Michael Smith, MedPage: Interview with Carl Carl Dieffenbach, NAIAD

Interview with Carl Carl Dieffenbach, NAIAD
Michael Smith, MedPage, September 26, 2011

to download slides, click here

 

video links:

https://ifara.info/16th_CROI_Video_Library/400%20Carl%20Dieffenbach%20MD.html

http://www.medpagetoday.com/clinical-context/HIVAIDS/28702

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http://www.medpagetoday.com/clinical-context/HIVAIDS/28702

Transcript:

MICHAEL SMITH: I’m Michael Smith with MedPage Today, and I’m here today with Dr. Carl Dieffenbach, who is Director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases. Dr. Dieffenbach, welcome toMedPage Today.

CARL DIEFFENBACH, PhD: It’s a pleasure to be here with you, Michael.

SMITH: We’re going to talk today a little bit about HIV, and, specifically, how it does what it does; nasty little virus. Can you just describe the process of infection to begin with?

DIEFFENBACH: Sure. It’s actually a very interesting situation with HIV. HIV is a relatively difficult virus to transmit, except when it isn’t, and there are some very specific circumstances that tend to promote HIV transmission, so let’s just go through the basic process first.

So, the virus must reach a mucosal surface, whether it’s on the surface of the penis or in the vagina or in the rectum. The virus must then penetrate through that mucosal surface and find an activated T cell, and the T cell is the primary food for HIV.

Once that cell is infected, progeny virus are produced, and you start going through a cycle of repetitive infections and spread to a point where enough virus-infected cells build up so that the virus can then leave that target tissue and go establish infection in the intestinal tract and in the lymph nodes of the body.

So, the different phases are establishment of infection at that cellular level, then building up to that critical mass, and then spread where ultimately you get persistence, the establishment of reservoirs, and then you are essentially past the point of no return and infected.

The reason it is relatively difficult to transmit is that an activated T cell, in most normal cases, is a relatively rare cell in those target tissues. The diseases like STDs or other forms of disease, or tears in the tissue where you have some sort of inflammatory process, would then promote infection. The data is very clear that there are things that truly enhance HIV transmission.

SMITH: Can I just get a little clarification on this? Because this was something that I found out only very recently. Where does the virus replicate?

DIEFFENBACH: The virus replicates primarily in tissues. Let’s be absolutely clear about this — HIV is a disease of tissue. We measure HIV in blood and we measure CD4s in blood simply for convenience, but HIV replicates in the lymphoid organs of the body, and that’s important to remember. There’s an expression: Tissue is the issue.

SMITH: Nicely phrased. Now, we know a number of ways to stop the infection before it starts. There are condoms, for instance, and, of course, if you don’t have sex or don’t exchange needles — blood exchange, for instance — then you don’t have any risk. But once you have an exposure, what happens? What’s the process? How long does it take to get from exposure to an established infection?

DIEFFENBACH: Great question, great question. So let’s go back and talk about prevention strategies. They fall into two camps: one is a barrier method, like a condom; you basically prevent the virus from leaving the infected host. But at a certain level, we’ve also recently heard the phrase “treatment is prevention” — reduce the viral load in the host so there is no virus leaving the host to go to the index case or the potentially infected partner.

The other prevention strategy is seeing what can you do to abrogate or prevent the virus from taking hold or spreading once it reaches the tissues. And then, if it does take hold, how long does it take? So if you think about it, preventing HIV from finding that initial target cell will be the absolute game changer. So if you can prevent that first cell from ever seeing the virus or ever getting infected, infection can’t occur.

Each time HIV does successfully find a target T cell, you have an amplification, and HIV just gets a little bit stronger. So if you can prevent the next cell from becoming infected, that’s another place, and then the next cell, so at some point we reach the point of no return.

So clearly, drugs that would act to prevent that cell from getting infected, like preexposure prophylaxis or microbicides, would be great ways of preventing that initial cell from getting infected.

Additionally, a vaccine would work at that point with an antibody-base system, could clean up the virus, and then a T cell could kill that, or ultimately early infected cell. That entire process, from initial cell infection to the point of no return, where you have established, persistent infection takes on the order of 14 to 17 days; it’s a very short window.

So all of our interventions must work primarily within the first 72 to 96 hours, tops, to really stop an infection.

SMITH: After that, as you say, it’s too late.

DIEFFENBACH: Yeah, the horse is out of the barn, as they say.

SMITH: Now, during that 14-day to 17-day window you talked about, is the virus detectable?

DIEFFENBACH: The virus becomes detectable with very sensitive methodologies, probably around day 7 to 10. And it would be on the order of starting with a couple hundred virus particles per milliliter in the blood, because that’s what it takes. Because essentially in all viruses’ infections, there’s this thing called the eclipse period, where the virus is present but it’s undetectable. Once you break through that eclipse period, the virus peaks between 7 and 14 days, and that peak is then seen in the blood at the level of a million to 10 million copies of virus; that’s how fast the virus moves within the body.

SMITH: Right. And I wanted to ask a question that maybe a lot of people don’t understand and I think it’s important, because it involves these target T cells. If I get a cold or the flu or just an infection of some sort, I shake it off. If I get HIV, barring some of these things we’ve talked about, I don’t shake it off. What’s happening? Why is the immune system not able to kill this?

DIEFFENBACH: That is the $100 million, $100 billion question.

So, HIV does a couple of things that are different than virtually every other virus. HIV, by infecting that activated CD4-positive T cell, is actually tackling what in many ways could be viewed as the quarterback of the immune system.

That cell is the critical cell that basically is the traffic cop and directs both the cell-mediated response against viruses and the antibody response. So by killing that initial cell, you’re really in many ways hindering the immune response from the beginning.

The other issue with HIV is persistence.

So, HIV will infect that cell. Because it’s an activated T cell, a certain fraction of them become resting memory T cells, because the whole point of the immunity is the recall to previous exposure to diseases. But by having a cell that’s infected and moving to the resting state, HIV is becoming an integrated virus and essentially being carried as a latent virus within our own host.

So in many ways, it’s like establishing a form of cancer; that cell, while resting, has the ability to rekindle the HIV infection at a moment’s notice. So those cells are established early and they persist at a level, while not huge, are enough to always rekindle and cause disease.

SMITH: Assuming one stops, for instance, treatment.

DIEFFENBACH: If one stops treatment, they will always be there at some level, participating in the disease process.

SMITH: Now a parallel; you talked about the 100,000 or more copies of the viral RNA that’s found in the blood. Parallel with that, of course, is a loss of T cells, these CD4 T cells.

DIEFFENBACH: Right. Well, the body engages in an all-out war with HIV, so that’s something else that we really need to acknowledge is that the body doesn’t take this lying down. The body continually pumps out fresh T cells, always pushing new soldiers into the field, always creating the army to help try to control HIV.

The earliest part of the establishment of infection leads to a peak of viremia that will be on the order of a million to 10 million cells. As the body begins to equilibrate to an HIV infection, it reaches a degree of a steady state, where the body is mounting an immune response to struggle to keep up and the virus is staying one step ahead. But the effectiveness of the HIV response in the body leads to something called the viral set point.

And you go then into a stage of an HIV infection, where this stable set point defines the speed with which you will progress toward AIDS.

The average person infected with HIV ends up with a viral load probably around 10,000 to 50- or 60,000 copies, and that would be, you know, just somebody we would refer to as just a standard, run-of-the mill HIV infection.

A rapid progressor, somebody who moves toward AIDS relatively quickly, will have a viral load of about ten to 100 times that.

But then there are these people called elite controllers, or nonprogressors, who actually control their virus very effectively and can have very low or undetectable viral loads.

But at the same time, the other really important thing to remember is when these T cells are being pumped out into the body to be the soldiers, they’re coming out as activated cells often. And essentially what the body is doing is falling prey to the trap that HIV has set, because HIV needs activated cells for growth.

It triggers the production of activated cells and therefore becomes this persistent infection that is self-perpetuating because it has harnessed the host response to help kill the host. It’s a devilish little thing.

SMITH: If it weren’t a virus, you’d think it was very, very clever. Let’s switch to the other side now. We’ve talked about what’s going on with the immune system and what’s going on with the virus. What’s happening with the individual at this point?

DIEFFENBACH: That’s a really interesting question because there is an acute retroviral syndrome that occurs in a certain number of patients that can be seen with swollen lymph nodes and sweats. In severe cases, actually, some of the opportunistic infections that we see late in disease can actually occur very early in the disease.

But by and large, that all resolves over about a month to six weeks, at which point then the individual hits a phase which we would call a clinical latency, where there’s no detectable disease other than virus and antibody in the bloodstream, so they feel reasonably well and they will go through what appears to be a disease-free period.

All that time, the virus is continually replicating, killing T cells, mounting this pitched battle with the body, but essentially you have no constitutional symptoms.

As you get infected for longer and longer, you start developing swollen lymph nodes, you start developing other symptoms.

Oftentimes, your first opportunistic infection will be thrush or a herpes zoster or some other form of disease. If you live in a TB endemic area, often the first sign of HIV infection is a very fulminant form of tuberculosis, and that is why TB and HIV are linked so tightly, particularly globally.

SMITH: And of course, the course is once the opportunistic infections begin, nowadays, at least, people very often present for treatment and it’s quite late in the course of disease. What happens if they don’t present for treatment?

DIEFFENBACH: Well, what you’re describing is the early days of HIV infection.

So, 30 years ago, somebody who presented with HIV/AIDS to a clinic or to a hospital had a life expectancy on the order of six months because the opportunistic infections were so massive we didn’t understand how to treat. Now if somebody doesn’t go on therapy we still have that same set of issues, but they can be treated for some of those opportunistic infections and prolong survival.

By and large, globally we’re trying to get everybody who is in need of drugs on antiviral therapy for the purpose of preventing that period of rapid progression and death that comes at the end.

SMITH: Now, we talked a little bit about reservoirs and viral persistence. Let’s go back to the virus again. It has only a very few number of genes; it’s not a very complicated organism. And we’ve developed medications to sort of try and stop the virus in its tracks at various points in its life course. Let’s walk through that life course.

DIEFFENBACH: Sure.

SMITH: That infective course.

DIEFFENBACH: Yes, that’s a good point. We started this conversation with just jumping in and saying the T cell gets infected, the initial activated T cell. What does that actually mean?

Well, the first thing a virus has to find is the appropriate cell. And what defines that appropriate cell? Well, it’s the molecules that are on the surface of that cell that HIV can bind to and then enter the cell, and those molecules are the CD4 molecule and a co-receptor, which is CCR5, which is one of the standard co-receptors for chemokines. That molecule is specifically expressed on the surface of activated T cells.

Once the virus enters the cell it goes through a process of uncoating. It opens up, and the defining activity of a lentivirus or retrovirus is the process of reverse transcription. Dr. David Baltimore won the Nobel Prize with Howard Temin for describing that process of reverse transcription, because that is what the dogma was: DNA/RNA/protein. What this enzyme does is it goes RNA/DNA/protein.

So it takes the RNA copy of the virus, makes it into DNA, and packages it away so it can enter the nucleus of the cell and integrate into the human genome.

At that point, it is no different than any other human gene. It will go through the natural process of transcription, like all human genes, and produce the proteins. The proteins then capitalize on the cellular machinery of assembly that is usually used for making vesicles that are part of the normal process of the cell.

But basically the entire machinery is then hijacked for the production of HIV. The virus assembles, and it assembles as an immature particle. And as that immature particle then buds from the cell, it will then undergo maturation.

Now, to start and talk momentarily about how these drugs all work, we’ll start from the maturation step first. Because, essentially, the virus that leaves the cell is immature, but a protease inhibitor, if in that patient, will keep that virus in an immature state and keep it from becoming infectious, that it cannot mature, and basically that virus is then inactivated and digested by the body as a form of food.

The other targets we have are that key step of integration. Recently we have new — not so new anymore, I guess, it’s two or three years now — integrase inhibitors have come to the market and they’re very effective at preventing that piece of DNA from integrating into the host genome, and that essentially abrogates the infection at that point in time.

And the other key steps that we target are the other two we talked about: reverse transcription. There are a number of classes of drugs that prevent the reverse transcriptase from making the RNA copy into DNA, and then we also have entry blockers, so we can hit the key steps with drugs: entry, virus-nucleic acid synthesis, the movement of the nucleic acid into the host genome, and the assembly maturation.

SMITH: What do you see as the most important new areas of research that need to be looked at?

DIEFFENBACH: So let’s actually really focus in on that question for a moment because that really defines the future research that we need to do as scientists, as society, to really ultimately control and end this global pandemic.

So all of these drugs that we’ve just described essentially are suppressive; they keep the virus suppressed in the body. And as we talked about earlier, if you stop drug therapy, the virus rebounds.

So one of the areas we need to do is be able to identify that latently infected cell and either find immunological ways to control it and kill it, or find ways to remove that latent provirus, that integrated piece of HIV DNA from that cell so it can’t rebound.

That would give us a cure or a functional cure. The definition of a cure is the absence of disease — no disease in the absence of therapy; that’s the ultimate goal. If you can eliminate the virus either by immunological methods, or somehow eliminate the virus on a molecular basis from the cell, we can achieve a cure.

The other key piece we need is to work toward an HIV vaccine. All of these therapies are great, but they require a level of adherence. The ultimate path to controlling the HIV epidemic will be a highly efficacious HIV vaccine that prevents infection.

SMITH: And then let me just see if I can drill a little bit more into that. When we talk about cure strategies, well the vaccine is sort of the ultimate barrier method, if you will.

DIEFFENBACH: That’s exactly right. That’s a great way for the audience to think of that.

SMITH: And we know that there has been some evidence that this can be done. It took a long time, but a couple of years ago a major trial found a small efficacy, so there’s work to be done. There was a signal.

DIEFFENBACH: Yes.

SMITH: It might work. On the other hand, we have this evidence of a patient in Germany in whom there appears to have been a complete cure, and it was a very difficult way. They had to give him bone marrow transplants.

DIEFFENBACH: Yes.

SMITH: And particular bone marrow transplants, and it eventually worked. That’s expensive, difficult, and dangerous. What other strategies are there?

DIEFFENBACH: So let’s go back and talk about a cure and a functional cure. I talked earlier about the group of patients called elite controllers, where essentially people are known to be HIV infected, will have these reservoirs even at lower levels, but they have no detectable virus or a very low detectable virus in their bloodstream. So they don’t progress in their HIV disease and they don’t transmit, so that’s the natural experiment that has already been done.

Now, those people have a very specific HLA or genetic makeup that makes them prone to develop that type of an immune response. Can we learn from those people how to take others that don’t have that genetic ability and enhance their immune response in some way to give us the signal that we need to help them control?

Additionally, through other diseases and other types of gene therapy, progress is being made in terms of essentially using molecular scissors, other approaches, other forms of activation. So I think it’s going to be a multi-pronged approach that will get us the cure. So I think we’re going to need some immunity in terms of therapeutic vaccine and other approaches, but also some very unique new agents that can activate or somehow target that integrated provirus.

So again, like we have for treatment today, it’s a combination of strategies. The cure will also be a combination of strategies.

SMITH: Well, Dr. Dieffenbach, it sounds as though we know a great deal. There’s clearly much more to be done. It looks as though you won’t be wrapping up the Division of AIDS at the NIAID anytime soon, but thank you for sharing your knowledge and insight with us.

DIEFFENBACH: It’s been my pleasure, thank you.

SMITH: So, in summary:

• HIV targets activated CD4-positive T cells.
• Transmission is made easier by breaks in the genital and anal mucosa.
• HIV forms a reservoir in lymphoid tissue early in the course of infection.
• The course of untreated infection includes a period of latency of months or years during which a patient may have few or no symptoms.
• And finally, the HIV replication cycle offers several targets for intervention, including reverse transcription, maturation, entry, and integration.

 

I’m Michael Smith, MedPage Today.

Dieffenbach has disclosed that he has no relevant financial relationships or conflicts of interest to report.

 

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