Ordinary mice cannot be infected with HIV, so previous HIV mouse models have used mice that carry human stem cells or CD4 T cells, a type of immune cell that can be infected with HIV. But these models tend to have limited utility because the human cells soon perceive the tissues of their mouse hosts as “foreign,” and attack — making the mice gravely ill.

By contrast, the new mouse model, described in a paper in the Journal of Experimental Medicine on May 14, avoids this problem by using a subset of human CD4 cells that mostly excludes the cells that would attack mouse tissue. The researchers showed that the mice can usefully model the dynamics of long-term HIV infection, including the virus’s response to experimental therapies.

“We expect this to be a valuable and widely used tool for studying the basic science of HIV infection, and for speeding the development of better therapies,” said co-first author Dr. Chase McCann. During the study, Dr. McCann was a Weill Cornell Graduate School student in the laboratory of senior author Dr. Brad Jones, associate professor of immunology in medicine in the Division of Infectious Diseases at Weill Cornell Medicine. Dr. McCann, who was supported at Weill Cornell by a Clinical and Translational Science Center (CTSC) TL1 training award, is now the Cell Therapy Lab Lead in the Center for Cancer and Immunology Research at Children’s National Hospital in Washington, DC. The other co-first authors of the study are Dr. Christiaan van Dorp of Los Alamos National Laboratory and Dr. Ali Danesh, a senior research associate in medicine at Weill Cornell Medicine.

The invention of the new mouse model is part of a wider effort to develop and test cell therapies against HIV infection. Cell therapies, such as those using the patient’s own engineered T cells, are increasingly common in cancer treatment and have achieved some remarkable results. Many researchers hope that a similar strategy can work against HIV and can potentially be curative. But the lack of good mouse models has hampered the development of such therapies.

Drs. Jones and McCann and their colleagues showed in the study that the cell-attacks-host problem found in prior mouse models is chiefly due to so-called “naïve” CD4 cells. These are CD4 cells that have not yet been exposed to targets, and apparently include a population of cells that can attack various mouse proteins. When the researchers excluded naïve CD4 cells and instead used only “memory” CD4 cells, which circulate in the blood as sentinels against infection following exposure to a specific pathogen, the cells survived indefinitely in the mice without causing major damage to their hosts.

The researchers observed that the human CD4 cells also could be infected and killed by HIV, or protected by standard anti-HIV drugs, essentially in the same way that they are in humans. Thus, they showed that the mice, which they termed “participant-derived xenograft” or PDX mice, served as a workable model for long-term HIV infection. This term is akin to the “patient-derived xenograft” PDX models used to study cancer therapies, while recognizing the contributions of people with HIV as active participants in research.

Lastly, the researchers used the new model to study a prospective new T-cell based therapy, very similar to one that is now being tested against cancers. They put memory CD4 T cells from a human donor into the mice to permit HIV infection, and then, after infection was established, treated the mice with another infusion of human T cells, these being CD8-type T cells, also called “killer T cells.”

The killer T cells were from the same human donor and could recognize a vulnerable structure on HIV — so that they attacked the virus wherever they found it within the mice. To boost the killer T cells’ effectiveness, the researchers supercharged them with a T cell-stimulating protein called IL-15.

The treatment powerfully suppressed HIV in the mice. And although, as often seen in human cases, the virus ultimately evolved to escape recognition by the killer T cells, the ease of use of the mouse model allowed the researchers to monitor and study these long-term infection and viral escape dynamics in detail.

“I think that the major impact of this model will be its acceleration of the development of T cell-based therapies that can overcome this problem of viral escape,” Dr. Jones said.

He and his laboratory are continuing to study such therapies using the new mouse model, with engineered T cells from Dr. McCann’s laboratory and others.

New sensors developed by Professor Otto Gregory, of the College of Engineering at the University of Rhode Island, and chemical engineering doctoral student Peter Ricci, are so powerful that they can detect threats at the molecular level, whether it’s explosive materials, particles from a potentially deadly virus or illegal drugs entering the country.

“This is potentially life-saving technology,” said Gregory. “We have detected things at the part-per-quadrillion level. That’s really single molecule detection.”

Broad-Based Applications

Because Gregory’s sensors are so small and so powerful, there is a wide range of applications.

“The platform is broad-based, so you can apply it to lots of different venues, with lots of different end users,” said Gregory.

While his research is largely funded by the Department of Homeland Security, other government agencies have taken notice of Gregory’s sensors.

The Department of Defense may be interested in using it to monitor wounds in soldiers and to detect roadside improvised explosive devices (IEDs).

If a soldier or first responder suffered an open wound from shrapnel, Gregory’s sensors could help determine if the wound became infected.

“Hydrogen peroxide generated by the human body for wounds is an indication of how good or how bad antibiotics are working to fight the wound,” said Ricci. “Our sensor could be used as a wearable device to sniff out peroxide coming from the wound at the part-per-billion level.”

At Miami Heat basketball games, dogs have been used to sniff traces of COVID-19 coming from the pores in people’s skin. In an article published in the prestigious journal Nature, Gregory stated that his sensors could be used for the same purpose.

“Where dogs are detecting it from the skin, our sensors would detect it from biomarkers in people’s breath,” Ricci said, who is from West Warwick.

The Coast Guard has shown an interest in using the technology to “sniff out” illegal drugs being smuggled into the United State aboard ships.

Shrinking the ‘Digital Dog Nose’

“Anything that can typically be sniffed out by a dog we can do,” said Gregory. “That’s why we’ve called it the Digital Dog Nose.”

The Digital Dog Nose was featured on shows such as CBS This Morning in November 2019, but what was once the size of a toolbox has been reduced to a quarter of the size of a pack of cigarettes.

“By decreasing the thermal mass of the sensor, we’ve decreased the amount of power required to run the sensor,” said Gregory. “We started with a thermal mass on the order of grams. Now the thermal mass of our sensor is on the order of micrograms.”

One of the keys to making a device as small and powerful as Gregory’s is to find the right battery.

“We have partnered with a company that makes very thin, low-mass batteries in Colorado called ITN Energy Systems,” Gregory said. “They make lithium batteries that are no thicker than a piece of paper. The process has been about finding the right partners, which helps us improve our catalysts and improve our sensor platform.”

Passing the Test

In March 2021, the Naval Research Laboratory brought its mobile testing unit to URI’s W. Alton Jones Campus to put Gregory’s explosives sensors and others to the test.

“They set up a field test outside using their vapor test bed,” said Ricci. “They were able to select an explosive molecule and deliver it to the sensor system. Knowing what the level was, they wanted to see how our sensor would respond. One of the tests was at the part-per-quadrillion level.”

Staying a Step Ahead

As bad guys have developed new explosives or new ways to improvise on existing explosives, the good guys have tried to stay a step ahead.

“The Department of Homeland Security has asked us to be flexible enough to anticipate and adapt to emerging threats that may come several years down the road,” said Gregory. “We can tweak our catalysts for a specific molecule that is the current threat. That’s what we do with biomarkers. That’s what we do with drugs. What’s nice about this platform is that it’s flexible.”

Coming a Long Way

The sensors Gregory and Ricci have developed have been tested and improved upon over a long period of time. The professor’s research was originally funded 20 years ago by the Defense Advanced Research Projects Agency (DARPA), a research and development agency of the United States Department of Defense that is responsible for the development of emerging technologies for use by the military.

After two years of DARPA funding, the Army funded the project for a year. The Department of Homeland Security has provided funding ever since.

“At the time, this research was very novel and very different,” said Gregory. “DARPA funds projects that are high risk, high reward. We’ve demonstrated that the gamble they took on our concept back then has paid off.”

Michael Silevitch, the Robert D. Black Distinguished Professor of Engineering at Northeastern University, has collaborated with Gregory on his research for more than 10 years.

“This is breakthrough technology,” said Silevitch. “Otto’s work on chemical detectors has evolved to the point of being ready for use in many applications, including the deployment of his sensors on a drone-based platform to help protect soft targets such as schools, shopping malls or places of worship.”

Taking the New Steps

Now that the sensors are very small and lightweight, they could be attached to drones, leading to many new applications.

“We’ve been talking to drone companies about using our sensors on their drones,” said Gregory. “Drones need very lightweight, portable power supplies and you have to tap into their wireless communication. It’s a much different set of engineering conditions than using a robot arm that the Army is looking to use for roadside IEDs.”

Gregory and Ricci are also working on sensor arrays, to differentiate one explosive, or threat, from another.

“We’ll need an array of sensors to detect a specific explosive in the presence of other explosives or precursors,” said Ricci. “If there’s a plume of three different explosives, we may need to identify one from the others.”

Ready to Use

Now that the sensors have proven to be effective, implementing them in real-world situations is just a matter of funding.

“Our sensor is not an off-the-shelf commercial product yet, but we have a potential partner,” Gregory said. “We just need a customer to step up to the plate and say here’s an order for 1,000 of these, can you deliver them?”

The research is published in Nature Communications, a peer-reviewed, open access, scientific journal published by Nature Research.

Instead of using chemicals or radiation, immunotherapy is a type of cancer treatment that helps the patient’s immune system fight cancer. T cells are a type of white blood cell that are of key importance to the immune system. Cytotoxic T cells are like soldiers who search out and destroy the targeted invader cells.

While there has been success in using immunotherapy for some types of cancer in the blood or blood-producing organs, a T cell’s job is much more difficult in solid tumors.

“The tumor is sort of like an obstacle course, and the T cell has to run the gauntlet to reach the cancer cells,” said Paolo Provenzano, the senior author of the study and a biomedical engineering associate professor in the University of Minnesota College of Science and Engineering. “These T cells get into tumors, but they just can’t move around well, and they can’t go where they need to go before they run out of gas and are exhausted.”

In this first-of-its-kind study, the researchers are working to engineer the T cells and develop engineering design criteria to mechanically optimize the cells or make them more “fit” to overcome the barriers. If these immune cells can recognize and get to the cancer cells, then they can destroy the tumor.

In a fibrous mass of a tumor, the stiffness of the tumor causes immune cells to slow down about two-fold — almost like they are running in quicksand.

“This study is our first publication where we have identified some structural and signaling elements where we can tune these T cells to make them more effective cancer fighters,” said Provenzano, a researcher in the University of Minnesota Masonic Cancer Center. “Every ‘obstacle course’ within a tumor is slightly different, but there are some similarities. After engineering these immune cells, we found that they moved through the tumor almost twice as fast no matter what obstacles were in their way.”

To engineer cytotoxic T cells, the authors used advanced gene editing technologies (also called genome editing) to change the DNA of the T cells so they are better able to overcome the tumor’s barriers. The ultimate goal is to slow down the cancer cells and speed up the engineered immune cells. The researchers are working to create cells that are good at overcoming different kinds of barriers. When these cells are mixed together, the goal is for groups of immune cells to overcome all the different types of barriers to reach the cancer cells.

Provenzano said the next steps are to continue studying the mechanical properties of the cells to better understand how the immune cells and cancer cells interact. The researchers are currently studying engineered immune cells in rodents and in the future are planning clinical trials in humans.

While initial research has been focused on pancreatic cancer, Provenzano said the techniques they are developing could be used on many types of cancers.

“Using a cell engineering approach to fight cancer is a relatively new field,” Provenzano said. “It allows for a very personalized approach with applications for a wide array of cancers. We feel we are expanding a new line of research to look at how our own bodies can fight cancer. This could have a big impact in the future.”

In addition to Provenzano, the study’s authors included current and former University of Minnesota Department of Biomedical Engineering researchers Erdem D. Tabdanov (co-author), Nelson J. Rodríguez-Merced (co-author), Vikram V. Puram, Mackenzie K. Callaway, and Ethan A. Ensminger; University of Minnesota Masonic Cancer Center and Medical School Department of Pediatrics researchers Emily J. Pomeroy, Kenta Yamamoto, Walker S. Lahr, Beau R. Webber, Branden S. Moriarity; National Institute of Biomedical Imaging and Bioengineering researcher Alexander X. Cartagena-Rivera; and National Heart, Lung, and Blood Institute researcher Alexander S. Zhovmer, who is now at the Center for Biologic Evaluation and Research.

The research was funded primarily by the National Institutes of Health (NIH) and University of Minnesota Physical Sciences in Oncology Center, which receives funding from NIH’s National Cancer Institute. Additional funding was provided by the American Cancer Society and the Randy Shaver Research and Community Fund. The University of Minnesota Imaging Center provided additional staff expertise. Some of the researchers also are part of the University of Minnesota Center for Genome Engineering and the University’s Institute for Engineering in Medicine.

Mullen designed a maze game that could be played in both virtual reality and conventional formats, then the research team recruited 41 UC Santa Cruz undergraduate students to test the game. Participants played in both formats, with researchers randomizing which version of the game each student started with. Both versions were essentially the same, but the mazes in each varied slightly so that there was no repetition between formats.

Participants were asked to stop playing the game whenever they felt like five minutes had passed. Since there were no clocks available, each person had to make this estimate based on their own perception of the passage of time.

Prior studies of time perception in virtual reality have often asked participants about their experiences after the fact, but in this experiment, the research team wanted to integrate a time-keeping task into the virtual reality experience in order to capture what was happening in the moment. Researchers recorded the actual amount of time that had passed when each participant stopped playing the game, and this revealed a gap between participants’ perception of time and the reality.

The study found that participants who played the virtual reality version of the game first played for an average of 72.6 seconds longer before feeling that five minutes had passed than students who started on a conventional monitor. In other words, students played for 28.5 percent more time than they realized in virtual reality, compared to conventional formats.

This time compression effect was observed only among participants who played the game in virtual reality first. The paper concluded this was because participants based their judgement of time in the second round on whatever initial time estimates they made during the first round, regardless of format. But if the time compression observed in the first round is translatable to other types of virtual reality experiences and longer time intervals, it could be a big step forward in understanding how this effect works.

While there are many informal descriptions of time compression in virtual reality from people who have experienced it first-hand, it’s still an active area of research. One particularly well-known prior study applied virtual reality time compression to shorten the perceived duration of treatment for chemotherapy patients, but that experiment didn’t compare virtual reality with conventional screen formats.

“This is the first time we can really isolate that it’s not just that you’re playing a video game, or the content of whatever you’re seeing,” Mullen said. “It’s really the fact that it is virtual reality versus a conventional screen that contributes to this time compression effect.”

Time compression could be useful in some situations — like enduring an unpleasant medical treatment or passing the time on a long flight — but in other circumstances, it could have harmful consequences.

“As virtual reality headsets get more comfortable to wear for longer periods of time, and as more immersive games are made for this format, I think it would be good to avoid having it become like a virtual casino, where you end up playing more because you don’t realize how much time you’re spending,” Mullen said.

Research on game addiction shows that losing track of time during gameplay can negatively affect a player’s sleep cycle and mood. These effects could be more pronounced in virtual reality, but Mullen says game designers can help to minimize the risk, perhaps by integrating a clock that would appear at regular intervals during gameplay.

It will also be important to discover why virtual reality seems to contribute to time compression. In the paper, Mullen describes one possibility, which relates to the fact that, in virtual reality, a player has less body awareness. Psychology Professor Nicolas Davidenko, a coauthor and advisor on the paper, explained why this might be important.

“In virtual reality, when you look down, you might see nothing where your body normally would be, or you might see a schematic of a body, but it won’t feel like your body,” Davidenko said. “There are theories that we may rely on our heartbeat and other bodily rhythms to help our brain track the passage of time, so if you have a less vivid sense of your body in virtual reality, you might be missing the pulses of this timekeeping mechanism.”

Future experiments to test this theory could yield new insights to help designers maximize benefits and minimize harm from time compression as virtual reality technology continues to grow.