Jeff Galvin: So, I gotta say that the first thing that stood out that intrigued me about your work is this idea of the intersection between HIV research and advocacy. Why did that make sense to you to put those two things together?

Dr. Deanna Kulpa: One of the things that I think is interesting about HIV research is if you go to an HIV conference, such as the International AIDS Society Conference or the HIV Persistence Meeting, a lot of people living with HIV attend these conferences. The HIV community is very integrated into HIV research, into the process, into asking questions. I mean, when they come to the meetings, they stand up to the mic and ask questions just as much as you see faculty or clinicians doing. So, it makes a lot of sense to partner with them. They are very interested and motivated in being a part of the process.

One of the things that I also thought was very interesting was I was at a meeting a few years ago, and through the development of antiretroviral therapy, we've obviously come a long way from the multiple drugs a day to the one pill a day regimen. But now they're looking at injectables and things like that, where you could potentially have one shot a month or one shot every six months. 

There was a lot of excitement in the scientific community presenting this idea that, "Oh, you could just get an injection a month, and won't that be great?" Then I saw a discussion in a community board where they were actually saying, "We don't want that." 

So, I felt they were saying, "Look, I am on antiretroviral medication. I don't want to go to a clinic every month. Going to a clinic exposes me to an atmosphere I may not necessarily want to be in if there's a lot of sick people around. Right now, I can get my medication and not have to go through that." 

So, I thought it was an interesting thing to say. If we're really excited about it as scientists, but the community isn't excited about it, then we're not talking to each other enough. And so, clearly, making that partnership makes a lot of sense.

Jeff Galvin: Wow, so that's really interesting. A lot of things just came up in what you just said. I mean, one being that it looks like the major thrust of the industry to reduce the frequency by having injections may not necessarily be the panacea that the people living with HIV community really wants. That's fascinating because I hear so much on the other side because I'm so deep in the industry, and so I can see immediately why it's so important to get out there with the consumer, with the person that we're trying to help and to find out what they're really looking for. And that is amazing that already, you know, that kind of observation comes out of it.

Jeff Galvin: When these folks engage with you, what sort of questions are they asking? I mean, I get that input, but, you know, what do you see in terms of sort of the big themes of the questions that are coming from people living with HIV? Are they scientific questions, or are they related to schedule or priorities, or what kind of things do people stand up and talk about there?

Dr. Deanna Kulpa: The first question I always get is, "When are we gonna have a cure?" Over and over and over again, that is priority number one. Whether it's through direct messaging on social media, people find your name and you know, they'll message you, and the only thing they'll say is, "We need a cure. You know, please work harder." You go to conferences and community advocates, they'll all say the same thing, "We need a cure. We need a cure." 

So, all the drugs that we have are amazing. Antiretroviral therapy, you cannot deny that it has made a significant impact in the health of people living with HIV worldwide. I mean, that's undisputable. At the other end of it is still the people living with HIV saying we need a cure for this, and that is their top priority. 

And I think also why you will find, in terms of clinical studies where we need volunteers to participate in different therapeutic intervention studies, they are very willing to be a part of the solution and to find a cure. And they're just a really inspiring community to work with.

Jeff Galvin: Yeah, you know, we get very similar feedback as well in our pursuit of an HIV cure, and it's very interesting to see that, as a more formal advocacy venue, that you're getting a lot of the same thing. So, what's your impression about why a cure is so important to them besides the fact that a cure would be better than the situation now? Like, what makes it significantly better? Because I'm seeing a level of desperation for a cure that kind of surprises me. 

HIV has been treatable for a long time and with the single pill regimen, we're really down to somewhat a minimal treatment protocol in order to keep people not just free from developing AIDS, which of course is the most critical factor, is that you know, we stop the progression towards this deadly disease of AIDS, so we keep it as a chronic viral infection of HIV. 

But also, if they're taking their pills religiously, you know, like reliably every single day, they're not infectious as well, so they are actually reducing the spread of HIV and protecting everybody around them.

So what do you see as the delta between there and the cure for, from their perspective? 

Dr. Deanna Kulpa: The general gist that I get is really it's about stigma and, you know, looking at it from a philosophical standpoint, I grew up in the '80s when we were just starting to hear about HIV, so, to me, one of the biggest factors of how it came into the United States or we first started recognizing it when he was in the United States is, there was always this conversation around how did you get it? 

I mean, you know, if someone has a cold, you don't ask them, "Well, how did you get that?" It was always, if you don't remember, but, you know, at the time, we had blood transfusion acquisition, or intravenous drug use, or sexual contact, and there was always this kind of, at least to me, the sense in the media or how it was presented culturally was, there was always this little asterisk like, "Well, they got it through a blood transfusion, so they were good," you know what I mean? There was that judgment…

Jeff Galvin: Yeah, yeah, there was a judgment.

Dr. Deanna Kulpa: …about they got it as a blood transfusion, where in, you know, in the back of that statement is, well, it must have been your fault if you got it in a different way, which has a real negative connotation to it. And I think that has carried forward through the entire epidemic. There's always this statement when you read articles like, "They got it through this," you know, I'm like, "Well, does it really matter?"

Jeff Galvin: Does it matter? 

Dr. Deanna Kulpa: We need to work on the future and how we can get rid of it. Focusing on how you got it is a little invasive, and I think that kind of contributes to that idea that there's, I don't know, there's the stigma…

Jeff Galvin: And how you got it says something about your value in a way, right?

Dr. Deanna Kulpa: Exactly.

Jeff Galvin: Yeah, that's really interesting. I mean, you would think that in the United States, if you got it legally, that should be all that matters, right? But yeah, I get it, you know, because in the early days, of course, it was thought of as a gay disease. It was actually named gay-related immunodeficiency before it became HIV, and, yeah, they have not managed to completely shake that off, right? 

It is crystal clear that HIV has no preference for any race or any particular preferences or backgrounds or anything, but yet there is that stigma surrounding it. And I wonder also, is there some stigma in terms of that people misunderstand HIV to the extent that they actually are scared by people that are living with HIV that are open about it?

Dr. Deanna Kulpa: You know, I would love to say that's not true anymore, you know? You would like, I know enough, the messaging has been clear for such a long time that, you know, casual contact, I mean, you're not just going to pick it up just walking down the street.

And actually, I feel like there probably still is some of that more than, you know, I guess I want to admit that, you know, we still have those thoughts in our head, which is why I think like the undetectable equals untransmissible messaging needs to be stronger. 

It is such a powerful statement and it is such a powerful piece of information for people to have. I think that we could go anywhere in terms of how we need to kind of better get our messaging out is making sure that people are aware of "U equals U." 

And I'm always kind of surprised, because we're sort of soaking in it, so we know, we hear all that messaging, but I'm surprised when I talk to other people. I'm like, "You don't even look at the bus stop. They've got the billboards and the HIV testing and the undetectable equals untransmissible." And people still look at me and go, like, "I don't know what you're talking about." It's all around us, but it's still not being absorbed.

Jeff Galvin: Yeah, that's really interesting that you point out that the messaging has been crystal clear for a long time. Even in the early days, it was made crystal clear that if somebody has HIV around you, it is exceedingly hard for you to get. You need some blood contact or at least intimate sexual contact. You can't kiss them on the lips and get it. You can't French kiss them and get it. It was not an easy thing to move from person to person, but that never really sunk in. 

And we come from the opposite end of the spectrum because I look here at our company and in our labs, you know, people go in and work with HIV all day. They wash their hands and go to lunch like it's no big deal. And that's because they're so familiar with it. They know exactly how it's transmitted. And yet, I was shocked to hear that medical doctors sometimes have trepidations about treating people with HIV, and then it can be difficult to get a dentist, for instance, and you know, things like that. 

And so, even amongst educated people in some cases, I suppose there is still some misunderstanding. And as a result, the people living with HIV will feel that.

Dr. Deanna Kulpa: Right.

Jeff Galvin: So, I think it's an important discussion topic. And, you know, I'm glad it came up here, and also I'm glad that folks that are really working in this industry understand the difficulty with which HIV moves around, and how well that just that antiretroviral therapy prevents transmission even in situations where it would otherwise transmit. So, it's good that that came up.

The other thing that I've noticed, I wonder if you've seen this as well, is just overall discussion about HIV seems to have diminished. I see a little bit of resurgence of interest in HIV on slow news days, so, you know, the New York patient came up and said that that seemed to be something that people were talking about for a little bit of time, and, uh, but, you know, it's not like in the old days when Hollywood was making movies, and, you know, HIV was making the news a lot. So, there seems to be not just misinformation but lack of information in some cases around.

I remember that the movie Philadelphia really helped me to empathize with people that were living with HIV and the stigma of HIV, and, you know, all those things. I don't remember that there's been a lot of stuff since then that has helped the general public to understand their relationship to HIV and to assuage some of the fears that might sort of build up from lack of understanding. 

What do you think? Has it affected your research at all? It's great that you just got this grant, but, you know, is there less of an interest that you see in the various aspects of your entity?

Dr. Deanna Kulpa: So, I certainly agree with that. I feel that the conversation around HIV is kind of a "we still have that" sort of thing. 

But I think one of the things that's important to recognize is that if you think about the COVID vaccine and there will be a lot of parallels between how quickly we develop the COVID vaccine and why don't we have a vaccine for X, Y, or Z. The reason why we got the COVID vaccine so quickly is because we spent decades studying the immune system because of HIV and how much we accelerated the pace of immunological research when HIV was coming onto the scene and we had to learn about the immune system in order to even be able to figure out what it was doing to the immune system. 

And I remember being in college and first hearing about, you know, we didn't even know where the virus was going at first and finding out that it was like we could it find in the lymph nodes, well, what was happening there? What were they doing in the lymph nodes and what was happening there that the virus was going there? 

And so we learned so much about the immune system and vaccine development and what works and what doesn't that it set the stage for bringing the COVID vaccine online that much more rapidly. I think if we had had a COVID in 1981, we would not have had a vaccine in two years. I mean, that just would not have, we learned so much immunology because of HIV and from here I think we just get better. 

And to me, there's a lot of hope in HIV research right now, especially as you mentioned the New York patient. Whenever we see a cure, that is kind of the wind beneath our wings all over again to keep moving forward.

Jeff Galvin: Yeah, I think one of the real interesting things that just came out in what you just said was the idea that the attempt to understand HIV was like a moon shot that brought us all sorts of benefits, right? You know, the Teflon and the ceramics and, you know, all the rocket science, you know, turned out to be an understanding of the immune system. And, you know, even when I think about what AGT does right now, we're using lentiviruses, which are essentially just cracked open HIV. You scoop out the HIV genome and you use the empty shell to deliver other things that are benefits to your body instead of diseases, right? So it birthed an amazing amount of technology. And yeah, that's a really good point that it's even bigger than HIV. It's the idea of the quest in order to improve humanity sometimes results in collateral benefits that you just didn't anticipate.

So swinging for the fences and trying to cure it obviously has a lot of benefits in other areas. We shouldn't think of this as just something for people that have HIV. We should think of this as something for all of society.

Jeff Galvin: So, what's your thoughts about a cure? Where do you see the cure research at this point? Not to sound like one of the HIV advocates that stand up at one of your meetings, but what do you got for us doctor? Is there anything that is on the horizon that would encourage us along with these successes with the Berlin Patient, London Patient, and New York Patient? What else is happening?

Dr. Deanna Kulpa: I think that the three patients or individuals that you just mentioned, they get attention, but it's also important to know that there are other individuals out there. Like two off the top of my head, the San Francisco Patient and the Esperanza Patient who have been shown to have naturally cleared the virus without intervention, right?

The San Francisco Patient was an individual who was diagnosed with HIV in the 80s, and at the time, the antiretroviral therapy that was available was pretty toxic. So the prevailing clinical treatment was to wait and see, because introducing antiretroviral therapy at the time, you could develop resistance. You had a lot of bad side effects. 

And so if you were doing okay, it made sense to sort of wait and keep monitoring to see if your CD4 T cell counts, you know, where they went. And when it started to decline, then we could make an intervention. 

With her, her CD4 T cells actually not only never declined, but actually were right at the beginning higher than you saw with even an HIV-naive individual, and they stayed that way. And through time, she has been a very motivated individual for being a part of donating glucophoresis and blood and spending her own money to fly herself to the NIH to donate samples so that they could look for virus in her. And they can't find it. 

Jeff Galvin: They can't find any virus, even in tissue samples and things like that like lymph nodes? Wow, that's amazing. 

Dr. Deanna Kulpa: So, you know, completely untreated, and at this point, they can't find anything in her. So she's considered cured, and through no, you know, she didn't need a bone marrow transplant or any of those sorts of things.

So, there are these individuals out there. Obviously, we have like the elite controllers and the long-term non-progressors. There are people we can learn from. And even now, the studies through like the Visconti cohort, where they were doing early antiretroviral therapy intervention followed by treatment interruption, where they found a subset of individuals who naturally controlled infection after that. 

So understanding that there is a lot that immunology contributes to this. Like we think about the virus, but it's really, it's the virus and the immune system, right? So, we can knock the frequency of the virus' virally infected cells down by logs, but if you don't have the immune component, then, you know, you're still going to have, you're still going to be in trouble. What we've seen over and over again in these individuals, this is about the immune system and how well it's working. 

And I think that's where we're headed with our research, trying to understand how we can better support the immune system in very specific ways, to learn from these individuals who have done it on their own naturally or however you want to say it, so that we can make that same process available for everyone.

Jeff Galvin: So, elite controllers and long-term non-progressors, just in case not everybody understands what that is. So, you do have some people that get HIV and somehow their immune system gets on top of it that we call elite controllers and they can keep their viremia. Do they keep it as low as somebody that's on ART? Are they still uninfectious as elite controllers? 

Dr. Deanna Kulpa: For the most part with elite controllers, they usually have some level of detectable viremia, but it's very low, and there are a number of different MHC class 1 alleles that are associated with control, but there's also a lot of people where that mechanism has not been identified. They're still, you know, we're trying to figure everything out. 

So yeah, they're out there, and to me that is what gives me the most hope, is knowing that it's biology, it's immunology, and whenever you put that in front of me, I feel like, "Well, we'll figure it out. It's not going to be forever."

Jeff Galvin: And of course, your specialty is genetics, and what this may boil down to is relatively minor differences in gene expression within these people that allows their CD4s to somehow stay on top of this. Is a long-term non-progressor very similar to an elite controller, or is that a separate sort of category?

Dr. Deanna Kulpa: So, the nomenclatures kind of changed and evolved over time. There's elite non-progressors, and like there's all these sub-populations. There is a virological designation, and the other one is like an immunological designation, and sometimes the two can do this, but not necessarily.

Yeah, there's a whole group of people that have all these different explanations for why they have such low virus detectable in their blood without antiviral treatment. And I think that's, to me, the biggest key, is that these individuals are, when they're not on therapy, their immune system is naturally able to control the virus to a point where we don't believe they will ever develop AIDS. 

Jeff Galvin: So, the exact distinction doesn't really matter. There's some sort of vernacular in the industry from different perspectives, but the essential commonality between these ones is that they don't need antiretroviral therapy. We don't fully understand why, but they're somehow suppressing their virus naturally.

And they're not the same folks that are in Northern Europe that just happen to be born without CCR5 on their T-cells, right? Because that's another place where you get a high level of resistance, but they tend just to never get HIV as opposed to stay on top of it that way. Got it.

Jeff Galvin: Well, you're probably aware of this, but next month we hope to start withdrawing people from antiretrovirals that are in our HIV cure study. And our approach was to go ahead and pull out leukocytes to isolate the HIV CD4-positive T-cells and to modify them slightly so that they cannot be infected and depleted by HIV.

The theory being that the CD4 cell is the linchpin in the immune cascade, and if we can keep those helper T-cells from being eliminated - they're kind of the conductor of the immune orchestra - we might see an immune response that would be able to suppress HIV on its own without antiretroviral therapy.

So, is this something that you see going on in other places or is this something that within your background you have some perspective on that approach - the idea of going in and modifying the T-cells? We've seen it with other companies, like Sangamo had a zinc finger nuclease clipping. What are your thoughts in that area?

Dr. Deanna Kulpa: So, I'm familiar with the Sangamo study. My former mentor was on the basic research side of working with that program. To me, it's a brilliant strategy because, as you mentioned, CCR5 seems to be, as a co-receptor for entry of HIV, seems to be a co-receptor that, at least in the delta 32, the individuals or homozygous for the delta 32 mutation, they do just fine without CCR5. 

So we know that at least in terms of the function of that, there's probably some redundancy in the pathway, but HIV doesn't have that redundancy. It uses CCR5 as a co-receptor, and so if it's not there and it's a CCR5 tropic virus, it's not getting in. 

And from what I've seen of the other studies that have targeted CCR5, what I think is fascinating about it is you don't need 100% of your CD4 T-cells to be deleted for CCR5 in order for it to work. There seems to be kind of a threshold for once you over, you know, whatever it is, 30% or something, of your CD4 T-cells, um, you know, uh, to have this CCR5 removed, you're just enough in order to kind of prevent really effective spread. 

So to me, that's a very positive thing, because if you had to say, "Well, every single CD4 T-cell has to absolutely have this removed from it in order for a cure to work," then good luck, you know. 

Jeff Galvin: That's a lot. 

Dr. Deanna Kulpa: If we can hit a balance where we have enough CD4 T-cells that just like kind of, you know, um, kind of like a vaccine approach, right? You don't need to have the 100% people vaccinated. You need to have just enough of them to kind of keep things from spreading around. 

And so with that approach too, you've got just enough of your CD4 T-cells that can keep the virus from getting out of control. And I think that to me is what's fascinating about that approach is that you can see how it works. It makes sense intuitively. 

Jeff Galvin: Yeah, sort of probabilities, right? You reach a certain threshold and you increase the probability that your immune system will win out against the invader. But not every T-cell has to be effective. It's the overall number that are effective. And that makes total sense.

Jeff Galvin: Now, of course, Sangamo did get some durable remission. So did they reach that threshold in some of the patients? Is that what the explanation is?

Dr. Deanna Kulpa: That's my understanding, and from what I understand about the study is that when you're thinking about gene therapy, one of the things you want to know about it is how long it lasts.

So, are you incorporating your genetic modification in a cell type that's going to live for two weeks and then you're done, or is it a cell type that's going to be like a memory cell or some sort of progenitor cell that's going to be maintained for a long time in the body? 

That's one of the things that they were focusing on looking at was were they able to target enough of those memory stem cells that would be able to propagate and keep alive, or maintain, the edited population of CD4 T-cells? Because if you do the transfusion and all your edited CD4 T-cells are terminal effectors or something that dies off fairly rapidly, then what happens to you in a year when you start to see some virus coming out of the central nervous system or some place, and you've really depleted your population that you need to be there to be resistant?

Jeff Galvin: CD4 cells have some stem-like properties in that they will replicate themselves when they're stimulated. Of course, HIV would last in the body for a long time, so they'd be getting occasional stimulation even if the viral count is low, and the viral reservoir is low; they would be receiving some signal that would tell them to stick around or to even increase their numbers. 

Dr. Deanna Kulpa: Our immune system is meant to last our entire life. So if you got sick when you’re 15 and you developed a memory against that infectious agent, when you encounter it again when you’re 65, you’re relying on that memory to protect. So our immunological memory has had to be maintained through one mechanism or another over time. Through, as you were saying, it can be activation, otherwise memory cells go through homeostatic proliferation, where they just divide just to maintain themselves, just to keep the memory going. In that way, you can have your immunological memory last your entire life, and that's what it's meant to do.

Jeff Galvin: The immune system is amazing, and it's tremendous that over the last 40 years, we made huge leaps and bounds in understanding the complexity of the immune system. It seems like with a lot of the body, every time you learn something, you realize more about what you don’t know, and you keep making these discoveries. We probably don't know everything already, but we do know a lot. 

The Sangamo study was going ahead and doing bulk T-cell modification, so they were modifying not just HIV-specific CD4 cells, but all of them or maybe even CD8 cells. CD8 cells are of the type that you were talking about, effector cells that maybe don't last that long, but those CD4 cells could be something that would last for a while, and I know of one patient that we stay in touch with that's now been maintaining suppressed viremia for over seven years. I think maybe even over eight years by now. So, that's impressive, with no antiretroviral therapy. That is a functional cure. This person is no different than anybody else.

Jeff Galvin: There still are some side effects of antiretrovirals, is that right? Like if people are on antiretrovirals, they have some short-term side effects. You hear the ads at night for Vitarvey or even some of the newer, longer-lasting ones, but they always mention things like diarrhea, nausea, fatigue, and surprisingly things like liver and kidney disease.

Is that still true even with the modern agents that we're using?

Dr. Deanna Kulpa: It is. I mean, and you mentioned a whole lot of them that we still see, and anecdotally I remember just a couple of years ago I was having some work done on my house, and one of the repairmen who came to my home was making small talk and asked me what I do. I told him that I do HIV research, and he was telling me about a close friend of his who had recently passed away from AIDS. 

He said it was because she made the decision to stop taking her antiretroviral therapy because the drugs were so toxic. She couldn't find a combination that made her feel okay. She was tired of feeling sick, and just basically was like, "I'm done with this," and just experienced so many adverse side effects that she made the decision to discontinue her therapy after years of trying to fight to find the right combination. Then, she eventually ended up passing away from AIDS. 

He was one of those people who came to me and was like, "You know, find a cure for this because the drugs still aren't the complete answer."

Jeff Galvin: So, on top of the stigma, quality of life is a really important thing that could come out of a cure. It's just amazing to think that 1.2 million Americans are living with HIV and nearly 38 million globally. I know some of this is a little bit of an estimate, but it's huge numbers of folks that are affected by this.

Dr. Deanna Kulpa: I think it's also important to note that we talk a lot about antiretroviral therapy, but if we look at the world, it's like 40 percent of people who need antiretroviral drugs are getting them, right? Because there's a large distribution of people living with HIV in places where the resources are not available. So where there are some of the highest incidents of HIV in the world, we don't have the drugs available. 

It's a privileged perspective to talk about how well our antiretroviral therapy is working when there are parts of the world where they don't even have the access that they need. 

Jeff Galvin: Wow. 

Dr. Deanna Kulpa: Another motivation for me in HIV cure is thinking about how we can make this so that if we're going to design a cure, we want to make sure that it's something that we can eventually bring to the table for everyone.

Jeff Galvin: Yeah, that is a really good point in two different ways. I love that perspective of, you know, even though we have 1.2 million people in the United States, at least they have the option of taking ART, even if it diminishes their quality of life. They don't have to progress to AIDS. But it's also a very sad story that somebody would go ahead and opt out of ART because they felt like the quality of their life was too low. I mean, that's incredible. 

I have met some people with HIV. I see the effects of early aging. I've seen the fatigue. You know, people don't tend to talk about their nausea and their diarrhea necessarily, and I don't know the statistics, but I understand that liver, kidney, heart disease, extra cancers… the other problem that these folks have is they're in and out of doctors all the time to treat, essentially, it's either the side effects of the ART or it's the low-grade infection. And in fact, it's probably the chemotherapeutics. I mean, it makes sense that those are going to have an impact on those organs.

Jeff Galvin: So, wow, yeah, I mean, there really is. I'm so glad to hear your passion for making a difference. What are some of the scientific theories that you're pursuing at this point? You know, what are some of the angles you're working on for HIV cure?

Dr. Deanna Kulpa: So, one of the things that I kind of touched on was the idea that the immune system is kind of our key, right? So I guess I'm less worried about the virus in some ways than I am about the immune system. 

So, one of the collaborators we have in the ERASE HIV collaboratory is someone who's really been studying cellular metabolism. So, CD4 and CD8 T cell metabolism. And this is Asier Sáez-Cirión, who's at Institut Pasteur. And one of the things, through his studies, that he's identified is there is not just a quantity of your HIV-specific CD4 or CD8 T cells, it's the quality of them. And it's very specifically about the cellular metabolism. 

So, we hear a lot about immune exhaustion, right? So, you hear about regulation of PD-1 is one that we see a lot in cancer and HIV. So, we hear these molecules that are associated with an immune system that's fatigued, you know, overstressed, through chronic infection, you have chronic inflammation, so your immune system maybe isn't working as well as it should be, because it's experienced this chronic inflammation. 

And then, but if you start to look at the cellular level, it's deeper than that. So, it's this idea that metabolically, if you can make your CD4 or CD8 T cells to have a quality in their metabolism, a cellular health, as you might say, that is more in line with stemness, survival, proliferation capacity, and coming right down to it, glycolysis. So, we're like getting basically into whether or not you're going into a glycolysis-based metabolic pathway, which is more associated with stress and exhaustion, and those are very specific signaling pathways. Those are very specific markers that we understand in terms of immune system function. 

And so, you know, what we're thinking a lot about is how we can make that metabolically exhausted, drained immune phenotype into one that is more built upon cellular health, capacity for proliferation, capacity for effective function, capacity to respond to effectively to antigen presentation or antigen challenge, being able to have the reserves there.

And when it comes down to metabolism, to me, that's something you can do something about. You know, we think about how we change our diets to help our metabolism, you know, we work out to help our metabolism. We can do that with ourselves too, right? There are interventions that we can do when we understand the biology of it that can improve our cellular health. And that, to me, is kind of like the basis for where we need to go if we're going to talk about a cure for HIV.

Jeff Galvin: That I gotta say, I'm listening to you and I'm just eating it up because I think that relates to what we're doing, right? Because we're going in there, we're doing modifications in order to make it harder for HIV to get into the cell and infect and deplete it. But while we're in there tweaking that, maybe there are tweaks that we can do that improve the metabolic efficiency of the cell, or maybe at least during our process, we can select for the ones that are best.

Dr. Deanna Kulpa: And that was actually one of the things that I wanted to talk to you about was in looking at your process, you're expanding specifically the HIV-specific CD4 T cells, right? And with the idea that they're very low frequency in HIV and people living with HIV. And if we can just expand those numbers, we've got, we've got a sense for how we can actually, like, you know, just kind of increase the size of the army. 

But I think also that there is an opportunity there to qualitatively assess how well those cells work, right? Because making better fighters, I guess, and not just more of them, I think is also an important part of the tactic. Because if those CD4 T cells are metabolically exhausted, how well are they going to be able to fight when you need them to? 

Jeff Galvin: How durable would they be as well?

Dr. Deanna Kulpa: Exactly. You know, CD4 T cells, they're part of their function is to, um, as you mentioned, their helper cells, right? They really help to stimulate the CD8 T cells, cytolytic responses, the B cells, they have so many different roles in the immune system. And having them charged and ready to go is very important. But I think part of it is making sure that at the, you know, the cellular metabolism level that you have cells that are essentially working at a capacity that makes them fully functional and in the right pathway and not contributing more to overall exhaustion.

Jeff Galvin: Yeah. I think that your metaphor was a good description of what we're doing, right? We're increasing the size of the army. I think the other thing that we're doing is we're trying to put body armor on those cells so that they don't get invaded. But what you're talking about is we can go ahead and make these cells more fit and give them better weapons, perhaps. 

So, there's a lot of different angles that we could take on these on the CD4 population to improve the immune response. And it sounds like you think that that may be an important key to an eventual HIV cure.

Yeah, we're going to have to send you some blood, right? I mean, because I would love to see in a cell product that we make, if we have a sample of it, that we could share with you. I'd love to know your collaborator's perspective on, you know, sort of the health and metabolism of those cells. That might be really interesting to see. 

And I'd also love to hear his or her theories on what the pathological underlying drivers of good metabolism are, because when you initially mentioned it, I thought, "Are we going to have to go into mitochondrial DNA, which is another step in gene and cell therapy, right, to go in there and start modifying the mitochondrial DNA?" But we know it's very important. I mean, there are diseases where your underpowered mitochondria makes a huge difference in your life. But, you know, maybe that's one of the things that will eventually fortify these T-cells in a way where they'll be more effective fighters when they get out on the battlefield with HIV.

Jeff Galvin: Any other things that are interesting going on in your collaborations? I mean, that was enough, by the way, that was fantastic. But any other interesting angles that you could see or research that might be valuable in the HIV cure?

Dr. Deanna Kulpa: So one of the things that we have spent a lot of time thinking about is apoptosis, right? So if we're thinking about targeting HIV-infected cells, we want to be able to get rid of them. Well, we know that there's HIV just by the, it's an endlessly fascinating virus, but one of the things that we've seen HIV integration do is kind of trigger a… if we’re thinking about apoptosis, we’re seeing anti-apoptotic pathways being triggered in these cells. So we're seeing a kind of - I don’t want to call it a selection - but a kind of bias of retention, bias of persistence of these cells. They're not dying when they should.

Jeff Galvin: So you're saying with the infected cells, somehow HIV is immortalizing or extending the life of these cells in order to be more effective in the body? It has more time to spread? 

Dr. Deanna Kulpa: It's really interesting biology, right? Because if you think about the virus, what is it? What does it do? It needs to, it's an RNA virus, so it needs to make a DNA copy of itself and integrate into the host cell genome.

Jeff Galvin: Right. 

Dr. Deanna Kulpa: The virus itself, HIV, does not require nuclear envelope breakdown in order to get into the genome. So essentially, it's an active transport mechanism of getting that DNA into the nucleus. And then it typically integrates right where the first genome, the first genetic region it sees, right?

And what are the regions that are by a nuclear pore? They’re going to be the more actively transcribed genes. So you're not going to find it in the middle of heterochromatin that's buried somewhere. It's going to be the gene regions that are more accessible. That's what HIV is going to see. 

And what are those genes that are typically going to be active in a lot of different cells as cells genes related to proliferation, self-survival? So it's not really random in that sense where it's just hopping into the first place it sees. And when it's in these cells, those are the genes that happen to be pretty universally active. In doing that, they can cause dysregulation of those cell survival genes, and that cell may end up surviving for longer than it normally should have. 

So we're thinking about apoptotic pathways and controlling Bcl2, for example, as a using like BH3 memetics in order to trigger apoptosis in HIV-infected cells, to kind of complement the immunological approaches that we're doing.

Jeff Galvin: Yeah, I'm, I gotta say that this is the most technical discussion we've ever had on the Cure Chronicles, and I find it fascinating. And I'm amazed that I can keep up with what you're saying, but I'm learning so much from this conversation. I'm really enjoying this. 

You know, that's something I did not know about HIV. But every time I learn something new about HIV, I realize why it's so insidious and so intractable. It's like evolution has given us almost a perfect virus. In a way, that was what made it so amazing and so fruitful when we studied it. This thing was one of the most advanced viruses on the planet, and it pulled a lot of tricks in the body that meant that as we tracked down those tricks, we learned a lot about the body and the immune system, just like you said. 

But that is really something about even the nature of the integration and where it chooses the integration sites, and I did not realize that in some cases, the cell life might be extended. But of course, that's perfect for the virus, isn't it? Because it's making little HIV copies, right? And so the longer the cell stays around, the better.

Dr. Deanna Kulpa: Yes, exactly.

Jeff Galvin: Wow. Well, fascinating discussion. This may be the first one where not everybody in the audience understands everything that we talked about, but this was great stuff, and I appreciate it so much that you came on the Cure Chronicles with us. Is there anything else that you'd like to cover before we wrap this one up?

Dr. Deanna Kulpa: No, I guess the only thing that I would say is, you know, thank you to the HIV community for all their participation in HIV research and clinical trials, and also their motivation motivates us. Whenever we end our talks, we always thank the participants who work with us on these programs. 

Even at the basic research side, we get clinical people who come in and donate blood so that we can do basic research to understand the immune system and understand the virus, even if there's no clinical intervention. So they're not going to get a drug out of it, but they are donating blood or lymph node biopsies so that we can learn. And their participation is absolutely essential to what we do, and without them, we wouldn't be happy as far as we are. So absolutely, they get all the credit in the world for that.

Jeff Galvin: Well, your organization really leverages both sides. I see why you have this advocacy side, and I got to say that your intelligence is apparent in this and your extensive knowledge of the subject matter. But also what comes across in speaking with you is your passion and your empathy for the folks that are living with HIV. And I really appreciate you sharing all of that with us here today, and I hope we'll have another conversation. And I really want to stay in touch because I'm very interested in becoming one of your collaborators.

Dr. Deanna Kulpa: I love it. Absolutely, this has been a great pleasure for me. I really appreciate the invitation. Thank you so much.

Jeff Galvin: Thank you.