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Interviewer: Traditional medicines that interfere with life saving AIDS treatments, up next on The Scope.

Announcer: Examining the latest research and telling you about the latest breakthroughs. The Science and Research Show is on The Scope.

Interviewer: For the 35 million people worldwide who are living with AIDS, antiretroviral therapies are life saving medicines that can slow or halt the disease. But in some non-western countries, cultures can impact the effectiveness of treatment.
I'm talking with Dr. Lou Barrows, professor of pharmacology and toxicology at the University of Utah. He's investigating interactions between traditional medicines and antiretroviral therapies in Papua New Guinea. Dr. Barrows, how much of a problem is AIDS in Papua New Guinea? Why did you focus on that problem?

Dr. Barrows: Well, Papua New Guinea is an interesting case, it has, it's the only country in the South Pacific with and established HIV epidemic, but it's fairly low level. It's less than 1% nationwide, but in some villages the incidents of HIV is around 10%, and so it's of great concern that it still might spread.

Interviewer: So maybe you can talk a little about traditional medicines in Papua New Guinea, and how much that is a part of their lifestyle there.

Dr. Barrows: It's generally accepted that Papua New Guinea is like many of the developing countries in the world where about 80%of the people use medicinal plants for health purposes, and it's certainly part of the culture. And so we had some, quite a bit of background data on commonly used medicinal plants in Papua New Guinea, and some understanding that a lot of people use them a lot. And that when people are being treated with western medicine they go home and they also take their vitamins, their nutritional supplements or their herbal medicines, whatever you want to call it.
So, it's clear that there is potential for these things to interact, and there is lots of data from western medicine showing interactions of dietary supplements and medicines. So it was a logical question to ask.

Interviewer: And so what did you find?

Dr. Barrows: The approach we took, basically some in vitro assays looking at the ability of one drug to interfere with the activity of another, either by interfering with its metabolism, interfering with your body's ability to get rid of it, or by inducing enzymes that allow your body to get rid of things faster. And so, obviously if your drinking grapefruit juice and it inhibits liver cytochrome P450 3A4, then drugs that are metabolized by 3A4 are going to be at higher levels in your body and they might actually reach toxic concentrations, and this has happened.
That's the same system, identical system we use. But instead of things you might find at our grocery store, we use, we had our list of the hundred most used medicinal plants in Papua New Guinea from the database and so we went and collected them and looked at their ability to interfere with drug metabolism.

Interviewer: So when you see this enzyme, the cytochrome, when you see it go up, the activity go up.

Dr. Barrows: So if the enzyme goes up, then it's more effective at clearing the drug from your body. So then the drug might not reach effective levels and this has also been shown to happen.

Interviewer: So you found that some extracts from some traditional medicines actually raised the levels of the cytochrome and some lowered them. Are you talking about big effects or is it enough to suggest that it might, in some cases, totally inhibit the effects of the antiretroviral therapy or can you make those sorts of conclusions?

Dr. Barrows: I think we can because there's enough experience in drug development in western countries with big pharma and my colleagues here have actually been working in that capacity. So they have the same standards for what's considered a predictor of a clinically relevant effect.

Interviewer: What do you intend to do with the information you have now?

Dr. Barrows: I'm actually also an adjunct professor at the University of Papua New Guinea. So my colleagues at UPNG are quite interested at making sure this information gets back to the national AIDS council, well it actually already has. And they and the national AIDS council are now keen at putting together basically a little pamphlet that will go around to the AIDS clinics just identifying the different plants in the local languages. Papua New Guinea is an interesting place because there's supposedly over 800 different language groups, it's very diverse.

Interviewer: Barrier number one.

Dr. Barrows: Right, so it'll be a long pamphlet. Basically some of the most, what we think are the most problematic ones, the patients coming in for their antiretroviral therapy can be counseled to avoid consumption of this while you're taking these drugs.

Interviewer: What are the chances of that working? I mean, you're going against hundreds of years of culture, right?

Dr. Barrows: You know, its funny, I'm sure there will be a whole spectrum depending on the person and the village and how much they believe, how much they believe or they don't believe the health care workers or whatever. Most of the people I've met out in the bush, they're all pretty independent thinkers and if they understand the issue, then they're going to the make the logical decision. And if they understand that you take this at the same time you're taking this, this won't work, then they'll follow it.

Interviewer: Does your research have any implications for us here in the United States?

Dr. Barrows: So, one issue for us here in the U.S. is that while these plants are commonly used in Papua New Guinea, they are not kind of the golden seal or the cranberry juice or the Echinacea that are the major products in the U.S. But there is kind of a shift in these dietary supplements available in the U.S. and that's because of this global access to everything over the internet.
You can now buy many of these plants that we thought were Papua New Guinea traditional medicines, you can buy them over the internet for all sorts of purported uses, whether they are active or not I don't know, but some of them are pretty active at effecting drug metabolisms.

Announcer: Interesting, informative, and all in the name of better health. This is the Scope Health Sciences radio.

Announcer: Examining the latest research and telling you about the latest breakthroughs; The Science and Research Show is on The Scope.

Host: Aids is one of the most significant public health challenges worldwide. My guest, Dr. Sundquist researches how HIV infects the body, with the goal of finding ways to stop it. His outstanding research contributions recently earned him a seat on the prestigious National Academy of Sciences.
You investigate how the human immunodeficiency virus, HIV, the retrovirus that causes AIDS infects people?

Dr. Sundquist: Yes, the thing we're most interested in right now is how the virus interacts with the host cells that it infects. So viruses are fairly simple replicating machines. In the case of HIV they only make 12 proteins and that's as compared to 20,000 proteins that a human cell would make. And so one of the interesting aspects of viruses is that they have to use host cell machineries and pathways to replicate and that's something that interests us.

Interviewer: Why does that interest you? What do you hope to gain by learning that information?

Dr. Sundquist: I guess there are a series of reasons to do it. One is a simple curiosity, I think; understanding the world around us is a valuable goal. But of course we would expect that understanding leads to important spin-offs. And two, areas where one can envision such spin-offs and that have been realized in a number of cases, one is in therapy, so of course HIV is still a very important biomedical research problem. There are literally more than 20 million people who are HIV positive worldwide and so that's a huge health problem, and drug resistance is an increasing problem. And so we need to understand new vulnerabilities of the virus and we can only do that by understanding how the virus replicates.
But maybe a less obvious but still very important aspect of this type of work is that we can learn a lot of cell biology as well. So viruses, because they use host cells pathways, are actually the ultimate cell biologists, and so if we follow them we can learn a lot about cells work. And that's been famously, for example, oncogenes, which are the genes that go awry when people get cancer were discovered by studying retroviruses and understanding how they transform cells. And so this is something that keeps happening again and again is that we study a good model system and make fundamental discoveries that have impacts in other areas that we couldn't have predicted.

Interviewer: So can you talk about one area of your research, what are you focusing on?

Dr. Sundquist: Sure, one of the things we work on fairly intensively is understanding how the virus exits cells. So if a cell is infected in order to spread the infection the virus has to leave that cell. And we're interested in how that happens. And we got interested in that in a collaboration initially with Myriad Genetics where we were able to show that by a tech company here in Salt Lake City. And together we were able to show that the virus uses a host cell pathway called the escort pathway to leave cells. And the interesting spin-off, that was just over a decade ago, the interesting spin-offs are that we now understand that almost all envelope viruses use the same pathway to leave cells, so this has turned out to have quite a global impact on our understanding of viruses in general.
But the other thing that's happened is that this pathway, which of course performs important cellular functions, the cell isn't making these proteins so they can be infected by viruses, but rather to do other things. It turns out that the most important function of this pathway we now think is in the final step of cell division. And so a lot of what we do now is study how cells divide, rather than how viruses leave cells, even though we got into the problem through our interest in viruses.

Interviewer: Okay, so the escort pathway actually is something that occurs in human cells, but the virus needs it to get out of the human cell so it can infect other cells; is that right?

Dr. Sundquist: That's exactly right.

Interviewer: Okay.

Dr. Sundquist: And that's fairly common; as I said HIV and other simple viruses have only a dozen genes and so they have to use host cell pathways and reprogram them in order to do many of the steps of viral replication.

Interviewer: Why do you think this work is so fascinating? I mean, you've been studying HIV biology...

Dr. Sundquist: Why can't we quit?

Interviewer: Exactly. Is it an addiction?

Dr. Sundquist: Yeah, it is a little bit of an addiction. I think that you have on the best days, and they don't happen very often, you have a feeling that you're seeing something you and your students and your post-docs are seeing things that nobody has ever seen before, and understanding things that nobody has ever understood before. And that's sort of an exhilarating feeling, and it doesn't happen so often. Much of what we do is quite routine, but I think the idea that you can discover something that hasn't been known before is quite exhilarating.

Interviewer: What are you most excited about right now, in looking at that...?

Dr. Sundquist: The thing that I'm most excited about right now? There's are a subset of machinery of the escort pathway that we think forms filament strings basically and that those strings act like a noose from inside the neck of a budding virus and pinch the membrane together so the virus can leave. And they seem to do the exact same thing when cells divide. So they sit at the region between the two dividing cells and pull the membranes together. And we have a very talented young faculty member in our department, Adam Frost, and together with Adam Frost our lab and people in our lab have been able to I think make real progress in understanding the structure of those filaments. That's quite recent; we haven't yet published that. And it gives us at least ideas about how the noose might work.

Interviewer: I know Adam Frost has come up with these really cool visualization methods for these machines and cells. Have you been able to see a picture of this noose?

Dr. Sundquist: Yeah, we have at least what we think is the first picture of what it looks like. And I should say that we have a long-time collaboration with another structural biologist, Chris Hill, who is also in the Department of Biochemistry. And between the two of them they've given us a huge number of pictures of how the escort machinery works.

Interviewer: It sounds like cliche, but a picture is worth a thousand words, right?

Dr. Sundquist: It is.

Interviewer: But what can looking at a picture of that structure do for you?

Dr. Sundquist: Yes, I think if you view this in analogy let's say to a car, you have no idea of how an engine works until you look at an engine and see what it's parts look like and how they all fit together. And that still doesn't tell you how it works. But it means that now you have ways of thinking about it in concrete terms, what a piston might do, and so forth. So I'm a big believer in structural biology and other ways of actually seeing what things look like. I think that often gives you clues about how they work.

Interviewer: You seem to not be afraid to collaborate with people who do different types of research than you do. Would say that's a fair assessment?

Dr. Sundquist: I hope that's a fair assessment. I think that one of the really fun aspects of science is that you have interesting bright people who are doing different but complementary kinds of things, and some of the most exciting science gets done when they get together.

Announcer: Interesting, informative, and all in the name of better health.