Researchers solve viral superinfection mystery

By Liz H. ‘10

Interaction between a T-cell (purple) and another cell of the immune system.

The ability of a common virus known as CMV to cause a “superinfection” and infect humans multiple times has puzzled scientists until recently.  Researchers at the Oregon Health and Science University Vaccine and Gene Therapy Institute have reported the mechanism that CMV uses to evade the immune system and re-infect humans, in a study published in the April 2nd issue of Science.  Their findings shed light on how this virus may be used in the development of CMV-based vaccines for other diseases.

Cytomegalovirus (CMV) does something that not many viruses can do:  it can re-infect people who previously have been infected by CMV and have already developed an immune response to the virus.  This is unusual for a virus, because the immune system usually “remembers” previous infections with viruses and other pathogens and can mount a strong immune response upon re-infection with a specific pathogen.

The researchers studied CMV-infected monkeys in order to understand how the virus overcomes detection by the immune system.  They discovered that CMV avoids a special type of white blood cell called CD8+ T cells, which are responsible for killing cells that are infected with a pathogen.  CD8+ T cells recognize infected cells by small molecules on the exterior surface of infected cells known as MHC I.  These molecules display small pieces of an invading pathogen and present them to the T cells.  This presentation of infectious material ultimately signals T cells to start destroying infected cells.

In order to evade these T cells, CMV makes proteins that interferes with the presentation of viral pieces by MHC I molecules and stops them from recruiting T cells to infected cells.  “In essence, CMV is able to cut off an infected cell’s call for elimination. This allows CMV to overcome this critical immune barrier during re-infection,” explains author Klaus Frueh.

The study has interesting implications in the design of CMV-based viral vaccine vectors.  Viral vaccine vectors contain a modified, harmless virus that carries a vaccine for another pathogen to the body.  Although the body develops immunity to the pathogen, it also develops immunity to the viral vector, which means that the viral vector can only be used for one type of vaccine.  Since CMV does not elicit an immune response upon re-infection, it makes an attractive vaccine vector candidate that could potentially carry vaccines against other pathogens, such as HIV, hepatitis C, tuberculosis, and malaria.

CMV is a member of the herpesvirus family and infects 50-80% of the US population by age 40.  Most people do not have any symptoms of CMV infection and do not become ill.  But for those with weakened immune systems, including infants and the immunocompromised, CMV can cause serious complications.  With this new understanding of how CMV evades the immune system, scientists may be able to start utilizing the virus for the benefit of human health.

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An uncommon use for a common drug offers hope to millions of HIV-positive patients

By Liz H. ‘10

Microscopic view of HIV (green) emerging from an infected T-cell. CDC

A promising new HIV treatment has been discovered in an unlikely source:  a widely available acne medication developed in the 1970s.  A team of scientists from Johns Hopkins University reports that minocyclin stops HIV-infected human cells from reactivating and replicating, in a study published in the April 15th issue of the Journal of Infectious Diseases.  Their findings may lead to an improved and more effective treatment regimen for HIV infection.

The researchers focused their study on latent, non-replicating HIV-infected human T-cells.  T-cells are a type white blood cell that normally fights infection.  HIV infects T-cells and can “rest” inside of them for an extended period of time.  The virus does not harm the T-cell during this latent phase, but can eventually “wake-up” and re-activate the T-cell, which spreads HIV infection and weakens the immune system.

In this study, the scientists treated latent HIV-infected human T-cells with minocycline and measured the level of re-activated T-cells over time.  They also performed the same measurements on cells that were not treated with minocycline.  The researchers found that the minocycline-treated cells did not display detectable levels of reactivation while the untreated cells displayed elevated levels.

Upon closer analysis of the activity of minocycline inside of cells, the scientists discovered that the drug interferes with important cellular communication pathways that cause the T-cell to activate and spread HIV to other cells.  “It prevents the virus from escaping in the one in a million cells in which it lays dormant in a person…That’s the goal:  Sustaining a latent non-infectious state,” explains Gregory Szeto, a Hopkins graduate student who worked on the project.

These findings suggest that minocycline could be used in conjunction with HAART, the current HIV treatment standard, to keep the virus dormant inside of T-cells.  “While HAART is really effective in keeping down active replication, minocycline is another arm of defense against the virus,” says author Janice Clements.  Minocycline is an attractive addition to the current arsenal of HIV medications because it is relatively inexpensive, does not inhibit the ability of T-cells to fight other infections, and is not likely to cause viral drug resistance.

Current treatment for HIV/AIDS involves a combination therapy approach known as HAART.  Patients on HAART take at least 3 antiretroviral drugs daily that act on the virus in different ways to reduce its levels in the bloodstream.  Although HAART can extend the life of an infected individual, it is not a cure and causes unpleasant side effects and the development of drug resistance.  For the 40 million HIV-positive individuals worldwide, this new use for minocycline promises improved outcomes.

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Taking the flight (and bite) out of the pesky mosquito

By Liz H.

The bite of the female Aedes aegypti mosquito can transmit the virus that causes Dengue fever to humans
The bite of the female Aedes aegypti mosquito can transmit the virus that causes Dengue fever to humans.

The days of the flying mosquito may be drawing to a close.  In a study published in the February 22nd issue of the Proceedings of the National Academy of Science, a team of American and British researchers report that they have engineered a mosquito in the lab that produces offspring that cannot fly and consequently cannot infect humans with the virus that causes Dengue fever (full article).  Their findings may lead to a sustainable mosquito population suppression strategy that dramatically reduces human morbidity and mortality from a variety of diseases transmitted by mosquitoes.

In this study, the scientists specifically focused on the Aedes aegypti mosquito that causes Dengue fever.  The researchers manipulated the genetic material of the males of this species in the lab to carry a novel trait:  the inability to fly.  When these modified males were mated with normal, wild-type females, they passed the trait on to their female offspring.  By rendering the female offspring flightless, the scientists effectively imposed a death sentence on this group.  If the females cannot fly, they cannot elude predators, mate with males, escape from water, or seek out human blood.  Most importantly a flightless female may lead to the eradication of Dengue fever, since the disease is transmitted by the bite of female Aedes aegypti mosquitos.

The researchers predict that 6-9 months after introducing the modified males into the wild, the wild-type females in the area will be completely replaced by the flightless offspring of the modified males.  This is big news with important applications in the control of mosquito-borne disease.  This method of control offers several advantages over traditional techniques because it specifically targets the species of mosquito that causes Dengue fever and bypasses the use of toxic insecticides.  And as senior author Luke Alphey notes, “Another attractive feature of this method is that it’s egalitarian: all people in the treated areas are equally protected, regardless of their wealth, power or education.”

The next step for the researchers is to study the mating competitiveness of the modified males in the wild and whether their flightless female offspring will actually suppress the wild-type population as predicted.  Additionally, the methods used by these scientists could be adopted to control other species of mosquitoes that spread serious diseases such as West Nile virus and malaria.

Dengue fever is a flu-like illness with no vaccine or treatment that infects 50-100 million people each year in over 100 countries in tropical and subtropical climates, including Puerto Rico and tourist destinations in Latin America and Southeast Asia.  It is the most common mosquito-borne disease and the CDC estimates that one third of the world’s population lives in areas where the disease is endemic.  Other diseases transmitted by mosquitoes include West Nile virus, malaria, Rift Valley Fever, and Yellow fever.  Taken together, these illnesses represent growing public health issues that require effective and sustainable mosquito population control measures.  The flightless mosquito may just be the answer to this urgent problem.

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CDC site on Dengue fever

Flu to the rescue!

By Shelly Hwang

February 17, 2010

It’s flu season, and with the H1N1 virus being the spotlight of current news and the CDC pushing for nation-wide flu vaccination, people have become terrified of the influenza virus. However, a recent study done by researchers at the Yale University School of Medicine (published in the February 18 issue of Cell Host and Microbe) revealed that the stress response caused by the flu actually protects against death by secondary infection by using mice with bacterial infections.

Influenza can damage the lungs but usually does not kill. However, secondary infections such as pneumonia can occur after infection with the influenza virus and are much more deadly. Each year, more than 200,000 U.S. residents are hospitalized for flu-related complications, and about 36,000 Americans die on average per year from complications of the flu (CDC Statistics).

While previous studies on the flu have shown repressing of the immune system, such studies have only studied a single pathogen and focused on local effects of influenza at the site of infection. In reality, organisms are exposed to multiple infectious agents at a time and the effect of influenza on the whole immune system has not been studied.

This study, led by Dr. Rusian Medzhitov from the Department of Immunology, used a mouse model to examine the effects of the lung infection caused by influenza on the immune response to bacterial infection. Surprisingly, the researchers found that the influenza lung infection led to increased production of glucocorticoids (GC), which are produced in response to stress and known to play a key role in regulating inflammation. They found that virus-induced GC production is essential to controlling inflammation, as shown by the death of mice lacking GC’s that were infected by multiple pathogens.

So the next time you find yourself miserable and overwhelmed with the unpleasant flu FACTS symptoms (Fever, Aches, Chills, Tiredness, Sudden symptoms), remember to thank the virus for protecting you from fatal secondary infections.

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Department of Immunobiology at Yale

Structure of key HIV protein solved, offers hope to millions of HIV/AIDS patients

Views of the integrase enzyme bound to viral DNA and to the integrase inhibitors MK0518 and GS9137 (b and c).

By Liz H.

After nearly 4 years and 40,000 trials, a team of researchers from Harvard University and Imperial College London has reported the structure of the HIV enzyme integrase in a landmark study published in the January 31st issue of Nature (full article).  Integrase is a key retroviral enzyme that allows the virus to insert its DNA into the chromosomes of host cells and replicate. This discovery sheds light on how current integrase inhibitors target the enzyme and may lead to the development of more effective therapeutics.

Scientists grew a crystal of the enzyme obtained from the Prototype Foamy Virus, a model for HIV, and used a synchotron machine at the Diamond Light Source in South Oxfordshire to take a picture of the enzyme’s structure using a method known as x-ray diffraction.  These crystals were then soaked in integrase inhibitors and the drugs’ actions were also studied using x-ray diffraction.  Scientists hope that their findings will allow them to develop improved next-generation integrase inhibitors.

Over 33 million people are infected by HIV and combination antiretroviral therapy (ART) is used to slow the progression of disease (source). However, the increasing prevalence of multi-drug resistance, high cost, and side effects of therapeutics undermines the efficacy of current treatments.