Episode Transcript
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[00:00:04] Tony: Hello and welcome back to another episode of Microbe Matters, presented by ID Pitstop, where we discuss, dissect and demystify topics in infectious diseases with our experts here at UPMC and the University of Pittsburgh. I’m your host, Tony Morrison, media specialist here at Pitt ID, and I’m just as curious as you may be about navigating through a world full of microscopic organisms. Please join us as we examine both the dangerous and beneficial microbial microcosms that surround us, promote public health and showcase research and treatment of modern infectious diseases.
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The HIV epidemic endures within the global health sphere. In 2022, approximately 39 million people are living with HIV AIDS worldwide. Eliminating the viral threat remains challenging.
Scientific and clinical efforts to eradicate HIV AIDS have been ongoing for decades. Yet we are still left without a vaccine or cure for the virus.
But there is still much hope and promise in modern research.
Major strides have been made in developing therapies for people living with HIV. And preventing new infections within communities.
The light at the end of the tunnel grows brighter as research and development ramp up.
This week, we examine the current state of HIV research.
Please join us as we consider the unusual characteristics of the HIV virus. And why they create difficulties in vaccine development. We also discuss approaches to treatment as prevention. The roles vaccines play in therapeutic HIV treatments. And developments in reaching undetectable status.
Is there still hope for an end to the epidemic?
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With me to talk about vaccine therapies is Dr. John Millers. He’s the chief of our division at the University of Pittsburgh. John, thank you so much for taking some time away. From your busy schedule to speak with us.
[00:02:17] Dr. Mellors: Thanks, Tony. Pleasure to be here.
[00:02:19] Tony: Also here with us is Dr. Bernard Macatangay. But we just like to call him Beej. Beej is an associate professor of medicine at the university as well. He is also the co director of the University of Pittsburgh Immunology Specialty lab. And associate program director of our fellowship program. Thank you for joining us. Beej, always a pleasure.
[00:02:40] Dr. Macatangay: Great to be here. Tony, thanks for the invite.
[00:02:43] Tony: How about we dive right into the topic? Is there a preventative vaccine for HIV? And if no, why not?
[00:02:51] Dr. Mellors: So, Tony, I think we got to take a step back. And differentiate a preventive vaccine from a therapeutic vaccine. A preventive vaccine prevents the establishment of HIV infection. Or attenuates the infection. So that it does not result in any health consequences. Most of the vaccines that are available for human use do not prevent infection. That’s a misconception. They prevent disease. A therapeutic vaccine is one that improves the outcome of disease. When the disease is present. So for HIV, why is there no preventative vaccine?
[00:03:31] Dr. Macatangay: Oh, that’s a pretty loaded question, but I think part of it is the virus mutates a lot. In order for the immune system to actually target something, it has to be something that’s conserved, that it can easily recognize and have an immune response to it. Right now, I know that people are talking about some epitopes of the virus, but given all the different studies that looked at all the vaccines, we still have yet to have one that actually is effective as a preventive vaccine.
[00:04:06] Dr. Mellors: Beej is right on. For HIV, arguably, there are tens of millions of variants of HIV, and when we talk about conservation of regions of HIV, it’s all relative. So we’re dealing with a very heterogeneous virus that we have to try to block. So that’s challenge number one. Challenge number two is that HIV is a terrible immunogen. What do I mean by that? It does not induce an immune response. My colleague Mitko Dimitrov hypothesized that the HIV envelope does not bind to the human germline B cell receptors, and that is now widely accepted that it doesn’t bind. The only way we get a response to HIV is by reaction to other proteins with some partial cross reaction to HIV that results in an immune response. But the immune response is to portions of the virus, largely that are not essential for the virus to infect cells. It induces an immune response on top of a cross reactive response that already has occurred. And it induces what we call a decoy response, meaning it directs the immune system away from the areas of the virus that are needed to function and towards areas of the virus that antibodies can bind to and have no consequence for infection. So those are the two fundamental issues.
Huge diversity, lousy immunogen. The efforts now are directed towards germline targeting immunogens, but let’s also recognize that it is not clear what is needed from a vaccine to protect. There was, initially, everybody said it had to be antibodies, and then the field shifted to it had to be cells that were induced, and then it swung back to antibodies again. And that’s pretty much where it is now because of studies that show if you give neutralizing antibody to an individual, you can protect them as long as the virus they’re exposed to is sensitive. So we don’t know, in essence, the correlates, the immune correlates of protection.
[00:06:34] Dr. Macatangay: And that has been the biggest problem.
[00:06:36] Dr. Mellors: Right.
[00:06:37] Dr. Macatangay: Because in order for you to be able to see if the vaccine works, you could do some lab tests to be able to see whether this could probably work. We don’t know what to test.
[00:06:47] Dr. Mellors: We do not know what is the most important component of immune response. What I mean, is it t cells, is it b cells, is it other cells? The combination, is it a combination of the two and a response to what portion of the virus is important? So, in a nutshell, that’s why we don’t have a vaccine.
[00:07:09] Tony: Since there is no preventative vaccine. What vaccines are recommended for people living with HIV?
[00:07:15] Dr. Macatangay: Well, I think even if there is no vaccines for HIV, some of the people living with HIV who we are seeing in the clinic are recommended to receive vaccines for other infectious diseases, such as the pneumococcal vaccine or the shingles vaccine. For individuals who are young enough, the HPV vaccine is also recommended.
[00:07:36] Dr. Mellors: In addition to that, like most of the population that has risk factors, we’re recommending a COVID vaccine and the flu and influenza vaccine, both a and b for older, certainly for people over 60, RSV. RSV is now vaccine to protect against serious RSV respiratory sensitial virus disease, and it’s been approved for pregnant women.
[00:08:04] Tony: So it’s safe to say that HIV operates in unusual ways.
And because of that, we’re still without a vaccine today.
But what can we do to prevent new HIV infections?
[00:08:17] Dr. Macatangay: Well, if you treat someone who has HIV and that person becomes undetectable, then that person won’t be able to transmit the virus. What we call you equals you. So that is what we call treatment as prevention. The other thing for someone who is not living with HIV, we have a preexposure prophylaxis or PrEP. It could be something that you take on a daily basis, or it could be something that’s injected as well. And there’s also post exposure prophylaxis. If you are exposed to HIV, then you can take some medications to prevent that from happening. These are just three, but there are multiple ways to actually prevent HIV, some strategies that are not just concentrated on HIV, but on other things. For example, diagnosis and treatment of sexually transmitted infections. There are some sdis that would increase the risk of someone getting HIV. So regular screening of individuals for stis, those who are exposed, and treatment can definitely help. We also talk about barrier protection for men and women. Not all of them alone may be effective, but a combination of these different factors would be very important in preventing HIV. John?
[00:09:40] Dr. Mellors: Well, just to add to that, in Pittsburgh we have a program called AIDS Free Pittsburgh, and it’s a community based program to drive the number of infections down to zero, and it’s actually countywide. And the recent data are very encouraging. We’re getting closer to zero infections. The last reported year were around 70 infections in the entire county. And it has a combination of strategies that Dr. Macatangay described. Number one, awareness of risk, that it still is out there. So awareness, number one, prevention and access to care. Two key components of care. If somebody is found to be HIV positive, then they’re immediately linked to care, put on treatment so that their virus in the bloodstream becomes undetectable and they’re no longer a source for transmission of HIV. So that’s part of the solution. The other part is protecting the uninfected. But there’s now PrEP in variety of forms. There’s oral pills that can be taken daily, there’s pills that can be taken before and immediately after a sexual encounter. And most recently, and very excitingly injectable PrEP in the form of long acting integrase inhibitor is available and approved for HIV prevention with efficacy in the 80% to 90% range. So if you’re aware you’re at risk, then you can protect yourself. Now, the big challenge is the medical establishment, by and large, is hard to penetrate, relatively inaccessible, and so we need community based programs to deliver these in a non judgmental, open, and non financially burdensome way.
[00:11:40] Dr. Macatangay: Exactly.
[00:11:41] Dr. Mellors: So for HIV prevention, I think behavior change and long acting drugs to block HIV will have a big impact on the prevalence and incidence of HIV long term.
[00:11:54] Dr. Macatangay: And the progress with these small molecules have been just astounding.
[00:11:58] Dr. Mellors: Right, astounding. There are long acting formulations of anti HIV medications that may be amenable to dose once every six months or two injections a year.
[00:12:11] Dr. Macatangay: That’s unbelievable.
[00:12:12] Tony: Yeah.
[00:12:12] Dr. Mellors: Right now it’s a matter of months, but there’s going to be many, many forms of protection in the future.
[00:12:20] Tony: Even though we have no approved vaccine for HIV right now. Do vaccines play any role in HIV, specifically in HIV management?
[00:12:29] Dr. Macatangay: Well, so what John mentioned earlier is that there are other types of vaccines called therapeutic vaccines, which are an immunotherapy, where someone who is already living with HIV is given a vaccine that could potentially boost the immune response to the vaccine. I think we don’t have one yet, but there are a number of studies that are looking at these therapeutic vaccines to see whether this alone or in combination with other therapies may be an important strategy for management of HIV.
[00:13:03] Dr. Mellors: So we said that it’s a huge challenge to protect an individual from HIV with a vaccine. Imagine trying to control the infection in somebody who already has the infection as potentially even a higher challenge because the individual may have immune damage, there may be very diverse virus within the individual, and their immune response was not capable of controlling the infection to begin with. So now we have to magically convert an unsuccessful immune system into a successful one. And frankly, we do not know how to do that. So far, the straight out studies of vaccines that induce immune responses have been wholly unsuccessful in controlling. So will there be a therapeutic vaccine that people can get? I don’t think so. I think it’s got to be a combination of several approaches. But that begs the issue. Combination of what?
[00:14:03] Dr. Macatangay: And I think just because of the different populations of individuals living with HIV, right, we have someone probably who got HIV and was immediately started on medication versus someone who was diagnosed when he was, or they were already in AIDS, or someone who is in North America, others in Africa or in Asia. There’s just so many different factors and variables to consider, and it’s unclear whether one or a combination therapy would be something that can be given to all of them and would have the same response. I still believe maybe there’s something that’s there, but I think it’s going to be case to case basis. What do you think?
[00:14:46] Dr. Mellors: I totally agree with that. Not only do we have to deal with the inherent diversity of the virus, we have to deal with individual person heterogeneity. So there’s a huge spectrum of HIV infection, ranging from rapid progression to AIDS and death left untreated to control of the virus for decades. And I believe it’ll be easier to induce a remission in those who are almost controlling or those who were started very, very early on treatment with little immune damage, less viral diversity, and a smaller so called reservoir of HIV.
[00:15:25] Tony: Now that we have effective treatments and therapies to treat HIV, you hear about people living with HIV achieving an undetectable viral load. How do either of you define HIV remission?
[00:15:39] Dr. Macatangay: Well, I think based on the different studies that are being done to target HIV remission, the definition would be someone who stops taking antiretroviral therapy and the virus does not rebound. That said, so for me, it’s not just the virus being detectable again, but in people living with HIV, even if they’re virally suppressed, there is damage that’s done to the immune system. And that damage, that residual damage to the immune system, affects other aspects of a person. We now know that since people are living longer with HIV rather than dying of AIDS, people are now at a high risk for getting chronic diseases. When we think about remission or cure. I think it has to be something that you stop taking antiretroviral therapy and your virus does not rebound. But at the same time, your risk for developing some of these chronic diseases also decreases. I’m not sure if that is possible because a lot of damage happens very early on.
If someone gets infected, a lot of damage happens within the first three to four weeks. Some of them get better, but some of them persist. And that, I think, contributes to what is happening. So I’m not sure if it’s possible, but I think for me, an ideal definition is something that would include improvement in that immune dysfunction.
[00:17:01] Dr. Mellors: Remission is really a broad term.
So I’ve been around long enough to see people with progressive HIV infection developing AIDS and dying. And if you use the cancer analogy, people who have progressive cancer would want a remission from their disease. If the cancer becomes controlled to the point that it’s not progressive, that’s considered a remission. Better yet, if the cancer cannot be detected, that’s a remission. Well, we’ve achieved that with HIV. If you look at people who had no treatment, had progressive disease, and were put on ART, their disease was put in remission, they didn’t have progressive disease, they didn’t die of AIDS. So that’s one form of remission and.
[00:17:50] Dr. Macatangay: Their life expectancy is approaching someone who doesn’t have HIV. Correct.
[00:17:54] Dr. Mellors: We can’t just say, well, good, it’s done. But that was a major triumph of biomedical science and clinical science. What now we’re talking about? Remission is the ability of the body to control HIV in the absence of that antiretroviral therapy. So stopping treatment, as Dr. Macatangay said, and not having the virus reappear and cause disease. And so that’s how I would define remission. In the current era, what other modalities.
[00:18:26] Tony: Have been developed or are being developed to achieve remission?
[00:18:30] Dr. Mellors: So let’s just start with maybe one of my biases, that this miraculous progress in inducing remission is now progressing further in the form of antiretroviral therapy, that is, fewer drugs and longer acting drugs. We talked just a bit about preventives that could last six months. So it’s not beyond the possibility that within a few years we could control HIV with one or two injections a year. And we’re already doing that with injections every eight weeks, and there’s evidence that that interval can be extended. So a remission could consist of two injections a year and potentially self administered in the future.
[00:19:19] Dr. Macatangay: John, you were there when people were taking multiple medications three times a day, and now you’re talking about an injection possibly once or twice a year, is really the success of research here.
[00:19:32] Dr. Mellors: It’s the success of science, and it’s remarkable innovation and progress. So short of that, Tony, there are a huge spectrum of approaches to try to induce a remission without these small molecule antiretroviral. And they range from using CRISPR or gene editing, if you will, putting cuts in DNA that are specific for the HIV only, knocking out every molecule that’s integrated in the human genome that encodes HIV. We talked about how it integrates into our DNA. Well, going in there and precisely cutting it out. Cutting it out, that is theoretically possible, but to achieve it with such precision is going to be a major challenge. And then there’s been tremendous progress in malignancy using engineered T cells, so called CAR T cells, chimeric antigen receptor T cells. And these have been life saving for malignancies. And that technology, not specific for a malignant cell, but for an HIV containing cell, is being tried to clear out the reservoir. Now, there’s a huge problem, and that is one of the ways HIV persists. It sits silent for many weeks to months and even years, but has the potential to be turned on and spread. And so we have this population of cells constituting the reservoir that are invisible to the immune system because the HIV virus that’s integrated is silent. And so one of the key components of remission strategies is trying to wake up those late proviruses in the cell DNA. That’s called latency reversal. Many believe that latency reversal combined with better ability to kill cells that have.
[00:21:28] Dr. Macatangay: HIV by boosting the immune system, by.
[00:21:31] Dr. Mellors: Boosting the immune cells with either CAR T cells or antibodies or both, could lower the reservoir to the point where the individual’s own immune system could take over. And how to do that today is not known. There are little hints here and there tidbits of information that might suggest the path forward, but I would say it’s reasonable to conclude that we’re in the fog still.
[00:22:02] Tony: Efforts to develop a cure for HIV have been ongoing for decades now. And apart from preventative and therapeutic developments, we’re still left to wonder if the cure is ever possible.
Do either of you think that there will be a cure for HIV? Is there still hope?
[00:22:20] Dr. Mellors: For one?
[00:22:22] Dr. Macatangay: Wow, that’s, I mean, loaded. I know that we’ve had these three cases of individuals who have been, technically, they said, cured of HIV.
And although that is very aspirational, I think there’s just so many challenges right now that I think, yes, I want to be optimistic. I want to be the half full guy to say that it’s possible, but I think it’s going to be really challenging.
[00:22:53] Dr. Mellors: I think it’s going to be a major challenge, but I would never say it’s not possible.
[00:22:58] Dr. Macatangay: Yeah, true.
[00:22:59] Dr. Mellors: If you met a gentleman on the street in the year 19 one and said that before the end of the century, we’re going to put a man on the moon, they would have said, you are crazy.
[00:23:12] Dr. Macatangay: Yeah, true.
[00:23:12] Dr. Mellors: Right. Or that we’re going to put a probe on Mars or develop nuclear weapons that could destroy the earth, they wouldn’t be in complete disbelief. And so it’s only our kind of biases and imaginary constraints that can’t envision a cure. I think one is definitely possible, but it will require advances in many fields that are then applied to HIV. And one great thing about HIV research has been the remarkable discoveries on how to design drugs, how to formulate them so that they’re not toxic and long lasting, and how to diagnose and treat infectious diseases and curb spread of the infection in communities like Pittsburgh.
[00:24:01] Dr. Macatangay: And I just would like to add to that in what, June of 1981, when we first became aware of yet an unnamed virus that was causing this disease till what, mid 90s, when the first combination antiretroviral. That’s a short amount of time from people dying of AIDS to living with HIV and the progress that we have so far. So you’re right. Yes. I think there’s so many challenges, given the passion and the drive of people working in the field of HIV and their ability to try to see what can be done, how can we improve this? It’s definitely possible.
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[00:24:47] Tony: John, Beej, thank you both again for joining me today to talk about current and future strides in HIV research and treatments. I think it’s safe to say that I learned a lot.
[00:24:57] Dr. Mellors: And it’s remarkable, I think, to say that an immunologist and virologist generally agreed without any sweating or outbreak of emotion.
[00:25:12] Dr. Macatangay: That’s true.
[00:25:13] Dr. Mellors: So thank you for hosting a calm session.
[00:25:17] Tony: And that’s it for this week’s episode. Until next time, I’m Tony Morrison, and this is microbe matters.
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