May 9, 2014 — AIDS is one of the most significant pubic health challenges worldwide. Professor of biochemistry Wesley Sundquist, Ph.D., researches how HIV - the retrovirus that causes AIDS - infects the body, with a goal of finding ways to stop it. His outstanding research contributions recently earned him a seat on the prestigious National Academy of Sciences. He describes the inroads his team has made in understanding the tactics of HIV, and his latest research, which provides insights into fundamental aspects of cell biology.

Interview

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.