A research group supported by the National Institutes of Health (NIH) has uncovered a new route for attacking the human immunodeficiency virus (HIV) that may offer a way to circumvent problems with drug resistance. In findings published today in the online edition of the Proceedings of the National Academy of Sciences, the researchers report that they have blocked HIV infection in the test tube by inactivating a human protein expressed in key immune cells.
Most of the drugs now used to fight HIV, which is the retrovirus that causes acquired immune deficiency syndrome (AIDS), target the virus’s own proteins. However, because HIV has a high rate of genetic mutation, those viral targets change quickly and lead to the emergence of drug-resistant viral strains. Doctors have tried to outmaneuver the rapidly mutating virus by prescribing multi-drug regimens or switching drugs. But such strategies can increase the risk of toxic side effects, be difficult for patients to follow and are not always successful. Recently, interest has grown in attacking HIV on a new front by developing drugs that target proteins of human cells, which are far less prone to mutations than are viral proteins.
In the new study, Pamela Schwartzberg, M.D., Ph.D., a senior investigator at the National Human Genome Research Institute (NHGRI), part of NIH; Andrew J. Henderson, Ph.D., of Boston University; and their colleagues found that when they interfered with a human protein called interleukin-2-inducible T cell kinase (ITK) they inhibited HIV infection of key human immune cells, called T cells. ITK is a signaling protein that activates T cells as part of the body’s healthy immune response.
“This new insight represents an important contribution to HIV research,” said NHGRI Scientific Director Eric D. Green, M.D., Ph.D. “Finding a cellular target that can be inhibited so as to block HIV validates a novel concept and is an exciting model for deriving potential new HIV therapies.”
When HIV enters the body, it infects T cells and takes over the activities of these white blood cells so that the virus can replicate. Eventually, HIV infection compromises the entire immune system and causes AIDS. The new work shows that without active ITK protein, HIV cannot effectively take advantage of many signaling pathways within T cells, which in turn slows or blocks the spread of the virus.
“We were pleased and excited to realize the outcome of our approach,” Dr. Schwartzberg said. “Suppression of the ITK protein caused many of the pathways that HIV uses to be less active, thereby inhibiting or slowing HIV replication.”
In their laboratory experiments, the researchers used a chemical inhibitor and a type of genetic inhibitor, called RNA interference, to inactivate ITK in human T cells. Then, the T cells were exposed to HIV, and the researchers studied the effects of ITK inactivation upon various stages of HIV’s infection and replication cycle. Suppression of ITK reduced HIV’s ability to enter T cells and have its genetic material transcribed into new virus particles. However, ITK suppression did not interfere significantly with T cells’ normal ability to survive, and mice deficient in ITK were able to ward off other types of viral infection, although antiviral responses were delayed.
“ITK turns out to be a great target to examine,” said Dr. Schwartzberg, noting that researchers had been concerned that blocking other human proteins involved in HIV replication might kill or otherwise impair the normal functions of T cells.
According to Dr. Schwartzberg, ITK already is being investigated as a therapeutic target for asthma and other diseases that affect immune response. In people with asthma, ITK is required to activate T cells, triggering lung inflammation and production of excess mucus.
“There are several companies who have published research about ITK inhibitors as part of their target program,” Schwartzberg said. “We hope that others will extend our findings and that ITK inhibitors will be pursued as HIV therapies.”
NHGRI researchers received support for this work from the NIH Intramural AIDS Targeted Antiviral Program. Chemical compounds used in the research were synthesized at the NIH Chemical Genomics Center, which was established through the NIH Roadmap for Medical Research and is administered by NHGRI. The Boston University group originally participated in the research while at Pennsylvania State University, where they received support from Penn State Tobacco Formula Funds, and where Dr. Henderson received support from the National Institute of Allergy and Infectious Diseases (NIAID).
Raymond MacDougall | NHGRI
Cancer diagnosis: no more needles?
25.05.2018 | Christian-Albrechts-Universität zu Kiel
Less is more? Gene switch for healthy aging found
25.05.2018 | Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut e.V. (FLI)
The more electronics steer, accelerate and brake cars, the more important it is to protect them against cyber-attacks. That is why 15 partners from industry and academia will work together over the next three years on new approaches to IT security in self-driving cars. The joint project goes by the name Security For Connected, Autonomous Cars (SecForCARs) and has funding of €7.2 million from the German Federal Ministry of Education and Research. Infineon is leading the project.
Vehicles already offer diverse communication interfaces and more and more automated functions, such as distance and lane-keeping assist systems. At the same...
A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.
The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...
At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.
At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...
There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?
At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
25.05.2018 | Event News
02.05.2018 | Event News
13.04.2018 | Event News
25.05.2018 | Event News
25.05.2018 | Machine Engineering
25.05.2018 | Life Sciences