Monthly Archives: February 2011

Guest Blogger, Immunology, Vaccines

Eat Your Vaccines

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Contributed by guest blogger: Nicole Engelhardt ’11

Usually when you get a vaccine it means you get a needle and a bandage. Not only that, but you get an attenuated virus. These weakened virus particles are strikingly similar to viable ones; they even infect cells. Because of their weakened state, they infect slower than natural virus particles, giving the body time to react. However, people who have weakened immune systems can still exhibit symptoms as if they were infected by the natural virus.

But a new tool may make this issue obsolete. What really matters when it comes to a vaccine is the shape of the particle, not the contents. The shape is recognized by B-cells in the body which then reproduce creating antibodies that attack all of the virus particles. However, these B-cells are very specific and very picky. Normally, it makes sense to use a weakened virus because it has the exact same shape as a normal virus and your B-cells will react to the vaccine as if it were the real thing. Is there any way, then, to produce the exact shape of the virus and therefore the correct antibodies without having the harmful side effects?

This paper explores the rotavirus particle which is the leading cause of gastroenteritis in the world. In some parts of the world, gastroenteritis can be deadly for many children. As it happens, the shape of the rotavirus particle can be mimicked almost exactly in plants. The shape of this virus is a capsid made out of proteins. First, the authors take the genes that code for the capsid proteins and insert it into the genome of the plants. Then the plants express the viral genes, creating the virus capsid proteins inside the cells of the plants. More incredible than that, these proteins self-assemble into the exact shape of the rotavirus capsid. Now you have a plant containing just the shell of the virus!

The experiments are still in their early stages, but when mice were fed these plants, the authors found they were producing the same antibodies that are produced when mice are actually infected with rotavirus. This bodes well for future research in humans. Once the antibodies are created, the severity of future infections is greatly decreased. If these transgenic plants do work, it could mean a safer and perhaps more affordable form of the vaccine that could help people the world over fight rotavirus before it can infect.

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Epidemics, Guest Blogger

The Relationship Between Diabetes and Enteroviruses

Contributed by Guest Blogger: Charlie Gray ‘11

Enteroviruses are a genus of positive sense, single-stranded RNA viruses which include poliovirus, coxsackie A & B, echovirus, and enterovirus. These viruses can cause a variety of symptoms ranging from the common cold and conjunctivitis to paralytic poliomyelitis. Researchers have also found an association between enteroviruses and type 1 diabetes, a disease whose incidence has increased over the past 25 years at an annual rate of 3%, a rate that cannot be explained simply by genetics.

In a recently published paper, Wing-Chi G Yeung and his colleagues conduct a systematic review of controlled studies that use molecular virological methods in an effort to compile what is currently known about the association between enteroviruses and type 1 diabetes, and to aggregate their results. Their meta-analysis included 34 papers, 30 of which used reverse transcriptase PCR or in situ hybridization to detect the enterovirus RNA; the other four used immunostaining for the enterovirus capsid protein, vp1, on autopsy pancreas specimens. Although the studies varied in age distribution, most investigated children and adolescents (i.e. less than 16).

Yeung and his colleagues found a strong association between enterovirus infection and diabetes, with a 9 fold increase in the risk of infection in diabetic individuals. They conclude that their meta-analysis of these previous observational studies do provide support to the growing collection of findings that individuals with type 1 diabetes have increased odds of suffering from an enterovirus infection.

Despite Yeung et al.’s findings, there was quite a bit of variation in the designs and methods used in the various studies that the authors analyzed. Only 10 of the 34 studies matched for three or more potential confounding factors such as age, genetic risk, geographical location and sampling time. In addition, the studies varied greatly in the site selection from which they collected samples (e.g., serum, stool, throat swabs). Enteroviruses invade cells and replicate at mucosal surfaces; therefore, detection rates could be significantly higher in samples that were obtained from the gastrointestinal tract.

Although this paper does provide evidence for a diabetes-enterovirus link, it does leave several questions for future research. It is unclear how strong the association between enterovirus infection and diabetes is, and if the other factors such as geographic location and genetics may influence the observation of enterovirus infection and diabetes. For example, previous studies have examined varying HLA (a gene encoding an important immune system protein) genotypes and how certain genotypes can modify the association between enterovirus infection and diabetes; however, those results have provided conflicting evidence. Therefore, further study is needed to determine how these confounding factors affect one another and the enterovirus-diabetes link.

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Antiviral Drugs, Immunology

A cell model of HIV latency for finding novel small-molecule therapeutics

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Contributed by Guest Blogger: Jack Bulat, ’11

Highly active antiretroviral therapy (HAART) has extended the quality and expectancy of life for people infected with HIV-1, but has been unsuccessful in leading to a cure for AIDS. This is because it proves ineffective at targeting the latent HIV-1 reservoir – a pool of memory CD4+ T cells in the quiescent phase of the cell cycle that harbor inactive integrated virus. Should an HIV-infected patient ever come off HAART, activation of this latent pool would cause the virus to re-emerge. Because HAART has become both expensive and toxic in the long-run, significant efforts have been directed at targeting HIV-1 latency for more effective treatment.

A considerable obstacle to studying HIV-1 latency in memory CD4+ T cells has been the lack of a latency cell model. Because only a small portion of CD4+ T cells infected with HIV-1 survive to become latently-infected memory cells, a resilient cell line mimicking latency has practical value for therapeutic screening. In a study, Yang and colleagues transduced primary CD4+ T cells with a lentiviral vector for constitutive expression of Bcl-2, an antiapoptotic signaling factor implicated in the generation and maintenance of memory CD4+ T cells. Upon confirming that the physical and biochemical properties of these Bcl-2-expressing cells are highly similar to those of freshly-isolated primary resting CD4+ T cells, they activated and infected the cells with an HIV-1 strain mutated to mitigate cytopathic effects. After establishing latency in the infected cells, the researchers screened more than 4400 drugs and natural products for the ability to activate the latent HIV-1 mutant. 5-hydroxynaphthalene-1,4-dione (5HN), a compound found in the leaves, roots, and bark of the black walnut tree, was a promising hit because it did not cause global T cell activation, which would be too dangerous for clinical use.

Despite this, it looks like 5HN will not be hitting the pharmacy shelves any time soon, since it is chemically reactive, affects several cellular proteins, and leads to the stimulation of inflammatory genes. Nevertheless, the study is significant for presenting a methodology for generating potentially useful cell lines modeling HIV-1 latency. A noteworthy criticism has been that a mutated strain, rather than wild-type virus, was used to infect the model cells. The scientists contended that the strain is suitable to study latency specifically because the genes implicated in HIV-1 activation were not modified.

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Epidemics, Guest Blogger

The Role of Social Networks in H1N1 Transmission Within a School

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Contributed by Guest Blogger: Aaron Grober ’11

The H1N1 subtype of the Influenza type A virus, known colloquially as “swine flu,” was the most common cause of human influenza infection in 2009, and remained a major concern in sparking a pandemic throughout the 2009/2010 flu season.

This recent paper examines the role of grade, class, and social network in transmission of this virus in a school setting. Taking a closer look at the actual transmission pattern of this novel subtype of influenza is critical in developing models to better predict and combat pandemic spread. In the case of this school, closure due to outbreak did not significantly affect transmission among students, indicating that it may have occurred too late to be effective, stressing the importance of more exact models. The study encompassed 370 students from 295 households, surrounding an H1N1 pandemic that occurred in a Pennsylvania elementary school in April and May 2009.

The researchers found that the structuring of the school into grades and classes significantly affected the probability of transmission: 3.5% between students within a class, five times less than that between students of the same grade but different class, and five times less than that between students of different grades.

The researchers took an in-depth look at fourth-graders. They note that children are four times more likely to play with members of the same sex, and found that this behavior had a significant impact on disease transmission; the onset of epidemic transmission occurred among boys significantly before that of female classmates. In addition, they found no significant difference between recorded playmate transmission rates, and the expected proportion for if being a playmate was not a risk factor. The researchers used class seating charts to determine if proximity to an infected individual affects the risk of transmission; as it turns out, they found that sitting next to an infected individual did not significantly affect one’s risk.

In addition to school structure, the researchers looked at spread within households. The probability of a child to adult transmission within a household depended significantly on the household size, where probability of spreading the disease is much lower in larger households than smaller ones. The predominant means of adult infection was from outside the home.

These unique findings shed light on the extremely complex transmission pattern within structured populations. The biggest factors for transmission within school are grade and class, but not seating arrangement, sex, but not playmate transmission. A number of obvious questions remain: Why does sharing a class, but not a desk-space affect transmission? Why is one more likely to transmit the disease in a smaller household than a larger one? This study is an extremely insightful epidemiological tool to help explain transmission, but our knowledge of how this virus spreads remains incomplete; it seems that the flu is far more complex than we imagined.

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Epidemics, Guest Blogger

Feeling tired all the time? You might have a virus.

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Update (Janyary 2012): Two studies identifying XMRV in CFS patients have been retracted, including the original paper that proposed the association. The current, best supported evidence, in this area suggests that the association was actually due to contamination. There appears to be strong scientific agreement that CFS is not related to infection with this virus.

Contributed by Guest Blogger: Nicole Krenitsky ’11

Patients with Chronic Fatigue Syndrome (CFS) perked up when a paper published in Science in 2009 linked the symptom-defined illness to xenotropic murine leukemia virus-related virus (XMRV). XMRV, also connected to prostate cancer, is positive sense, single-stranded RNA retrovirus of the class murine leukemia viruses (MLV). Four subsequent studies failed to find any MLV-related viruses in CFS patients or controls. Then in 2010, a paper published in PNAS reinvigorated the debate. The study did not specifically find XMRV but did find MLV-related viruses in the blood cells of CFS patients tested. Yet one month later, the CDC published report, stating that they had not found any MLV-related viruses in their own study of CFS patients.

Reasons for the inconsistent results are presently unknown. One hypothesis is that the PCR could have picked up mouse DNA or mouse viruses, contaminating the tests and producing false positives. Another involves the samples of participants; CFS is diagnosed solely based on symptoms and clinical case definitions such as the one published by the CDC do not differentiate well between CFS and depression, resulting in overdiagnosis. A study conducted by Ian Lipkin is underway and seeks to standardize sampling and analysis methods and use a larger sample size to settle the controversy.

Relating CFS to a virus has far-reaching consequences for patients and for public health. Antiretrovirals used to treat HIV have been shown to inhibit XMRV replication in vitro and some CFS patients have already begun ART following the 2009 Science publication. The AABB and the American Red Cross, erring on the side of caution, have banned patients with CFS from donating blood erring on the side of caution. If CFS is caused by MLV-related viruses, the blood supply would be tainted the syndrome passed to transfusion recipients.

One million Americans are affected by CFS and experience sleep disorders, cognitive difficulties, chronic muscle pain and headaches. Many dismiss the disorder as psychosomatic and doubt its legitimacy as an illness. In addition to diagnostic testing and finding clinical treatment or a cure for CFS, a link to a virus would give CFS scientific credibility. Mary Schweitzer, historian and CFS sufferer explains, “Patients are hopeful that now the disease itself might be treated seriously, that they’ll be treated seriously, and that there might be some solution.”

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