Deciphering the Mystery of Natural Host Resistance Factors
A VISIT TO THE COLUMBIA LAB OF TWO amfAR-FUNDED SCIENTISTS
October 5, 2004—Amid the crowded jumble typical of a research laboratory, Jeremy Luban, M.D., and Lionel Berthoux, Ph.D., work side by side, hoping to decipher some of the mysteries surrounding natural host resistance factors relevant to HIV [sidebar]. Dr. Berthoux is a postdoctoral fellow working under the guidance of Dr. Luban to establish a career for himself in HIV/AIDS. The two are interested in what makes humans, more than any other animal, such ideal hosts for HIV. (See bottom of this article to read descriptions of their amfAR-funded research.)
On paper, Luban and Berthoux might appear to be similar men. Both are scientists working in the same laboratory at Columbia University in New York City. Both are dedicated to advancing our knowledge of HIV/AIDS and seeking new ways to treat it. And both have been awarded funding by amfAR to conduct their research. But there the similarities end.
The two exhibit vastly different personal histories, which have converged to bring them together in a laboratory at the northern end of Manhattan. amfAR’s Dr. Rowena Johnston recently paid them a visit to learn more about these men and their work.
amfAR: Were you always interested in becoming a researcher?
Luban: Not at all! I do remember loving science when I was around five, and taking classes at the planetarium. But by the time I was 12, music was really all I was interested in.
As an undergrad I studied music and planned on becoming a musician. Then during college I wanted a job, so I got a work-study position in a genetics lab and asked a lot of questions. That experience really got me interested, and I ended up majoring in biology. After I graduated I worked as a lab technician in Ralph Steinman’s lab, then I went to medical school.
Berthoux: I think I always wanted to become a scientist. Even in school I enjoyed the rational aspect of science. I remember disliking what I thought of as the illogical thinking in the arts and humanities. I like it when things actually mean something. And I was very good at biology in high school.
amfAR: What got you interested in studying HIV?
Luban: In a sense my professional career grew up with the HIV/AIDS epidemic. I started medical school in 1983, and by our third year we were seeing a lot of AIDS patients in the local hospitals here in New York. During our fourth year of medical school we had the opportunity to take an elective, and I decided I wanted to go to Africa and work with AIDS patients. When I came back to the United States I did my internship/residency and then went to work in a lab as a postdoctoral researcher with Steve Goff. My feeling going into the lab was that we needed to know a lot more about the basic biology of HIV so we could come up with better therapeutics.
Berthoux: I finished my undergraduate degree in France and I had no clue what I wanted to do. Even though my degree was in biology, I had never worked in a lab before. Then I entered the army for my one-year mandatory military service in France. By the time I finished, I knew I wanted to do something that at least had some chance of improving human health. And I enjoyed it!
amfAR: If an HIV-positive patient were to ask, “What’s your research going to do for me?” how would you answer?
Luban: We’ve already demonstrated through our approaches that we can identify new ways to inhibit the virus. For example, our work with cyclophilin—we already know there are drugs that bind to cyclophilin and can block HIV replication. Now we need to test drugs that bind cyclophilin without suppressing the immune system. For me, I feel better knowing I might contribute towards developing new knowledge, rather than working on something we already know about to make it a little bit better. That’s why I’m working on finding new therapeutic targets rather than tweaking the ones we already have.
Berthoux: We’re working with genes that can inhibit the virus. In the long term, I could imagine how these findings might help in the development of new treatments. Let’s assume the appropriate advances are made in gene therapy. Once you know the identity of some of these factors that restrict HIV, once you understand how they work, you can imagine that you might one day be able to reproduce this restriction effect. This is actually one of the things I’d be really interested in working on. Another possible avenue is to develop drugs which render HIV-1 sensitive to inhibitory factors that are present in the infected cells but that normally fail to target HIV-1. These are long-term goals, of course.
amfAR: What are the challenges of your work?
Berthoux: Now that some of these resistance factors have been identified, I’m trying to understand how they work together and which other factors interact with them. That’s the important question, and we don’t know the answer. But the limits we face right now are not intellectual limits—it’s simply a matter of the amount of work that needs to be done. So I don’t get to take any vacation! But seriously, we know what we have to do. We just need to buckle down and do it.
amfAR: What achievement are you proudest of?
Luban: My kids! But in terms of my work, one of the best parts of what I do is to have someone come in and start in the lab. Over the course of a year or two they become expert at what they do, and there’s nobody in the world who knows more about their work than they do. When someone’s working on a virus as challenging as HIV, they need a tremendous depth of understanding, and to see that knowledge develop in my lab is hugely gratifying. Running this lab and working on this disease, I’m making a difference on all sorts of levels. For me that’s how I view what I do. That’s the whole point.
The human body possesses natural anti-HIV defense mechanisms that the virus has, unfortunately, evolved to outwit. amfAR is funding several scientists, including Drs. Luban and Berthoux, who are looking for ways to ultimately reinstate those natural defenses.
Jeremy Luban, M.D.
New York, NY
Screen for human cDNAs that promote HIV-1 virion production:
While HIV reproduces well in human cells, there is no other species in which the virus reproduces as efficiently. Dr. Luban is taking advantage of this phenomenon by attempting to infect mouse cells with HIV. With each attempt, he will add single human genes to the mix. The goal will be to identify genes that promote HIV reproduction—genes present in human cells but absent in mice. Once they are identified, scientists will be able to explore the possibility of developing drugs that block the ability of HIV to use the gene products, or proteins, to its advantage. These drugs would represent valuable new additions to the anti-HIV drug arsenal.
Lionel Berthoux, Ph.D.
New York, NY
Sponsor: Jeremy Luban, M.D.
Cloning of Ref1 and Lv1 retroviral restriction factors:
Dr. Berthoux was involved in the discovery and characterization of an entirely new protein called TRIMCyp, which inhibits HIV infection in certain monkeys. This work was published in the July 29, 2004 issue of Nature, one of the most prestigious international science journals. Dr. Berthoux and his co-workers have already begun teasing apart the mechanism whereby TRIMCyp and another related protein, TRIM5alpha, interfere with HIV-1 infection.