Recent studies in virology: a roundup

July 18, 2013

In recent weeks, I have read a large number of press releases describing studies that fit under the broad umbrella topic of virology. Some are drug studies; some approach viral diseases on the cellular or molecular levels. All are relevant to the clinical laboratory because they may have implications for future laboratory testing, including for viral load monitoring and pharmacogenomic purposes. I present summaries of some intriguing research in virology that researchers have shared with the public during the last couple of months.

IL-21 critical to fight against viral infections

Scientists at Emory Vaccine Center have shown that the immune regulatory molecule IL-21 is needed for long-lasting antibody responses against viral infections in mice. The results were published in the Journal of Virology.

“Our findings highlight how IL-21 could be important in the development of antiviral vaccines,” says research associate Ata Ur Rasheed Mohammed, the first author of the paper.

The findings could lead scientists designing future vaccines to incorporate IL-21 directly or to use the ability to stimulate IL-21 as a gauge of vaccine activity. IL-21 was discovered in 2000. Its effects have also been studied in the area of immune responses against HIV, and it has been in clinical trials for skin cancer and kidney cancer and autoimmune disorders.

A main objective of vaccination is to make the recipient’s immune system develop antibodies that can neutralize infecting viruses. Signals from IL-21 appear to be necessary for generating long-lived plasma cells, which reside in the bone marrow and secrete antibodies.

The researchers probed mice that were unable to respond to IL-21, because the mice were engineered to lack the gene for the IL-21 receptor. They examined the altered mice in the context of three different types of viral infections: LCMV (lymphocytic choriomeningitis virus), VSV (vesicular stomatitis virus), and influenza.

When infected with each of the three viruses separately, the altered mice did start to produce antibodies, but antibody levels faded out over the course of around two months. The mice “exhibited a profound defect in generating long-lived plasma cells and in sustaining antibody levels over time,” the authors write.

Rasheed’s team demonstrated that IL-21 plays a critical role in germinal centers, structures in the lymph nodes and spleen where cells that produce high-affinity antibodies are selected. In the IL-21 receptor deficient mice, germinal centers form but are not sustained. IL-21 signals are important both for the antibody-producing cells and for T helper cells that support them, researchers showed.

Drug therapy offers high cure rate for two hepatitis C subtypes

According to a team of scientists led by Weill Cornell Medical College researchers, a new drug is offering dramatic cure rates for hepatitis C patients with two subtypes of the infection—genotypes 2 and 3. The drug, sofosbuvir, offers more effective treatment for most patients studied in a Phase 3 clinical trial who had no other treatment options, report the researchers in The New England Journal of Medicine. The clinical trial enrolled 207 patients at 63 sites in the United States, Canada, Australia, and New Zealand.

Sofosbuvir, which has not yet been approved by the FDA, works by interfering with the ability of the hepatitis C virus to replicate. The drug also confers a high barrier to developing the complication of drug resistance. Sofosbuvir may emerge as an alternative to treatment with interferon, which many patients do not respond to or cannot tolerate. 

There are seven major genotypes of hepatitis C, but most cases are 1, 2, or 3. Genotype 1 is the most common subtype in the United States. Genotypes 2 and 3 are more common in Europe than in the U.S., and genotype 3 is very prevalent on the Indian subcontinent.

In the study, three-fourths of participants were randomized to treatment with sofosbuvir and the antiviral drug ribavirin, while one-fourth of participants were randomized to a placebo treatment. After three months of combined therapy with sofosbuvir and ribavirin, the patient response rate for those with genotype 2 was 93%, and 61% in patients with genotype 3.

New drug stimulates immune system to kill infected cells in animal model of hepatitis B infection

A novel drug tested in an animal model at the Texas Biomedical Research Institute in San Antonio suppresses hepatitis B virus (HBV) infection by stimulating the immune system and inducing loss of infected cells. The new report appears in the journal Gastroenterology. 

In a study conducted at Texas Biomed’s Southwest National Primate Research Center, researchers found that the immune modulator GS-9620, which targets a receptor on immune cells, reduced both the virus levels and the number of infected liver cells in chimpanzees chronically infected with HBV. Chimpanzees are the only species other than humans that can be infected by the virus. Therefore, the results from this study were critical in moving the drug forward to human clinical trials which are now in progress. 

 “This is an important proof-of-concept study demonstrating that the therapy stimulates the immune system to suppress the virus and eliminate infected liver cells,” says co-author Robert E. Lanford, PhD. “One key observation was that the therapy continued to suppress virus levels for months after therapy was stopped.”

The current therapy for HBV infection targets the virus and works very well at suppressing viral replication and delaying progression of liver disease, but it is a lifelong therapy that does not provide a cure.

The new drug binds a receptor called Toll-Like Receptor 7 that is present in immune cells. The receptor normally recognizes invading viruses and triggers the immune system to suppress viral replication by the innate immune response and kill infected cells by the adaptive immune response, thus orchestrating both arms of the immune system.

Team describes molecular detail of HIV’s inner coat

A team led by researchers at the University of Pittsburgh School of Medicine has described for the first time the 4-million-atom structure of the HIV capsid, or protein shell. The findings, published in the journal Nature, could lead to new ways of fending off the often-changing virus. Scientists have long struggled to decipher how the HIV capsid shell is chemically put together, says senior author Peijun Zhang, PhD.

“The capsid is critically important for HIV replication, so knowing its structure in detail could lead us to new drugs that can treat or prevent the infection,” she says. “This approach has the potential to be a powerful alternative to our current HIV therapies, which work by targeting certain enzymes, but drug resistance is an enormous challenge due to the virus’s high mutation rate.”

Previous research has shown that the cone-shaped shell is composed of identical capsid proteins linked together in a complex lattice of about 200 hexamers and 12 pentamers, Dr. Zhang says. But the shell is non-uniform and asymmetrical; uncertainty has remained about the exact number of proteins involved and how the hexagons of six protein subunits and pentagons of five subunits are joined.

The team used a hybrid approach, taking data from cryo-electron microscopy at an eight-angstrom resolution to uncover how the hexamers are connected, and cryo-electron tomography of native HIV-1 cores, isolated from virions, to join the pieces of the puzzle. Collaborators at the University of Illinois then ran simulations which positioned 1,300 proteins into a whole that reflected the capsid’s known physical and structural characteristics. The process revealed a three-helix bundle with critical molecular interactions at the seams of the capsid, areas that are necessary for the shell’s assembly and stability—potential vulnerabilities in the protective coat of the viral genome.

Dr. Zhang says, “The capsid has to remain intact to protect the HIV genome and get it into the human cell, but once inside it has to come apart to release its content so that the virus can replicate. Developing drugs that cause capsid dysfunction by preventing its assembly or disassembly might stop the virus from reproducing.”

Immune cells that suppress genital herpes infections identified

Fred Hutchinson Cancer Research Center and University of Washington scientists, writing in the online edition of Nature, have identified a class of immune cells that reside long-term in the genital skin and mucosa and are believed to be responsible for suppressing recurring outbreaks of genital herpes. These immune cells also play a role in suppressing symptoms of genital herpes, which is why most sufferers of the disease are asymptomatic when viral reactivations occur.

The discovery of this subtype of immune cells, called CD8αα+ T cells, opens a new avenue of research to develop a vaccine to prevent and treat herpes simplex virus type 2 (HSV-2). Identifying these T cells’ specific molecular targets, called epitopes, is the next step in developing a vaccine.

“The discovery of this special class of cells that sit right at the nerve endings where HSV-2 is released into skin is changing how we think about HSV-2 and possible vaccines,” says senior author Larry Corey, MD, PhD. “For the first time, we know the type of immune cells that the body uses to prevent outbreaks. We also know these cells are quite effective in containing most reactivations of HSV-2. If we can boost the effectiveness of these immune cells, we are likely to be able to contain this infection at the point of attack and stop the virus from spreading in the first place.”

Previous research has shown that the nerve endings reach the dermal-epidermal junction and release the virus that infects the skin and can cause lesions. The finding of CD8αα+ T cells in the skin was unexpected.

The research involved using novel technologies to examine the T cells in human tissues. The work provides a roadmap that can be applied to other human diseases.