Category Archives: Guest Blogger

Guest Blogger

Using HIV to treat HCV

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Contributed by Guest Blogger: R. Trenchard ’14

Traditionally, the go-to method used to treat patients with hepatitis C virus has been to administer a combination of antiviral agents called pegylated interferon-a (PEG-IFN) and ribavirin. These agents combat the virus particles that cause HCV, and regulate the immune system. Clinical studies of this type of treatment however, show that the mixture of these two agents achieves the desired sustained virological response (SVR) for only 36%-46% of HCV patients. This sad statistic has led to recent research that has proposed a more advanced treatment method that includes specifically targeted antiviral therapy for HCV (STAT-C). This treatment would work like HIV therapy and involve the inclusion of protease and polymerase inhibitors to the standard HCV antiviral concoction. It is expected to improve treatment outcomes, because every stage of the HCV life cycle could be a target for STAT-C agents.
The STAT-C agents mentioned above have worked in trials because they target enzymes that are essential for viral replication. Currently they have been used in addition to PEG-IFN and ribavirin, but once there are a sufficient amount of STAT-C agents licensed they can be used alone as a combination therapy used to act at distinct stages of viral replication and to create a barrier to resistance. Like HIV therapy however, these drug combinations increase the risk for drug-drug interactions (DDI) in patients. Some of these drug reactions include anaemia, haematological adverse events, and mitochondrial toxicity. Aside from this some patients for whom the treatment works for can suffer from side effects ranging from flu-like symptoms to anemia and cardiovascular problems.
This evokes a number of questions. With such dangerous risks involved, is the treatment worthwhile? What characteristics of HIV and HCV allow them both to be treated with protease and polymerase inhibitors? Can this type of treatment be used on other viruses as well?

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Guest Blogger

Ekybion: Inhibitor of influenza or immune-response?

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Contributed by Guest Blogger: H. Cushing ’14

Ekybion is a drug complex that was developed to treat inflammation in the respiratory tract caused by infectious agents. A series of experiments were implemented to test if Ekybion was capable of inhibiting the growth of influenza A/PR/8/34 H1N1 strain in vivo (mice).
The first experiment was performed in vitro. MDCK cells were treated with Ekybion 1 hour pre-infection, 1, 2, 4, or 12 hours post-infection. Samples of the different cultures were taken 24 and 48 hours after infection and the number of influenza viruses were counted using the hemagglutination assay method. The results showed that the treatment of MDCK cells (whether pre/post infection) significantly reduced viral growth for at least 48 hours and that pre-infection treatment was most efficient.
The first experiment done in vivo was testing the possible toxicity of Ekybion. They treated one of two groups of mice three times a day with Ekybion. The toxicity was determined by the mice’s weight and normalcy of lung tissue. The test was done with several different concentrations of Ekybion. The results showed that no toxicity was observed in the treated mice until 50x concentration level was reached – indicating that no toxicity would result from Ekybion use at 1x (concentration intended for medical use).
Ekybion’s inhibition of the virus in infected mice was tested at different treatment times and concentrations. Mice were weighted daily for 16 days and 2-5 mice were euthanized from each group on the second day post-infection to determine the amount of virus in lung tissue. The results showed no significant differences in weight loss and that the treatment with 1x concentration for 2 minutes was the most effective with a 46% survival rate (compared to 0% survival in the control). The lung tissues collected from the euthanized mice were used to determine cytokine levels at the site of infection. The results showed that mice treated with Ekybion had a lower cytokine quantity. This determined that Ekybion could suppress immune response as well as reduce viral growth. The question resulting from the experiments is whether or not the anti-viral benefits outweigh the immunosuppression effect of the drug.

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Guest Blogger

Sterile or Feral? Preventing Dengue Fever via Mosquito Population Control

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Contributed by Guest Blogger: E. Doyle ’14

In order to disseminate successfully, viruses, being immobile, must adapt and evolve to utilize their surroundings to effectively propagate. One group of viruses that’s done this particularly well are the Flaviviruses, which are transmitted to humans via bites by infected mosquitoes. Though beneficial for the spread of the virus, Flaviviruses such as yellow fever, dengue fever, and West Nile virus cause a significant amount of serious and painful illnesses and even death in human beings. Of particular concern are the dengue fever outbreaks that have, according to the CDC, recently been common in many parts of the world. Since there is no cure for this virus, prevention is the only way to stop the spread. Scientists are currently looking to do this by controlling the mosquito population.
In a recent study, scientists considered two known methods of mosquito population control (sterilization of male mosquitoes, and genetic alteration of male mosquitoes that would cause them to be genetically programmed to die, as well as any offspring they produced) and mathematically projected how these methods would be most effectively utilized. The variable in this experiment was the frequency of the release of the mosquitoes altered by these two techniques. Would fewer mosquitoes be produced if these altered males were released frequently in small bursts, or less frequently in larger numbers? The projected effectiveness of the different timelines was shown by the calculated number of mosquitoes present in the environment afterwards, keeping in mind the as well as the mating competitive ability of mosquitoes that have been altered to control their reproductive success. If the altered males are able to mate as successfully as the wild type males are and lower the population of mosquitoes below a certain level, the virus will no longer successfully transmit.
Though genetically altered or sterilized male mosquitoes may often lose out when it comes to reproductive success, as has been shown in other real-life experiments, the numbers showed that the release of these mosquitoes into the environment still works when they are released very frequently rather than at lower frequencies. It should be kept in mind, however, that releasing these mosquitoes more frequently also results in higher costs. Also, since the results of these experiments were merely projected using mathematical analysis, it begs the question of whether the anticipated results of frequent mosquito release would be as successful in real life as they are on the page.

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Guest Blogger

Using Viruses to Battle Breast Cancer

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Contributed by Guest Blogger: J. Warren ’14

Cancer is the second leading cause of death in the world today. This fact has made cancer research one of the leading studies in medicine, and any advancement in the field of cancer treatment is quite impactful. One of the more modern (and promising) approaches to treating cancer is through the use of viruses. An oncylitic virus is one that has been modified to infect cancer tissue in the body while not causing disease to the host. This should be possible due to the heightened susceptibility to viral infection of tumor cells, which have defects in certain antiviral response. The appeal of oncylitic viral infection is its ability to spread through the host, allowing it to attack any and all cancerous cells.
One highly attractive oncylitic virus is a mutant of vesicular stomatitis virus (VSV). A recent study investigated the effects of a mutant strain of VSV (rM51R-M) on breast cancer in both rats and humans. Though the virus was able to infect and kill the breast cancer cells without causing disease in the host mice, and could effectively destroy the tumors in vitro, unfortunately the research found that in vivo the viral infection is not sufficient for curing a host of breast cancer, and that VSV does not infect tumorigenic cells any more than normal cells.
Researchers grew several strains of human mammory epithelial cells with varying oncogenicity (chance to turn cancerous) and exposed them to varying multitudes of infection by rM51R-M. They observed that there was no significant difference in viral proliferation between the strains. They also looked at the effects of rM51R-M in mice with breast cancer, tracking the growth rate of the tumors according to the amount of infection.
Though the findings don’t amount to an effective way of defeating breast cancer, it does add valuable knowledge to the field. Future experiments can easily expand on these methods: using this data as a control, researchers could test other types of cancer, other oncylitic viruses, or perhaps the effects of compounding additional treatments. Perhaps this will also drive scientists to create completely new, engineered viruses that are able to infect only the tumor cells present and, some day, be able to completely eliminate multiple types of cancer.

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Guest Blogger

Can tobacco smoke enhance HIV infectivity?

Contributed by Guest Blogger: C. Matsuoka ’14

The relationship between tobacco smoking and HIV/AIDS progression still remains controversial. HIV is a retrovirus that causes the immune system to begin to fail, leading to life-threatening opportunistic infections. Infection with HIV-1 leads to a progressive decrease of CD4+ T cell count and an increase in viral load.
Although there is no concrete evidence that tobacco smoking has a major effect on the progression of HIV-1 of AIDS, there is strong evidence that it increases the risk of becoming infected with HIV. An aqueous tobacco smoke extract (TSE) was used to study the direct effect of smoking on HIV infection and its effects on gene expression in human T cells. Data demonstrates that TSE can enhance HIV infectivity and has antioxidant potential capable of protecting cells and virions from oxidative damage. To prepare the aqueous TSE, 5 cigarettes were puffed through 40 mLs of sterile saline (PBS). Researchers plated TZM-bl cells, which express CD4 and are useful for assessments of viral infectivity, and incubated them with serial doses of TSE. The cells were then infected with HIV-1. Assessed by the MTT cell viability test, cells with low amounts of TSE showed a mild proliferative effect, whereas larger amounts showed increasing toxicity to cells. The effect of TSE on HIV production/infectivity was also tested in human Jurkat T cells (immortalized line of T lymphocyte cells). The Jurkat cells were infected with HIV-1 and then treated with either PBS or TSE. When Jurkat T cells were infected with HIV, HIV production increased over 50% following TSE stimulation, comparable to the direct HIV-simulating effect of TSE in TZM-bl cells alone. To test the ability of TSE to protect HIV virions from oxidative damage by t-BOOH, HIV-1 viral stalks were added to media containing t-BOOH, t-BOOH/TSE, and PBS control. Researchers found that TSE has antioxidant (a molecule capable of inhibiting the oxidation of other molecules) activity, protecting cells against oxidant damage. Only when TSE is present can HIV virions, exposed to t-BOOH, retain its ability to replicate at the same level as the control untreated virus. In conclusion, researchers revealed a novel aspect of the interaction between tobacco smoking and HIV infectivity. Studying the effects of smoking on HIV infectivity has the potential to reveal a novel viral activation mechanism for which inhibitors could be discovered.
Since Marlboro Lights were used to make the TSE, would there be a different effect if a different brand of cigarettes were used? Are there real life human examples of this study that would back up the data? Does tobacco smoke have this effect on other viruses as well?
 

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Guest Blogger

Borna virus and psychiatric disorders

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Contributed by Guest Blogger: M. Bekhbat ’13

Borna disease virus (BDV) is a neurotropic RNA virus that is known to cause neurological disturbances in various animal species, potentially even humans. It can infect mammals and birds, and can cause fatal encephalitis in horses, cattle and sheep. Experiments with rats indicate that neonatal BDV infection significantly altered the normal pattern of social interaction in rats. A possible relationship between Borna virus infection and psychiatric disease in humans has been speculated for some time now, with disorders most often associated with BDV being bipolar disorder, depression, and schizophrenia. The topic is still debatable with various studies confirming and others rejecting the hypothesis. In this study , the presence of BDV circulating immunocomplexes (CIC), complexes in the circulation formed from antigen (Borna Virus) and BDV-specific antibody, was examined in psychiatric patients and healthy individuals. The study found, like many others did, that the incidence of BDV CIC was significantly higher in psychiatric patients than in healthy individuals. But perhaps the more interesting result was that the significantly higher level of BDV CIC was associated with the higher severity of psychopathology in comparison with patients with mild or moderate psychopathology. This finding is in accordance with results from another research : Patients in the early course of schizophrenia had lower BDV antibody titers compared to patients in the advanced course, while a higher proportion of patients in the early course had titer increases over time. These findings could be the first step to determining putative neurobiological causes and risk factors in common psychiatric disorders, including depression, manic depression, anxiety and schizophrenia, whose causes remain a mystery.

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Guest Blogger

Still no cure, but possibly a better method of diagnosis for “mono”  

Contributed by Guest Blogger: L. Kantor ’14

Infectious mononucleosis was first brought about in 1889 with the expressed symptoms of pharyngitis, fever, and lymphadenopathy.  In 1920, it was discovered that many patients with “mono” had similar blood films, demonstrating an absolute lymphocytosis with abnormally abundant cytoplasm in mononuclear cells.  In 1932, the monospot test, a form of the heterophile antibody test, began being used to test for the disease.  Epstein-Barr virus, the currently identified cause of infectious mononucleosis, was identified in 1968.  The virus causes a high white blood cell count with a relative lymphocytosis, which is usually confirmed by a positive monospot test.  However, it has recently been suggested that a lymphocyte to white cell count (L/WCC) ratio could be a quickly available alternative test for the detection of infectious mononucleosis.  In a recent study, the L/WCC of a series of infected patients was compared with that of a similar number of patients with bacterial tonsillitis.  The researchers were trying to prove that a lymphocite/white cell count shows better specificity and sensitivity than the mononucleosis spot test.
One thousand monospot tests in patients with tonsillitis both in an outpatient and inpatient study were analyzed to compare L/WCC ratios in 500 positive and 500 negative results.  The lymphocyte counts and white blood cell ratio was significantly different in the positive and negative monospot groups.  The mean lymphocyte counts and white blood cell ratio in the positive group was 0.49 and the mean lymphocyte to white cell count ratio in the monospot negative group was 0.29.  A ratio of 0.35 had a specificity of 72% and a sensitivity of 84% for detection of the Epstein-Barr virus.  However, these results show that a higher ratio will give a greater specificity, but a lower sensitivity, and vice versa.  Therefore, the mean lymphocyte to white cell count ratio is not sufficient to diagnose or exclude infectious mononucleosis.
However, some questions still arise.  Could the tests be equally accurate but simply at different stages of the infection?  Would the same results occur before the patient showed symptoms of infection?  Or after the symptoms disappeared?

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A cure for cold sores?

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ContribUted by Guest Blogger: A. Parayannilam ’13

The cold sores many of us see on our mouths or faces at one point in our lifetimes are caused by the prevalent Herpes simplex virus Type 1(HSV1). More serious symptoms can develop if the virus infects the Central Nervous System, causing herpes encephalitis and damage to the brain. A recent study has shown how interferon delta (IFN-λ), a member of a group of proteins known as interferons (IFNs), can reduce infectivity of the virus in the Central Nervous System. The results of the study are promising: perhaps by recruiting the body’s own defenses, we can avoid the use of potentially unsafe antiviral drugs in treatment for the disease.
 
Researchers observed IFN-λ to significantly reduce the quantity of the virus found in infected cells of the central nervous system, specifically astrocytes and neurons. Researchers investigated the mechanism behind IFN-λ’s anti-HSV-1 effect and found that IFN-λ activated several Type 1 IFNs. Type 1 IFNs play critical roles in our innate immunity and defense against viruses. To test the significance of Type 1 IFNs, researchers treated astrocytes and neurons with Type 1 IFN antibodies, essentially preventing IFN- λ from activating Type 1 IFNs in these cells. The antibody-treated cells became highly susceptible to infection, highlighting the importance of Type 1 IFNs in the virulence of the disease.
Another method by which IFN- λ reduces infectivity of the virus is by promoting cytokine signaling. Cytokine signaling is a method of intercellular communication cells use to warn each other of infection. Because HSV-1 suppresses cytokine signaling, uninfected cells aren’t able to prepare themselves for possible infection, making these cells more susceptible to infection.
The study raises a number of questions. The researchers discuss the interplay between HSV-1 and interferon delta, but how about the interplay between HSV-2 and interferon delta? The study examines how interferon delta can reduce infectivity in astrocytes and neurons– can interferon delta similarly reduce infectivity in cells outside the Central Nervous System? Is this a fix to the annoying, chronic cold sores that affect the majority of us?
 

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Guest Blogger

A new host for Ebola

Contributed by Guest Blogger: S. Brucker ’14

Ebolavirus is a relatively new threat to the living world and therefore still enigmatic to the medical community in many ways. The question of where Ebolavirus strains come from remains unsettled, but they are thought to mainly infect humans and non-human primates. However, the feasible targets for Ebola expanded when researchers ran tests on pigs in the Philippines. A recent porcine epidemic in the Philippines lead the worried government to contact the USDA along with other mammalian medical laboratories for help diagnosing the problem. The disease was originally thought to solely be Porcine Respiratory and Reproductive Syndrome Virus (PRRSV) also known as “Blue Ear Disease,” but as it turns out, the swine were carrying something else. A technique called microarray analysis was used to identify any other pathogens infecting the pigs. This process consists of comparing an unknown genetic sample to an array of signature sequences belonging to known pathogens. The results of this test showed 28 out of 28 positive matches of the pigs’ genetic samples to signature Reston Ebolavirus (REBOV) sequences. This finding came as a surprise to a scientific community who believed Ebola to only infect primates. This seemingly small discovery has large implications for the way we think abut Ebola. Although Reston Ebolavirus has not yet been shown to infect humans, it is of concern that Ebola strains are appearing in the human food chain. This discovery leads to many questions that must be answered. How long has Ebola been able to infect pigs? If it recently evolved to include pigs in its host tropism, then what is different about this strain? What else can it affect? Are more virulent strains also going to evolve to expand host range? The biggest danger about Ebola is the fact that there is so much that we do not know about it, and until we answer these questions, the virus will be a constant threat.
 

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Exit Pathway for Cancer-inducing Virus

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Contributed by Guest Blogger: M. Aradi ’14

It has been recently discovered that exosomes are used by virally infected cells and cancer cells to manipulate their environment.  The Epstein-Barr Virus, or EBV, significantly affects cell growth and leads to types of malignant cancer. The major oncogenic protein of EBV has been found to be LMP1, as it is often expressed with EBV cancers. Viruses use the exosomal pathway to leave cells and evade immune responses. It has been observed that LMP1 contributes to cell growth through the exosomal pathway. Exosomes generally transfer mRNA, micro RNA (miRNA) and proteins to other cells to affect cell proliferation, cell to cell communication and tumor cell invasion.  LMP1’s most important target is the cellular EFGR protein, which is a cell growth-signaling receptor.  EFGR is secreted from cells in exosomes, and then is taken up by epithelial cells where it functions for cell-growth pathways. It has also been discovered that cells infected with EBV release exosomes that contain LMP1, which inhibits T-cell functions.  

The question was: What are the effects of LMP1 on exosomal composition and biochemical properties that support EBV cell infection?  The test included two groups of EBV cells;  first group contained low levels of LMP1, and the second group had higher expression levels of LMP1.  The two group exosomes were tested for uptake potential by other cells, and it was found that the second group exosomes had a higher level of uptake.  This shows that LMP1 plays a role in controlling exosomal proteins involved in cell adhesion and interaction.  The two groups were exposed to epithelial cells and were observed for how the host cell signaling pathways were affected.  It was found that the LMP1 exosomes induced higher levels of cell growth signaling pathways in recipient cells, showing that LMP1 contains protein factors that induce cell growth necessary for tumor growth and metastasis.

Although the study revealed certain key mechanisms of LMP1 function with EBV, further questions involve which specific exosomal proteins are manipulated by LMP1? How do LMP1 and EFGR interact to successfully induce cell growth?  Which structure or pathway could possibly be targeted to prevent the spread of EBV and its tumor-inducing factors in efforts to cure cancer?

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