide investigators with an open doorway to the complex threats of viruses in general and eventually, so Juan C. de la Torre hopes, new ways to fight them.

A remarkable thing about these two, and many other viruses, is that they have a very simple genome, coupled with very low proteomic complexity, LCMV, for example, has only four gene products - expressed proteins. Notably, despite its limited genome complexity, LCMV manages to negotiate with its natural host a situation where the virus can live for a long time, so-called persistent infection. It's a remarkable standoff. There are two key requirements for persistent infection. First, the virus must be able to escape from the host immune surveillance system. Second, the viral gene expression program has to be regulated so that it does not compromise the survival of its host. Disruption of this balance frequently occurs when an arenavirus jumps from its natural host to humans, as exemplified by the severe disease associated with Lassa fever virus in humans, which is acquired by exposure to rodent secretions. De la Torre and his colleagues have developed a reverse genetics system for LCMV that provides another investigative tool to study the molecular mechanisms that these extremely pathogenic viruses use against their human hosts, including RNA replication, control of gene expression, assembly, and viral interactions with cell factors. LCMV is a Rosetta stone for the investigation of virus-host interactions. Scientists can now generate predetermined specific mutations within the LCMV genome and analyze their phenotypic expression in vivo to help elucidate the molecular mechanisms that underlie interactions between arenavirus and host cells and associated disease.

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Studying The Flock House Virus
The Flock House virus is a nodavirus and a member of the Nodaviridae family, which also include lethal fish viruses that continue to disrupt fish farms from Asia to Europe. The Flock House virus, on the other hand, kills insects - the New Zealand grass grub to be precise. Anette Schneemann, Ph.D., who is an associate professor in molecular biology at The Scripps Research Institute has been studying the Flock House virus for almost all of her adult life and has developed an abiding appreciation for its abilities. The Flock House virus is a clever virus, extremely simple yet exceptionally successful in its ability to propagate itself. Its genome is very small, with just three expressed proteins, yet it can reproduce itself 100,000-fold in an infected cell in 24 hours. It is the virus's ability to reproduce, the sheer ingeniousness of its assembly pathway, that has held Schneemann in its sway. The Flock House virus carries only two genomic packets of RNA somehow packaged into a single virion (the complete virus particle as it lives outside the cell) - a process that Schneemann calls an "unresolved mystery in virology." Once solved, information from this case could apply to other RNA viruses that cause such lethal and disparate diseases as influenza, childhood diarrhea, and food poisoning.

While a number of viruses carry multiple RNA segments in their genome, it is still unclear exactly how these viruses know which proteins and segments they need to join together to replicate themselves in the host cell. What makes the Flock House virus attractive as a research target is the fact that it is safe for humans to handle (not so for grass grubs) and it carries only two RNA segments. If scientists could understand how the virus selects those segments to package in that single virion, they could probably figure out how to interfere with the process. From there, a whole world of anti-viral therapeutic possibilities would open up. Schneemann's research has helped to pry open the door to this scenario a bit further, adding to the knowledge of how viruses function within the cell. Her research has initially found that there's nothing unusual in the virus RNA itself that plays a role in the selection process - the virus RNA is completely normal. What she did find is that the host cell contributes to the accuracy of the replication process by keeping the components localized - the coat-proteins and RNA segments are brought together within the cell. As these infection events unfold, the virus not only asserts temporal control, it also exerts spatial control by placing the coat-proteins and RNA next to one another, which helps the coat-proteins find the RNA. She and her colleagues think this is also true for other viruses, like polio viruses, so these findings could help point toward the way to the development of vectors to generate new vaccines.

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New "Checkmate" Method Provides Powerful New Tool For Preventing Spread Of Future Epidemics
Scientists from The Scripps Research Institute have developed a breakthrough methodology that can be used to rapidly predict how viruses such as avian influenza H5N1, a dangerous strain of "bird flu," will mutate in response to attacks by the immune system. The new approach, dubbed "checkmate analysis," may also predict which antibodies or small molecule therapeutics will best neutralize these viral mutations before they can develop into global epidemics.

In a high-powered collaboration, Richard A. Lerner, M.D., president of The Scripps Research Institute, Sydney Brenner, M.B.B.C.H., Dr.Phil., recipient of the 2002 Nobel Prize in Medicine and a faculty member of The Salk Institute for Biological Studies, Tobin J. Dickerson, Ph.D., assistant professor of chemistry at Scripps Research, and several Scripps Research colleagues developed the methodology. Because of its simplicity and low cost, this innovative approach will be accessible to scientists around the world. The new "checkmate analysis" allows scientists to explore all the possible routes that a virus might take to escape an immune response or a small molecule therapeutic. The result is a detailed chemical map of the trajectories of viral escape and antibody response.

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Key Protein Deficiency Leaves Mice Hypersusceptible To Viral Infection
Dicer is an enzyme that plays a critical role in the process known as RNA interference (RNAi), a uniquely efficient way to silence gene expression in a number of different cell types. The aptly named protein - it was given the name by a Long Island laboratory graduate student - slices and dices double-stranded RNA into smaller bits called small or short interfering RNA (siRNA) and microRNA (miRNA). In plants, worms, and insects, these fragmentary bits of nucleotide in turn attach themselves to various genes and inhibit replication, in particular, the replication of viruses. In mammals, however, such RNA interferences have not been clearly detected. Instead, double-strand RNAs are detected by specific receptors (such as Toll-like receptor 3), which leads to production of interferon. In turn, interferon exerts its own potent anti-viral influence in mammals.

Now, in a new study, research led by Scripps Research Institute scientists has demonstrated for the first time that Dicer can play a role in mammal immunology. The scientists showed that Dicer-deficient mice are significantly more susceptible - hypersusceptible, in fact - to the vesicular stomatitis virus ( VSV), a widely studied virus with symptoms similar to hoof and mouth disease. The study, led by Scripps Research scientist Jiahuai Han, Ph.D., provides solid genetic evidence to support the hypothesis that host miRNA can influence viral growth in mammals. It also supports the notion that miRNA represents another layer of the complexity of virus-host interaction. The scientists found that cellular or host miRNA could target VSV large protein and phosphoprotein genes, and that the lack of these miRNAs was responsible for increased virus replication. This suggests that host miRNA plays a major role in interactions with viruses in mammals, possibly in deciding the tissue preference of viruses and in determining the balance between host and virus ascendancy.

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Structure of H.I.V. Capsid Protein Reveals Potential Weakness of Inner Core of Virus
Scientists at The Scripps Research Institute have published a detailed molecular model of the full-length HIV CA protein - a viral protein that forms a cone-shaped shell around the genome of HIV. This structure reveals a never-before-seen molecular interaction that may be a weakness at the core of the virus. CA plays a crucial role in the lifecycle of HIV because it forms a protein shell inside infectious particles, providing a scaffold that organizes important components of the virus. The new CA structure has clinical implications and may help scientists develop new drugs for treating HIV. Scripps Research Professor Mark Yeager, M.D., Ph.D., led the study. There are several effective drugs and methods for treating and preventing HIV infections, but there is an ongoing need for new therapy due to the shear enormity of the disease and the emergence of drug resistance.

HIV infections can be successfully managed for years with a variety of existing drugs known as antiretrovirals, which interfere with critical parts of the viral lifecycle. Interfering with some of these stages can prevent the virus from replicating, integrating its genome into the cell's DNA, or processing new infectious viral particles. Doctors often prescribe a regimen of several antiretrovirals from different classes for people living with HIV because AIDS drugs with different mechanisms of action are more effective in combination than when taken alone. Finding new drugs with new mechanisms of action is important because HIV constantly mutates and may become resistant to existing drugs. In general, the capsid (the protein coat that covers the core of a virion) is an attractive target because it plays a crucial role in the viral lifecycle. It packages and organizes the HIV genome, and this is necessary for the virus to transmit and replicate efficiently. If chemical compounds could target the CA protein, scientists might be able to prevent the protein's assembly into capsid shells and thereby block infectivity of HIV. Capsid inhibitors would be a novel class of drugs that would complement existing pharmaceuticals.

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Scripps Research Scientists Find That A Naturally Occurring Peptide Inhibits Common Viral Infection
Scientists at The Scripps Research Institute have found that a naturally occurring peptide known for its antibacterial action can also inhibit viral infection. The new study shows that defensins, short antimicrobial peptides that disrupt bacterial membranes and prevent bacterial invasion, use a separate mechanism to ward off adenovirus. Adenovirus is a group of viruses responsible for a number of respiratory diseases as well as infection of the stomach and intestine, eyes, bladder, and skin. While these infections are generally mild, they can turn fatal in patients with compromised immune systems. The study revealed a previously unrecognized mechanism of antiviral action for defensins. Glen Nemerow, Ph.D., a Scripps Research professor of immunology conducted the study. The discovery suggests one potential way to block adenovirus infection effectively with a small molecule compound. Because defensins are natural peptides, this approach might also provide a novel way to design drugs that would be well tolerated. The study found that two forms of human a-defensins (expressed in specific types of white blood cells, epithelial cells of the small intestine, the female genitourinary tract, and air passages) had potent anti-adenoviral activity in cell culture. When added at the beginning of a 60-minute viral incubation period, defensins achieved 96 percent adenovirus inhibition at very low concentrations. At higher doses, defensins stopped virtually all viral infection activity.

Adenovirus cell entry involves close interaction with host cell receptors that mediate attachment, internalization, and finally penetration of the endosomal membrane-compartments within the cell. The Scripps Research scientists found that the defensins blocked infection by binding to and stabilizing the virus capsid - the protein shell that holds the viral nucleic acid - and preventing partial uncoating of the virus, which marks the start of the infection process. Defensins inhibit the release of an internal viral protein called pVI, which is required for endosomal membrane penetration during cell entry. This results in an accumulation of infectious virions in intracellular endosomes and lysosomes, where they are eventually destroyed. This is the first time this mechanism has been identified. Until now most research has focused on enveloped viruses such as hepatitis C and HIV. Adenoviruses, in contrast, are nonenveloped or naked viruses; they lack an outer coating of lipoprotein. Other nonenveloped viruses include polio, cold viruses, and human papillomavirus. The study suggests that this may be a general mechanism for inhibition of nonenveloped virus infections. It's tempting to speculate that these and other antimicrobial peptides may serve as valuable tools with which to reveal the precise pathways of virus entry into host cells.

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Scripps Research Team Solves Structure Of "Beneficial" Virus
Researchers at The Scripps Research Institute have, for the first time, solved the structure of a virus that can infect specific cancer cells. This new knowledge may help drug designers tweak the pathogen enough so that it can attack other tumor subtypes. The 3-D structure of the virus, known as Seneca Valley Virus-001, reveals that it is unlike any other known member of the Picornaviridae viral family, and confirms its recent designation as a separate genus "Senecavirus." The new study reveals that the virus's outer protein shell looks like a craggy golf ball - one with uneven divets and raised spikes - and the RNA strand beneath it is arranged in a round mesh rather like a whiffleball. It is not at all like other known picornaviruses that the scientists are familiar with, including poliovirus and rhinoviruses, which cause the common cold The study's senior author was Associate Professor Vijay S. Reddy, Ph.D. This crystal structure will now help the scientists understand how Senecavirus works, and how they can take advantage of it.

The Senecavirus is a "new" virus, discovered several years ago by Neotropix Inc., a biotech company in Malvern, Pennsylvania. It was at first thought to be a laboratory contaminant, but researchers found it was a pathogen, now believed to originate from cows or pigs.  Further investigation found that the virus was harmless to normal human cells, but could infect certain solid tumors, such as small cell lung cancer, the most common form of lung cancer. Scientists at Neotrophix say that, in laboratory and animal studies, the virus demonstrates cancer-killing specificity that is 10,000 times higher than that seen in traditional chemotherapeutics, with no overt toxicity. The company has developed the "oncolytic" virus as an anti-cancer agent and is already conducting early phase clinical trials in patients with lung cancer. But the researchers still did not know how the virus worked, so they turned to Reddy. He and his Scripps Research team, determined the Senecavirus crystal structure. Reddy described the differences they found between other picornaviruses and the Senecavirus as like variations among car models of the same manufacturer -- the chassis is the same, but the body style is different. How the body of a virus is shaped determines how it infects cells.

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Scripps Research Scientists Find Drug Lessens Body's Massive and Often Deadly Immune Response to Flu Virus

A team led by scientists from The Scripps Research Institute has shown that a drug that acts on a specific aspect of the immune system—rather than by killing the virus itself— may mitigate the virulence of influenza infection. The drug impacts the cytokine response, the body's signature immune reaction to influenza infection that can itself be lethal.   The study was led by Scripps Research Professors Michael Oldstone, M.D., and Hugh Rosen, M.D., Ph.D. When the influenza virus invades, it causes injury in two ways—by killing lung cells outright and by triggering an immunopathologic response that begins when T cells and dendritic cells respond to the pathogen by causing the excessive release of cytokines. Cytokines are small proteins or biological factors with specific effects on cell-cell interaction, communication, and behavior of other cells. These cytokines, in turn, attract damaging amounts of the immune T cells, polymorphonuclear leukocytes and macrophages to the infected site.  

A cytokine reaction can be severe enough to cause a "cytokine storm," a condition in which the alveoli of the lungs become so flooded and clogged with infection fighting cells that they can no longer properly absorb oxygen. The ability to elicit cytokine storms is what, in large part, makes certain epidemic strains of flu, such as bird flu, so deadly. Permanent lung damage often results from a severe cytokine reaction, even if the individual survives.    In this study, Oldstone, Rosen, and colleagues showed that administering a compound known as sphingosine analog AAL-R directly into the lungs of mice diminished the release of cytokines. Significantly, this effect was achieved while maintaining the humoral immune response—the aspect of immunity in which differentiated B cells (plasma cells) make anti-viral antibodies. In addition, even though the level of influenza virus-specific T cells was lowered, it was still sufficient to control the viral load. This is the first time scientists have been able to tamp down one aspect of the immune response while keeping another intact. With this work the scientists showed that by reducing the numbers of T cells and cytokines in the lungs, they could reduce the numbers of infiltrating polymorphonuclear leukocytes and macrophages, which are most destructive to the lung. Even though this compound does not kill the virus itself, the immunopathologic response was significantly impaired.  

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New Findings May Help Scientists Understand How Some Viruses Cause Disease, Including Cancer

Viruses are masters at taking over a host cell’s machinery and using it to their own advantage. In doing so, they often disrupt the cell’s mechanisms for keeping cell growth and division in check, wreaking havoc. Researchers from The Scripps Research Institute have described for the first time the structure of a protein from a type of virus called adenovirus as it grabs hold of two cell proteins, preventing them from performing their normal jobs.

By determining the structure, the scientists were able to understand at a molecular level how the virus interferes with cellular functions. Scripps Research Professor Peter E. Wright, Ph.D., who is chair of the Department of Molecular Biology, Cecil H. and Ida M. Green Investigator in Biomedical Research, and member of the Skaggs Institute for Chemical Biology at Scripps Research, led the study. Understanding how the adenovirus protein hijacks two cellular proteins for its own use should help scientists understand how similar proteins from related viruses, including the cancer-causing papillomavirus, cause disease, as well as direct the design of possible treatments.

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