Brad Jones, Catherine Bollard, and Douglas Nixon were sitting around Bollard’s office one morning, bouncing ideas back and forth. Other “collaboratories” — teams of researchers and institutions united under a National Institutes of Health (NIH) grant with a goal of curing HIV/AIDS — had devised clever, to-the-point names for their projects: CARE (Collaboratory of AIDS Researchers for Eradication), DARE (Delaney AIDS Research Enterprise), and the even more straightforward “defeatHIV.” The trio wanted to do their mission justice.
By Caroline Trent-Gurbuz
“I guess maybe a week before that, I was having a conversation with a friend of mine who’s living with HIV, who has followed the research very closely,” recalls Brad Jones, Ph.D., assistant professor of microbiology, immunology, and tropical medicine at the GW School of Medicine and Health Sciences (SMHS). “He said, in a moment of weakness, that he wasn’t sure if he believed there would be a cure for HIV.”
The word stuck with Jones. Believe. He played around with possibilities and was surprised at how easily he could create a spell-out for the acronym reflecting the goals of the collaboratory: “Bench-to-Bed Enhanced Lymphocyte Infusions to Engineer Viral Eradication.”
“Our program goes all the way from basic science to the bench to the bedside: We’re taking these lymphocytes, which is another word for immune cells, so-called T-cells, and enhancing them, putting them back into the patient, and trying to eradicate infection,” he says. “It just clicked.”
The BELIEVE grant, as it’s now known, is a multimillion-dollar grant awarded as part of the second iteration of the NIH Martin Delaney Collaboratory: Towards an HIV-1 Cure. Established in honor of late AIDS activist Martin Delaney, the five-year grant is designed to draw researchers out of their silos, pairing them with colleagues across the country. The grant also puts researchers together with private companies, in this case immunotherapeutic company Altor BioScience Corporation (Altor) as well as Torque Therapeutics (Torque), a biomedical engineering company, to accelerate the bench-to-bedside process.
“Part of the fun of this [grant] was finding partners that we think are doing really exciting, cutting-edge studies with products that we hope could also be of value in the HIV cure area,” explains principal investigator Nixon, M.D., Ph.D., chair of the Department of Microbiology, Immunology, and Tropical Medicine and Walter G. Ross Professor of Basic Science Research at SMHS. “It’s something important, for us to be working with industry partners.”
It’s just as exciting, he adds, to find other researchers doing the “best science,” a critical aspect of the inclusive, cooperative nature of the grant. “I think one of the things about this sort of team-type science is that no one group has all the expertise necessary, so you actually welcome the opportunity to reach out and find the best people.”
Driving the Research
To keep the research on track — and the communication flowing — the BELIEVE Executive Committee, composed of Nixon; Jones; Bollard, M.D., professor of pediatrics and of microbiology, immunology, and tropical medicine at SMHS; and Alan Greenberg, M.D. ’82, M.P.H., director of the D.C. Center for AIDS Research, and professor and chair of the Department of Epidemiology and Biostatistics at the Milken Institute School of Public Health at GW, will track progress among the teams.
“The way we’ve structured this grant, all of the different objectives have milestones and timelines that they need to meet,” explains Jones. If all of those milestones are met, the grant value could reach $28 million.
In essence, GW, in running the management and operations section, is the engine pulling the rest of the train. “Obviously,” Nixon adds, “you need all the parts to work together for a functioning unit. We have to keep all of our subcontracts in order, we have to keep the milestones on track, we have to have these compulsory meetings … we’ve got a lot of administrative components that are really important.”
Armed Against Infection
With GW leading the way, the BELIEVE grant has several initial research foci: enhancing the killing capability of HIV-specific T-cells, expanding the functions of natural killer cells, helping the killer cells find HIV in the body more easily, and bringing the best combinations into clinical studies.
“The overall idea is that the different foci come together to turn the immune system into a kind of weapon against the HIV reservoir,” explains Jones.
Although antiretroviral therapy can help reduce HIV levels, it cannot reach dormant, or hidden, HIV in the latent cells, which can reactivate and start the infection cascade over again. Previous researchers have used “kick and kill” strategies to try to eliminate infected cells, but their efforts have been limited, owing to the inability of the immune system to reduce the viral reservoir, or kill enough of the infected cells. The BELIEVE teams will use their expertise — and the products of Altor and Torque — to define the mechanisms that have prevented the immune system from completely clearing the infected cells.
Enhancing the T-Cell
The investigations at GW and clinical partner Children’s National Health System, led by Jones and Nixon, focus specifically on the grant’s first research target: making the most of the T-cell’s killing power.
“My goal is to figure out how we can best aim killer T-cells against HIV-infected cells,” says Jones. “[HIV cells] have ways that they usually hide from the immune system, but we want to expose them. Other people have strategies they’re working on to send these T-cells to the right parts of the body and to directly enhance the function of the T-cells, but I’m really working on how to direct them properly.”
In other words, Jones is focusing more on the “kill” side of “kick and kill.” To accomplish his goal, Jones is working closely with Altor, which has developed a molecule known as ALT-803. This molecule reverses HIV latency in cells and, when given as a therapeutic, activates T-cells and natural killer cells throughout the body.
“What’s unique about Altor’s molecule is it actually wakes up hidden HIV and enhances the ability of the immune system to kill those reactivated cells, so we think it’s really unique and exciting,” explains Jones, adding that the company’s scientists also bring a great deal of enthusiasm and insight to the project. ALT-803 is currently in clinical trials for cancer, which makes establishing similar trials using the molecule for HIV/AIDS a faster, more efficient process.
Torque, on the other hand, has found a way to attach efficacy-enhancing drugs to cytotoxic T-cells via nanoparticle backpacks, a delivery method that can help the researchers precisely coordinate the “kick” with the “kill,” potentially leading to clearance of the HIV viral reservoir.
Jones is also focusing on a pair of preclinical systems. The first involves testing the cells of those living with HIV, in vitro. “We have assays that let us test different ways of eliminating HIV in the test tube,” he explains. “We need to pass certain milestones in that kind of controlled setting before we can expect to have success in the more complicated in vivo setting.” To connect the test-tube setting to patients, Jones and his team of investigators will use a unique mouse model as a stepping-stone to the clinical phase.
Historically, small animal models have proven a tricky prospect for HIV researchers because mice cannot be infected with HIV; rather, researchers create “humanized mice,” or mice carrying a human immune system. Jones is taking a different tack: “We’re taking those immune cells from people who have been on antiretroviral therapy for years, and [we’re] putting them into mice, so you already have that natural HIV reservoir.”
Bollard’s work, meanwhile, is more translational. Her research “involves the manufacture of HIV-killing T-cells and the administration of these novel T-cells to HIV-positive individuals on antiretroviral therapy given either alone or in combination with the latency reversal agent ALT-803,” she says. “We will evaluate the safety of this combination and the efficacy of this therapeutic approach to clear the viral reservoir.”
She will base the HIV-killing T-cells she’s developing on the work Jones is conducting in the mice. Then, they’ll give those cells to patients.
“What’s unique about this grant is the rapid translation of novel ideas developed at the bench and then getting them to the clinic,” she says. “So much work is done that is focused on the mice or the monkey, and [it] never gets any further. It is refreshing to see such an emphasis on translation to the clinic.”
For Nixon, Bollard and Jones’ work exemplifies the greater goals of the grant. “We have an ambitious program in which we would like to be able to move into the clinic in Year Two,” he says. “We’ll have to see if that’s a possibility, but we’re certainly going to try and push for that. Our philosophy is best science plus getting into the clinic as rapidly as possible.”
“We want to be responsive to the community to make sure that in their perspective, the cures that we develop are a significant improvement over the current option, which is daily antiretroviral therapy.”
Outside the labs, the grant will prioritize community engagement through local advisory boards and ongoing communication.
“[It’s not] just teaching the community, [it’s] listening to people’s expectations about cure research, their fears, their hopes, so that we can be sure that we’re responsive to the people that we’re trying to help,” explains Jones.
Washington, D.C., in particular, has had some of the highest rates of HIV in the nation, according to Greenberg, and the grant helps establish the nation’s capital as “one of the focal points for NIH-supported HIV cure research,” he says, which is vital for the community.
Working with the community will also help the team address misconceptions about what a cure could look like; taking a pill or two, Jones says, is not yet on the horizon. What is available now, however, are the highly customizable procedures that the BELIEVE grant is pursuing. “There are a lot of approaches, like ours, that involve donating cells that are manipulated and then reinfused into individuals,” he says. “We want to be responsive to the community to make sure that in their perspective, the cures that we develop are a significant improvement over the current option, which is daily antiretroviral therapy. We want to make sure that we’re engaging in a dialogue at all steps of the process.”
With that conversation in mind, Jones adds that his friend, representative of the community, isn’t quite a believer — yet. “He does [know about the grant and the work we’re doing],” says Jones. “He’s quite touched that his comment became part of this large effort.”