An Interview with Dr. David Ho—HIV/AIDS Experience Propels SARS Research Effort
Dr. David Ho
June 2003—David D. Ho, M.D., is the founding Scientific Director and Chief Executive Officer of the Aaron Diamond AIDS Research Center, a world-renowned biomedical research institute based in New York City, and is an Irene Diamond professor at the Rockefeller University. Dr. Ho is perhaps best known for elucidating the dynamic nature of HIV replication, which led him and his colleagues to champion combination antiretroviral therapy, including the use of protease inhibitors. Among numerous honors and awards recognizing his seminal contributions to HIV/AIDS research, Dr. Ho was named Time magazine’s Man of the Year in 1996 and was awarded a U.S. Presidential Medal in 2001. In the first of two features in this issue to explore the convergence of SARS and HIV/AIDS in Asia, Dr. Ho granted this interview to the TREAT Asia Report.
TA Report: In your opinion, has the world changed much in terms of infectious diseases and AIDS as a consequence of SARS?
Ho: Certainly in China and Hong Kong, and much more recently in Taiwan, everybody stopped doing everything else to deal with SARS. So all the AIDS work kind of came to a grinding halt. Some of our collaborators at the Yunnan CDC, for example, have been doing nothing but SARS work for the last couple of months now, so SARS has had a huge impact. But I think the knowledge that’s been gained in HIV over the years is actually becoming extremely useful to us in dealing with SARS. The other thing is that people are looking to see how SARS might impact immunodeficient patients, including those infected by HIV. The two epidemics in China have not overlapped, but if that happens, we have to look out.
TA Report: Could you tell us a little about your involvement in SARS research?
Ho: We were just interested bystanders to begin with. Then friends in Hong Kong, and later in China and Taiwan, asked for our input. So I went as a consultant to the various governments and met with Chinese Health Minister Zhang and others.
I realized that we have a much better chance of fighting this virus than we do HIV, especially in terms of vaccine development. But we didn’t have samples, we didn’t have virus or even a proper facility. I was driving to work one day and heard on the radio that he sequence was posted. We looked at the sequence that same day and realized that now we could tackle the envelope of the protein of this virus, and from that we could branch off into therapeutics and vaccine. Based on animal coronavirus work, we know a vaccine is possible. It will be principally based on neutralizing antibodies and I already knew from colleagues in Hong Kong that patients who recovered developed neutralizing antibodies. So we made the synthetic gene and we’re moving ahead with the vaccine work now.
The Minister of Science and Technology and the Minister of Health in China and the Chief Executive of Hong Kong all wanted therapeutics developed as quickly as possible—within a year. We looked at the envelope and saw that the region with the two heptad repeats looked like those in gp41 [one of the HIV viral envelope proteins]. If you start with drug screening of a small molecule, it’s going to take years, so we decided to make a peptide therapeutic based on the same principle as T-20 [the newly approved AIDS drug Fuzeon]. We had that done in 10 days or so and the antiviral results were generated in less than a week. Now we’re just doing repeat experiments, refinement of the various peptides and figuring out ways of scaling up the peptides.
TA Report: Do you think the response to SARS could have a long-term benefit for collaboration in the region, beyond SARS?
Ho: I think there is a new attitude in China that is going to benefit HIV. They now realize that openness is important to health matters, and SARS is making that clear. They know that there’s this big HIV epidemic in central China that’s not talked about much. To some extent the Chinese accept the epidemics in the peripheral regions, whether it’s the Southwest in Yunnan Province and Guangxi or the Northwest in Xinjiang Province, because those are related to what they would consider aberrant—drug use—and they also affect largely non-Han Chinese. This allows 90 percent of the Chinese to say, “AIDS doesn’t really affect us.” But in Central China, it is very much AIDS in the heartland, and there’s no denying it. The reason they want to keep that under wraps is because of these blood stations that operated for so long and in some cases at least were controlled by local governments. The other thing is that, as you know, the SARS virus spread down from Guangdong to Hong Kong, up to Beijing, and on to Taiwan, Singapore and Canada, but it’s still largely greater China that’s affected. And I think everybody is trying to extend a hand and sweep aside the politics. You know, I’m the product of a ‘mixed marriage’—my father’s from mainland China and my mother’s from Taiwan. I’ve been on the phone with people in Taiwan and they don’t want to drag politics in, but they are very eager to participate in a scientific conference. There is also a great deal of interest from the Chinese-American population and I think there’s a lot of willingness to contribute money, energy, and so forth.
TA Report: What’s happening with antiretroviral production in China?
Ho: There’s a company in Shanghai that makes four generic AIDS drugs. A group of young chemists came out of college and formed a company that’s now called Desano. They made raw ingredients for various things like vitamins and sold them here in the U.S. And then they made some of the basic components for HIV drugs, precursors to the nucleosides and AZT and others, and they did a good business selling to Cipla in India and to Brazil.
They went on to make AZT, d4T, DDI, and now nevirapine. All of this is legal in China. They have the processes all done for several protease inhibitors, and they’re trying to license a compound we have, that was given to us (we didn’t develop it)—Uniroyal Chemical 781 (UC781) compound. It’s an NNRTI [non-nucleoside reverse transcriptase inhibitor, a class of AIDS drugs that includes nevirapine and efavirenz]. The major advantage is that this came out of Uniroyal’s insecticide program. They usually work on chemicals that you can make by the ton, so it’s very cheap to make.
TA Report: The U.S. Congress has passed a bill that authorizes $15 billion over five years for international HIV/AIDS programs. Are you optimistic that this will help make AIDS drugs more widely available in developing countries?
Ho: I think it’s a positive move. Of course, the $15 billion won’t affect China much because it’s earmarked mainly for other countries. We’re basically trying to conduct our work in China through other foundations, and of course hoping that the Gates Foundation will provide assistance for China, as it has done for Africa and India.
We went to China with a vaccine agenda, but when we got there we realized that we had to deal with their agenda—the local people, in Yunnan province in particular. Their labs needed upgrades, their people needed to be trained, both clinically, and in the laboratory, and their patients needed treatment. So there’s a quid pro quo here—if you want to pursue your vaccine, you have to address the needs of your collaborator. That’s how we got involved in this process. We haven’t forgotten our vaccine agenda and that’s moving along well.
TA Report: So you got drawn into education and training?
Ho: Right. We have a team in China and we’re training a lot of health care workers and some laboratory personnel. We have built several laboratories, including a virology lab that can do viral loads, CD4 cell count, and those standard things, and an immunology lab that could do Elispot assays and antibody titrations, and we built a clinic where the first antiretroviral trial of any magnitude is being conducted.
TA Report: Which drugs are you testing?
Ho: We negotiated with GlaxoSmithKline and they agreed to donate Trizivir® for our use in China. This has been extremely important to us in helping build our program. We’re looking to enroll 300 patients in a three-year trial. We only started late last year and I think we’re up to about 75 patients by now. The trial serves as a focal point for getting the labs running smoothly, getting doctors and nurses trained, and we can tap into the same infrastructure later for vaccine or for other trials. It’s something very different from what we typically do here.
Our strategy is to build a pretty comprehensive model whereby anyone from China can come to a single site and learn just about everything they want, both in the clinic and in the laboratory, both on the vaccine side and on the treatment side. In Kunming, the capital of Yunnan, we’ve got a clinic and two labs. Now we’ve built two more labs in the more rural region because much of the epidemic in China is still rural.
In the most western corner of Yunnan province, in a prefecture called Dehong, we have set up labs in two towns so that they can draw blood, put away plasma, and run antibody tests. Not very sophisticated, but enough to support some treatment and vaccine activities and train people. Now we’re going to take this Trizivir treatment study and extend it from the city to the rural area. We’re beginning to train the rural physicians on the use of these drugs, how they should be given, possible complications, and how patients should be monitored.
TA Report: The Aaron Diamond Center is obviously doing a lot of important work that is a little outside of your core mission. Does that make it hard to stay focused on the basic biomedical research?
Ho: I think it’s been rewarding for everybody around here to know that our work could extend this far. For the first decade of the Institute, the benefits of our work extended mainly to the U.S. and then to Canada and Europe, but we were not really affecting the wider epidemic much, and we regretted that. That’s why we decided to work on vaccines a number of years back. But we never realized that as we moved to vaccine research, we would take on all of these other things that were important and relevant but were not part of the research mission. It’s more of a humanitarian mission. I think we have to evolve in what we do, in the same way that the epidemic has evolved. If you want to really have an impact on human beings, you have to take on all the issues.
TA Report: Five years from now, is SARS going to be a problem in the world?
Ho: I have confidence that the epidemic can be controlled in Taiwan, Hong Kong, Beijing. I am less confident that SARS can be controlled in a rural setting, where the infrastructure is really bad and trained personnel are difficult to find. If it is in fact seasonal, as some people expect, and you get rid of it during the summer months, then the reservoir in the animal species is very important. It will come back. If you look at H5N1 influenza from birds in southern China, that hit Hong Kong hard in 1997, there have been a few outbreaks, but it’s been minor. I don’t know whether it will be like that scenario, or more like influenza, except with a high transmission rate and a higher mortality rate, and coming back with regularity. I hope for the mild scenario, but I think we should prepare for the scenario in which SARS will recur frequently.
TA Report: To what extent does the work that has been done on HIV continue to yield rewards for infectious diseases in general?
Ho: The fact that it is so hard to make an HIV vaccine led all of us to pursue many different strategies. Now at least the foundation has been laid for all of those strategies, and you can just take them and plug the various genes of the SARS coronavirus into them, and move exceedingly quickly. It would not surprise me if, six months from now, we are looking at lots of animal data from a multitude of vaccine strategies for SARS, and deciding what is likely to succeed in humans, and moving very quickly to then make the human version. That would not be possible, in my view, without all the vaccine work that was done for HIV.
The therapy that we’re working on is a fusion inhibitor that’s completely borrowed from the HIV book. And now people are looking at the two proteases in the coronavirus. One of them looks like the rhinovirus protease, and there’s a crystal structure for the protease of another coronavirus. You can model that in and I think drug development for that target will go quite fast. The protease inhibitor developed for HIV—that experience is going to be directly relevant. With all the molecular epidemiology that’s been done for HIV, people just have to look back on what’s been published on HIV and say, “We need to do the same for SARS.”
TA Report: Thank you very much, Dr. Ho.