To celebrate Pride Month, Enterprise Innovation spoke with Dr. Brad Jones, an associate professor of immunology in medicine, about his mission to find a cure for HIV and the recent progress in his research.
When did you first become interested in studying virology, and HIV in particular? How, if at all, has your identity shaped your research interests and objectives?
I first started researching HIV in a lab in 2002. At the time, I was a kinesiology major. I wanted to be a sports medicine doctor, but that was around the time I started coming out as being gay and saw the impact that HIV was having on my community. That's what motivated me to switch from sports medicine to studying HIV. I was also lucky because I had a very good mentor who took me into her lab. So, it was a convergence of those two things. I've been focused on HIV ever since. That makes it 21 years now.
While there are now several approved therapies for managing HIV infection, there are still no widely available curative treatments. Why is HIV infection so difficult to cure?
My lab is studying the immune response to HIV. We study two types of immune cells, called killer T-cells and natural killer cells. What we want to do is harness these cells to cure HIV infection. Currently, people can take medication and live a long and healthy life, but if they stop their medication, the virus comes back. We want to empower the immune system to be able to prevent the virus from rebounding so that people don't need to make a lifelong commitment to drugs. We have molecular research studying the ways in which killer T-cells kill their targets all the way through to some clinical trials that we're really excited to be running now.
You are a co-PI on a five-year $28.5 Million Martin Delaney Collaboratory grant, awarded in 2021, aimed at finding a cure for HIV. What are some of the potential strategies to cure HIV being explored in this grant? What aspect(s) of HIV is your laboratory focused on?
This is the second round of these big grants that I've had a chance to co-lead. What's interesting about this round is that it's a back-to-basics approach. We need to learn more about how HIV is able to stick around for life in people even though we've suppressed it with antiretroviral therapy. In these people only around one in a million CD4 T cells is infected with HIV, and one important recent finding is that these cells are often clones of each other. So, a very small number of infected cells have divided (clonally expanded) to create this larger population of cells. We want to understand why those cells are dividing and are not being killed, because if we learn that, then we can better use the immune system to kill them. We've managed to isolate and grow one of these ‘one in a million’ infected cell clones in the test tube. We can now use this to probe mechanisms underlying HIV persistence. From there, we can develop new therapeutic strategies to help the immune system kill these special cells – these clones that are expanded.
Even though this grant doesn’t fund clinical trials, we can partner with other groups and networks. We have a clinical trial that is enrolling now in New York testing a combination of agents that can boost the immune response in people with HIV. We found that this combination completely controlled HIV in two-thirds of our preclinical models, which is an exciting result. If we could achieve similar results in people, that would be amazing. We are about a couple years into this study now, so we'll be getting data over the next few years to see if we're actually having a similar outcome in people.
HIV is a retrovirus. What that means is HIV takes its genetic material and inserts it into our own DNA. It burrows into our DNA, and that makes it hard to cure. We're learning that the place where it inserts itself into our DNA is very important. It can insert into some places where the virus is more likely to go dormant, or it can insert into some places and change the expression of genes that are around it. We have a large effort underway to study what we call the integration site, where HIV lands in the genome, and how that influences whether that cell can persist and go on to form a reservoir that prevents cure or whether that cell gets cleared out relatively quickly. That's another area of emphasis in the program.
What do you see as the key next steps towards global containment of HIV?
Medications are extremely good both for maintaining the health of people living with HIV and preventing transmission to others. Pre-exposure prophylaxis (PrEP) is effective. A person with undetectable viral load cannot infect a new person. It seems like we have all the tools, so why are we not on track to end the epidemic? A big part of the issue is that a lot of people who are living with HIV don't know their status. There needs to be more testing happening. And that becomes complicated because it gets into issues of stigma and social factors.
One observation from other infectious diseases – particularly syphilis - was once there was a cure, testing rates went up. People might be scared to learn they have a disease for which there's no cure. If we can get to the point where our messaging is ‘get tested, get cured,’ then I think testing rates for HIV would improve a lot.
There's a lot that can be done on implementation science and policy. That's not my area of expertise. We have wonderful biomedical tools, but we're still missing the two most powerful tools, which are a vaccine and a cure. Both of those tools would help us end the pandemic.
Our program has a lot of young investigators, and some of them are in leadership positions. We have a focus on preparing the next generation of scientists because curing HIV is probably going to take the next generation, hopefully not the next generation or two.
You co-lead the Martin Delaney grant with Dr. Marina Caskey at The Rockefeller University, which is part of our Tri-Institutional community. Do you also collaborate with Sanders Tri-I TDI? How do you utilize the resources in our innovation ecosystem here?
We've had quite a few meetings with the TDI. As I mentioned, we're finding ways that infected cells can resist being killed. When we identify those mechanisms, we want to find drugs or therapeutic approaches that can help us overcome those mechanisms and kill those cells. We need to advance a bit further before it's time for TDI to engage and take a project forward. So, it's definitely on my radar that if we get to that point, this is a resource we can tap into.
I have a few patents from previous places. Anytime we come across something that we think could have a therapeutic benefit, we're talking to the Center for Technology Licensing (CTL) first. New faculty should be getting the message from their mentors and their departments [about these resources]. The discoveries that we brought to CTL in the past few years probably wouldn't have made it as patents, so there was a collective decision not to spend time and resources on these filings. More recently, however, we have discovered, from our in vitro experiments, a really novel way to make infected cells more susceptible to being killed. We're talking to CTL about protecting this discovery so that it'll be positioned for potential therapeutic development.