Breakthroughs Blog: Research Roundup

Scientists at University of California, San Francisco have identified several drugs that block the Zika virus from infecting brain cells. After determining the types of brain cells susceptible to Zika, the researchers screened more than 2,000 Food and Drug Administration–approved medicines for their ability to protect these cells from the virus. The project revealed that azithromycin, a commonly used antibiotic, could provide protection against Zika in laboratory-grown brain cells. Not only is azithromycin widely available, it is also safe for use in pregnant women, an important characteristic as Zika infection during pregnancy can impede fetal development and result in devastating birth defects. An existing drug for gastrointestinal disorders has shown promise in treating and potentially even curing HIV in monkeys. Existing treatment—antiretroviral therapy (ART)—suppresses HIV, making the virus nearly undetectable in the blood, however, adherence is critical as just a few weeks off of treatment can result in a resurgence of the virus. Due to the demands of adherence and the expensive and toxic nature of many of these medicines, only one third of patients in the United States manage to keep the virus at these undetectable levels. Now researchers may have found a “functional cure” for HIV. The drug—vedolizumab—is approved to treat ulcerative colitis and Crohn's disease in more than 50 countries. In preclinical trials, vedolizumab kept the virus at bay in monkeys for up to two years after cessation of treatment. The National Institutes of Health recently initiated human clinical trials in which people living with HIV and AIDS will receive infusions of vedolizumab every four weeks. After several months, patients will stop taking ART, and their HIV viral load will be closely monitored to determine if the same curative effect is seen in humans. An experimental vaccine against Middle East Respiratory Syndrome (MERS) has successfully combatted the virus in mouse models and offers new insights into the design of subunit vaccines. Vaccines prompt the immune system to develop antibodies that recognize and attack a specific pathogen. Different proteins on the surface of a virus can elicit the production of distinct antibodies that vary in their ability to mobilize a robust immune response. Rather than using the entire virus, subunit vaccines contain specific proteins found on the surface of the virus. Consequently, scientists are able to include only the proteins that elicit the strongest immune response. However, this approach exposes the immune system to certain parts of the virus (i.e., the underside of these surface proteins) that wouldn’t normally be visible, and this can distract the immune system, prompting it to produce ineffective antibodies. In developing a subunit vaccine against MERS, researchers at New York Blood Center overcame this challenge by masking the spot on the vaccine that was distracting the immune system. The slightly tweaked vaccine has proved to be much more effective in protecting mice from MERS. Not only does this finding offer promise for the MERS vaccine, but this technique could be used to increase the efficacy of other subunit vaccines.

Researchers at Massachusetts Institute of Technology and Harvard Medical School have designed a star-shaped pill that releases medicines over the course of two weeks. The long-acting pill has six arms that can be folded into a capsule. Once the capsule reaches the stomach, its outer layer is dissolved, causing the six arms to pop out. Due to its size, the expanded pill is able to remain in the stomach until its arms detach and are digested one by one. The research team used the antimalarial ivermectin to test this delivery system in pigs. The medicine was continually released for two weeks—an impressive feat as oral medicines rarely last longer than a day. Long-acting medicines can significantly improve adherence to complicated treatment regimens. The researchers are now using the platform to develop drugs for neuropsychiatric disorders, HIV and AIDS, diabetes, and epilepsy. Someday soon, one drop of blood and a USB stick could be all that’s required to determine a patient’s HIV viral load. The system uses an electronic chip to detect the virus and transform it into an electronic signal, which is then picked up by the USB, enabling users to access their results off by computer. The device was used to evaluate nearly 1,000 blood samples and proved to be accurate 95 percent of the time, providing results in 21 minutes on average. Current techniques to assess viral load take three days. Patients in remote areas often have to wait much longer because their samples must be transported to laboratories. The HIV virus can develop resistance to antiretroviral treatment, resulting in increasing levels of the virus in the blood. Patients could use this tool to regularly monitor their viral load, ensuring early detection of resistance. During infection, bacteria deploy minute molecules—siderophores—to steal iron from human cells. Microbes need iron to reproduce and interfering with this process could debilitate bacteria, preventing infection. Scientists have sought to develop vaccines that train the immune system to respond to the presence of siderophores; however, the molecules are too small to prompt an adequate immune response. Now, two independent groups of researchers have demonstrated that attaching siderophores to large proteins boosts the immune response. One team used siderophores from the strain of E. coli that causes urinary tract infections, while the other used the strain of Salmonella that causes food poisoning. Both teams vaccinated mice and then exposed them to the bacteria several weeks later. While neither vaccine provided complete protection, infections were much less severe in vaccinated mice. Mice that were vaccinated against E. coli had one-tenth the bacterial load in their urine and kidneys and less inflammation in their kidneys and bladders. The Salmonella-based vaccine triggered the production of antibodies against the siderophores, resulting in a bacterial load 20,000-fold fewer in vaccinated mice.

Researchers at the US National Institutes of Health (NIH) have developed a test that can rapidly screen chemical compounds for their ability to treat drug-resistant infections. The team at NIH has already put the test to use, evaluating approved medicines, promising compounds, and drug combinations against common drug-resistant bacteria. After screening an estimated 4,000 drugs and compounds, the researchers identified 25 that effectively killed drug-resistant Klebsiella pneumoniae in the lab, including not only antibiotics, but also antifungals, antivirals, antiseptics, and even anticancer medicines. The test has also revealed three drug cocktails—each comprised of three different medicines—that can effectively treat ten common multidrug-resistant bacteria. These findings will enable clinicians to prescribe drug combinations with near certainty that they will treat a drug-resistant infection without waiting on lab results. While the tool is not yet commercialized, it can be mobilized to rapidly respond to emerging drug-resistant infections. A new study has revealed that during the 2014–2015 Ebola outbreak in West Africa, the virus evolved, enhancing its ability to infect humans. Previously, Ebola was thought by many scientists to be relatively static; however, researchers at the University of Massachusetts Medical School and University of Nottingham have independently identified a mutation in the Ebola genome—A82V—that appeared during the outbreak and could have made the virus two to four times more virulent. The mutation affects the cells on the surface of the virus that are responsible for infiltrating a host’s cells. For viral cells, shape matters, as it enables them to latch onto host cells like a key in a lock. The researchers suspect that A82V adjusts the shape of these surface proteins, allowing them to better fit into human cells. The mutation also enhances the virus’ ability to infect the cells of chimps and monkeys, while hampering its ability to infect bats, dogs, cats, rats, and mice. The team also discovered that patients with the new, mutated strain of Ebola were 27 percent more likely to die. Further research is needed to confirm this finding. Last week, the NIH and the Walter Reed Army Institute of Research (WRAIR) initiated clinical trials of an experimental Zika vaccine—the first of five phase 1 trials evaluating the vaccine. The vaccine platform was first used by WRAIR in developing a vaccine against Japanese encephalitis, a fellow flavivirus. The Zika Purified Inactivated Virus (ZPIV) contains complete, inactivated virus particles that will not cause disease but train the immune system to recognize and mount a robust response to the Zika virus. In preclinical trials, the vaccine candidate successfully induced an immune response and protected animals against the virus. The five phase 1 clinical trials will test the vaccine compared to placebos in different doses and schedules, as well as in different populations, including individuals previously exposed to flaviviruses (including Zika, yellow fever, dengue, Japanese encephalitis, and West Nile) and dengue, individuals who have received yellow fever or Japanese encephalitis vaccines, and those who have received the NIH’s experimental DNA-based Zika vaccine.

A key target of the HIV virus is immune cells known as T cells. The virus infects T cells and hijacks the cell’s genetic machinery, enabling it to multiply and spread throughout the body. However, some T cells have genetic mutations that protect against HIV infection, and scientists at University of California, San Francisco (UCSF), are using CRISPR—a novel approach to gene editing—to insert these protective genetic mutations into ordinary T cells. First, the team used CRISPR to rapidly identify all T cell genes involved in HIV infection. Next, they inserted 149 different genetic mutations into T cells, 6 of which successfully blocked the virus. Eventually, the researchers hope that one or more of these mutations could be developed into a drug to prevent or treat HIV and AIDS. Biotech company Sangamo Biosciences is currently testing one such gene mutation that in early results appears to lower the viral load of participants. However, other studies suggest that the virus may be able to outsmart this approach, mutating until it is able to infect T cells. Consequently, an effective treatment may need to elicit multiple gene mutations in T cells, either concurrently or sequentially. Over the past five years, the Eliminate Dengue Program has released mosquitoes infected with the innocuous Wolbachia bacteria into small communities in Colombia, Brazil, Vietnam, Indonesia, and Australia. The bacteria colonizes a multitude of insect species, and while it doesn’t harm the Aedes aegypti mosquito—which spreads Zika, dengue, and yellow fever—it does prevent these viruses from replicating and blocks further transmission. Wolbachia is passed down from generation to generation of A. aegypti with each generation only living for a few weeks. Consequently, within weeks of releasing Wolbachia-infected mosquitoes into the wild, disease transmission drops drastically. Now, Eliminate Dengue will be conducting two large-scale trials in Bello, Colombia, and Rio de Janeiro, Brazil, to determine if this approach can successfully combat mosquito-borne illnesses in urban areas home to millions. The trials are funded by the United States and United Kingdom governments and philanthropic organizations the Wellcome Trust and the Bill & Melinda Gates Foundation. The highly drug-resistant Methicillin-resistant Staphylococcus aureus (MRSA) bacteria is only susceptible to a few, last-resort antibiotics, including daptomycin, which is effective against two-thirds of MRSA infections. Now, scientists at Imperial College London have discovered how the remaining one-third of MRSA infections evade antibiotics. The bacterial cells use chemical signals to communicate with one another, however, some cells can shut down this communication system. Once that system is deactivated, the bacterial cells are able to produce decoys—molecules that have a similar outer layer to the bacteria, and consequently are targeted by the antibiotics. Thus, the antibiotics are wasted on the decoy cells and the bacterial cells are able to thrive. These findings could pave the way for new ways to treat MRSA, by combining daptomycin with a drug that interferes with the decoy system. Currently, clinical trials are underway to test such an approach, combining daptomycin with approved and experimental antibiotics that impede either the production or release of decoy molecules.