Deepak Kaushal, PhD, on Chronic Immune Activation in TB-HIV Coinfection

In this podcast, Deepak Kaushal, PhD, talks about Mycobacterium tuberculosis and HIV coinfection, the role of CD4-positive T cells in chronic immune activation, and the macaque model his team has used to study tuberculosis infection in HIV.  

Additional Resource:

• Sharan R, Bucşan AN, Ganatra S, Paiardini M, Mohan M, Mehra S, Khader SA, Kaushal D. Chronic immune activation in TB/HIV co-infection. Trends Microbiol. 2020;28(8):619-632. https://doi.org/10.1016/j.tim.2020.03.015 

Deepak Kaushal, PhD, is a professor at Texas Biomedical Research Institute and the director of the Southwest National Primate Research Center, which is one of the 7 nationally funded primate research centers in the United States, at Texas Biomedical Research Institute in San Antonio, Texas.

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TRANSCRIPT:

Amanda Balbi: Hello everyone, and welcome to another installment of Podcasts360, your go-to resource for medical news and clinical updates. I’m your moderator, Amanda Balbi with Consultant360 Specialty Network.

Mycobacterium tuberculosis and HIV are two of the deadliest microbes known to humanity, which makes TB-HIV co-infection that much more deadly. A new review article, published in Trends in Microbiology, aimed to better understand the chronic immune activation in TB/HIV co-infection and shine light on the role of CD4-positive T cells.

For this podcast, we are joined by the lead author on the paper, Dr Deepak Kaushal, who is a professor at Texas Biomedical Research Institute and the director of the Southwest National Primate Research Center, which is one of the 7 nationally funded primate research centers in the United States, at Texas Biomedical Research Institute in San Antonio, Texas.

Thank you so much for joining me today, Dr Kausal.

Deepak Kaushal: Wonderful. Thank you.

Amanda Balbi: To start, can you talk about how common TB infection is among people with HIV? And why is it important to continue studying the connection?

Deepak Kaushal: Absolutely. So, TB kills 1.5 million individuals every year. You know, right now, every human being on Earth is thinking about COVID-19, but TB, AIDS, and malaria have always been around for centuries—in some cases, for millennia.

TB in particular has continued to kill between 1.5 to 3.0 million people every year for the past hundred years, since the records have been kept accurately. We don't hear the same amount of hoopla about it as we hear about, rightly so, with COVID-19. COVID-19 is the defining pandemic of our times. No doubt about it. But we sometimes forget about TB and AIDS.

The remarkable thing about TB in particular is that AIDS accentuates it, so AIDS is the best-known stimulus for reactivating tuberculosis. So, the unique thing about tuberculosis is that it doesn't only infect 1.5 million people—the number of people that die every year with it—it infects far more numbers, as is also the case with COVID.

It is expected that about 10 to 11 million cases of tuberculosis are reported every year worldwide. And we think that several more—maybe an equal number—goes unreported, so there's about 20 million infections probably that are happening every year. There are infected people, and they're coughing and expelling the basilar from their lungs in entropic forms and as aerosols. Then, people who are around these infected individuals can have the potential to get exposed once an individual gets exposed, much like COVID, there are 2 major outcomes.

Most individuals that get exposed to M tuberculosis, do not develop disease, but they have key cell reactivity to TB antigens. Again, much like COVID where many people that get exposed to the virus don't develop disease, but they have antibodies. If you do an antibody test and a PCR test, most people that have been exposed will come out positive by antibody for COVID and negative by RNA. So that means they don't have ongoing infection, but they've been exposed and either the infection was controlled or never happened. The same is true with TB.

Except, in the case of TB, we don't measure antibodies. We measure T cells, because it's the way immunology works. The majority of people that get exposed to TB control it in a way that is called latent tuberculosis infection or LTBI.

You would think that's a good thing. You know, you have immune responses and the person didn't have any disease. So that's a good thing. The problem with LTBI is that it's been known for a while that the bacteria that cause LTBI are not always completely eliminated, so they don't cause disease—so they're not going to battle with the host immune system—but they actually hunker down and form micro colonies within the granulomas and within the lungs of infected human beings and they just hide themselves in there, waiting for an opportune moment where the immune status of the person changes.

This could be ecause the person gets older and, you know, when people get older, their immunity wanes. This is a well-established fact. Or some other stimulus comes in that changes immune parameters and now these dormant, but yet alive (we call these persisting bacteria), they can come back and prove force and cause what is known as the reactivation of TB.

Now, in this process of latent TB, which goes on for most people and doesn't bother them throughout their lives and most people with LTBI actually die of natural causes or of car accidents, rather than reactivation. But in a subset of these people, 5% to 10%, there is reactivation. What we know is that if people get HIV, they almost always get reactivation. The chances of a person with HIV getting reactivation TB is 10-fold higher than a person that doesn't have HIV.

So that is the synergy between these 2 pathogens that we're working with that we wrote in this review paper.

Amanda Balbi: Absolutely. You mentioned before that CD4-positive T cells play a role in TB/HIV co-infection. Can you talk more about the roles they play in chronic immune activation?

Deepak Kaushal: Yes, so CD4-positive T cells, or T-helper cells, are an extremely important component of cell-based immunity, especially for bacterial intracellular pathogens—pathogens that hide inside some of ours cells, like TB hides inside phagocytes. In order to control the start of an infection, CD4 T cells are extremely important. So CD4 T cells neither make antibodies by themselves of the source that would be required to kill COVID or maybe HIV, nor are they killer T cells, which are absolutely required to control HIV, but they help both processes.

And, therefore, they're absolutely required to control TB. Now, HIV, which stands for human immunodeficiency virus. The kind of deficiency that it causes in the immune response is that it attacks the very CD4 T cells that are very important for the control of TB and for various other intracellular pathogens. So, during HIV infection in the acute early stages of HIV infection, CD4 T cells from various parts of the body are acutely killed and depleted. So that's why a person is part of known to have any immunodeficiency and that is why people with HIV are susceptible to all sorts of other opportunistic infections. [indecipherable 7:50] They are more susceptible to hospital-based infections.

For many, many years, the dogma has been “well one serves the other, right?” I mean, CD4 T cells are absolutely required for controlling TB, and HIV comes and takes away CD4 T cells, at least in the short term. Therefore, the TB escapes because “the jailers” are sort of—the police are sort of—taken out by the HIV. And so the inmates are now, you know, able to escape.

This is a review paper we're talking about, but I think it was really important to write this review paper focusing on our work, which was published in the Journal of Clinical Investigation last year, showed that the process is not as simple as it sounds. It's not just that HIV comes in and depletes CD4 T cells, and therefore, bacteria are free to escape. It's just not as simple as that.

If we remove CD4 T cells by a nonvirological method, if you add HIV—or in this case, because we are working with monkeys, we add SIV (simian immunodeficiency virus)—but it causes a similar effect on monkey CD4 T cells; it depletes them. We see reactivation, but if we use an antibody-based approach—a nonvirological approach—to take out the CD4 cells, you know, to the same amount with the same kinetics, same magnitudes, so the same 90% to 95% of T cells from the lungs are taken out, but the virus was not present. This is just an antibody that specifically targets CD4 T cells and does nothing else. Then we don't see the same kind of impressive reactivation of LTBI in our model that we solve it with wider mediated depletion.

So we conclude from there that is not just the CD4 cells; it's a little bit more than that. The virus must have some other impact on the immune system, as well, that is responsible for these differences that we see.

Amanda Balbi: Let’s talk more about the macaque model your team has created; the majority of your work has been done in this macaque model. How has your work with monkeys increased the knowledge base for controlling TB/HIV co-infection in humans? And what approaches for human infection might be developed from this knowledge?

Deepak Kaushal: This is a very good question. I think our model is critical.

So it's really difficult to study this co-infection in mice. There are a couple of individuals in the world, I think an investigator in the University of Texas Medical Branch in Galveston, Texas, comes to mind—Dr Avery, who is one of the very few people in the world that can study this sort of co-infection in mice. It's very complicated model she has. She’s one of the very few people that have expertise in it.

She's able to humanize her mice. Then she can study some aspects of disease, mainly the collagen, and she does beautiful work in that regard. But other than that, it's impossible to study this co-infection in anything else but macaques or humans.

The limitation with humans is that you're not going to go ask people that are diseased to give you pieces of their lungs, which is where the bacterium is or pieces of their intestine, which is where the virus is, and the virus is also in the lungs.

The best you can do with human patient is, you know, you can draw their blood as they're going through the clinical regimen, wants to be diagnosed. Sometimes you can conduct research bronchoscopies, maybe one. So, the crumping of the compartments, where the diseas is and where the pathology is, and the intersection of these 2 important pathogens—TB and HIV—is you can't really get it from the human.

For decades now, people have relied on the SIV model in macaques first for studying immunopathogenesis of HIV. At least for 2 decades now, I and several other labs now—I must give credit to Dr Joanne Flynn in Pittsburgh; she was really the pioneer in this field—and others have followed suit. So there's probably a handful of labs now, including mine, that can do the TB-infection model in macaques and the co-infection model in mecaques as well.

So I do feel like without this model, it is impossible to make further inroads. What we've seen is both work from my lab, as well as work from other labs, that the models have become established, and the world's become more clinically oriented.

So for example, in another study that we published recently, we were able to introduce the concept of antiretroviral therapy in these co-infected macaques. I think this is the first such a report of taking macaques that are co-infected with TB and HIV and giving them the same drugs that one would prescribe to a human being that had HIV.

And now we're doing studies where we are, you know, taking these animals and giving them both the TB drugs and the HIV drugs all at the same time. Again, the idea is to be able to model these really critical human populations. But then in modeling them access their lung tissue and then understand the disease right where it is and understand the disease processes

And then also to test treatment options. We’ve studied various active TB and latent TB treatment options and various combinations of antiretroviral therapies to see what combinations are more or less toxic and what combinations work better and so on and so forth.

So, what see here in the in the decades to come, the model will continue to be leveraged, because this is one exception really only model. However, you will have more clinically relevant questions, immunotherapies, antiretroviral therapies, therapeutic vaccines, etc.

Amanda Balbi: So overall, what would you say is the key take-home message from your review on chronic immune activation in TB/HIV co-infection?

Deepak Kaushal: The take home message is in order to treat people that have TB and HIV co-infection, it's not just necessary to kill the virus.

If they killed the virus, the sleeper cells will come back, but the depletion of sleeper cells is not correlated with the development of disease.

So if we have to protect people that have TB and are at risk for getting HIV infection, we have to treat them with other effects of the virus. This is something that we didn't actually get into too much detail. Other than depleting CD4 cells, the virus actually causes dysregulated immune responses.

In many [indecipherable 15:07], this is termed as chronic immune activation. The immune system of the host gets chronically activated at low levels, because of the presence of HIV. This chronic immune activation actually does not die out, even when an individual is treated with antiretroviral drugs.

If we prevent reactivation of TB in people that have LTBI and are at risk for developing HIV infections—we all know who these people are: sub-Saharan Africa, teenagers. They're already infected with TB and they are entering a part of their life where they could get HIV—then we must attack chronic immune activation.

There are pathways that we've delineated in our review—and I won’t go into details about the molecular nature of these pathways in this interview—that we know are responsible for chronic immune activation. And we know that our dispatchers are drug of their targetable.

In some instances, the drugs are actually available and have been tried out for treatment of HIV. I think I would like to redirect everybody's attention to the fact that we need to treat these people, these at-risk people, people that develop HIV infection and have LTBI with blockers, drugs that target chronic immune activation.

It's not just efficient to bring their CD4 T cells back. It’s equally important, perhaps even more important, to cure chronic immune activation in their systems.

Amanda Balbi: Absolutely. Thank you again for speaking with me today and answering my questions!

Deepak Kaushal: Thank you so much. It was a pleasure.