How long have you been working in this area, and how did your background provide a context for your highly cited 1995 Science paper?

The conclusion I came to in what was happening with patients infected with HIV was rather different than with any other virus that was known at the time. This was that HIV must be replicating very rapidly throughout the whole course of infection, and that the latency period was not a period of viral inactivity, but an active process in which cells were being infected and dying at a high rate and in large numbers. This turnover was the only sensible way that one could generate genetic variation and thereby resistance to anti-viral drugs, which was becoming increasingly apparent.

That notion incubated for 10 years. Finally some more direct experiments on the effects of effective therapy, including papers by David Ho and George Shaw, really crystallized everything and motivated me to finally write up all of these thoughts. The paper is not really a research paper so much as a theoretical one. This paper had the same effect on a lot of other researchers, making them think about HIV as a viral population, a very rapidly replicating population that was under the sway of perhaps subtle, but important, selective forces that molded the virus genome. I doubt too many people had thought about it that way before. I think that’s why the paper really caught on. And it came out at about the same time as the papers by Ho and Shaw and collaborators. Although I could have written it without those papers, I think having them tied to it, in a sense, gave it that much more impact. In some ways it became a reference of convenience for a large body of work on the subject. Of course once things get cited a fair amount they take on a life of their own.

Quite a few HIV researchers have told me that it has significantly affected their work and started the field, if you will, of virus population dynamics. Meaning that the infection is not being carried forward by latency; it’s being carried forward day in and day out by its replicative process, which then allows it to evolve. Out of this came other important, although not yet tested, concepts, which include the importance of pre-existing mutations and drug resistance.

Generally, I’m interested in molecular retrovirology, interactions of retroviruses with their hosts, evolution of retroviruses, pathogenesis, population dynamics, and pathogenesis.

Retroviruses have always been at the forefront of technical information in molecular biology. Perhaps the biggest challenges are keeping ahead. These are very competitive, full areas of research. There are something like 8,000 papers published a year on HIV. So the biggest challenge is doing something original.

It moves along at a very rapid pace. All kinds of discoveries have advanced the field. Anti-retroviral therapy for example opened up new ways of looking at what happens in patients. Not only were they treating patients with this but it’s still an important way of looking at what the virus is doing. Advances in cell culture and virological technology allowed a closer examination of the nature of the retroviruses. That allowed me to come up with the ideas in the paper on which I elaborated.

  What is the implication of your work for the future of your field and allied fields?

Some of the important issues that came out of this work were how one thinks about HIV therapy and therapy for other viruses in terms of their impact on viral population dynamics, not just the individual virus. It was the thinking that if one didn’t see any viral load after a certain amount of time of therapy it really wasn’t gone, so it’s a reservoir for future bouts. It was this thinking that led to these issues regarding therapy that led to my part-time job as Director of the HIV Drug Resistance Program at the National Institutes of Health in Frederick, Maryland. Here, we’re studying the tools to test some of these ideas directly. For example, we’ve developed extremely sensitive assays for viral loads that in the past were considered undetectable by standard techniques. To find viral loads in these people who have been in treatment for a long time was quite surprising to us.

  Where do you predict the state of knowledge in your field will be in 10 years?

I hope we’ll have enough understanding of these processes to be able to apply them in HIV therapy to use existing drugs much more wisely. For example, to be able to interpret the patterns of genetic variation in terms of what it tells us about what’s going on in the patient. I think there’s a lot of information there. Like with tea leaves, they can be read to divine the internal workings of the virus and its interaction with the patient. I’m optimistic that we’ll be able to understand that fully.

  What advice would you give to those entering a research career in general?

One would be: do not ignore the interesting anomaly. The oddball result is sometimes something that’s interesting. The second would be: keep your research focused, but your mind unfocused. Try to make connections between things that may seem unconnected at first. I think that failing to make such connections is the biggest mistake that young researchers make.

  What would you like the general public to understand about your work?

That HIV is unique and it took a while to gain the understanding that it was different from any other virus. And that HIV infection, because of this, is an extremely difficult problem. The virus is designed to protect itself against all kinds of things we throw at it, much better than almost any infectious agent that we know of. That’s why development of therapeutics and vaccines has been a slow process. It’s been 20-plus years; how many dollars have been spent and how many papers have been published since the beginning of the AIDS pandemic?

  Is there anything you'd like to add?

Yes. My father, Louis F. Coffin, Jr., is also an author on a highly cited paper that appeared in the mid 1950s in the Transactions of the American Society of Mechanical Engineers (Coffin, L.F., "Thermal stress fatigue of a ductile metal," 76:931, 1954).The paper described the Coffin-Manson equation. This equation essentially tells you, for example, if you bend a paper clip back and forth, how long or how many bends you have to make before it breaks. For many years we had this running competition about who had the most citations in the pages of Current Contents for the month, and both papers are still being cited very frequently.

National Institutes of Health
National Cancer Institute
Frederick, MD, USA