Addressing AIDS in China

An Interview with David Ho

By Simon Noble, PhD*

David Ho, MD, has been at the forefront of HIV research for 20 years and is now one of the most instantly recognizable names in the field. He is the founding Scientific Director and Chief Executive Officer of the Aaron Diamond AIDS Research Center, as well as the Irene Diamond Professor at The Rockefeller University, both in New York City. Ho’s research has given an appreciation of the dynamic nature of HIV infection in different reservoirs in infected persons, an understanding that led him and his collaborators to champion combination antiretroviral therapy, including the use of protease inhibitors, an approach that has been invaluable to prolonging the life of infected persons who have access to these drugs. Ho has received numerous awards from the international scientific community and, to give some indication as to the breadth of his influence, was named Time Magazine’s Man of the Year in 1996 and awarded the Presidential Medal in 2001. In recent years he has increasingly been involved in HIV/AIDS in China and at the end of last year launched the Chinese AIDS Initiative to promote advocacy, prevention, education, and treatment of HIV/AIDS there. At the same time he began an AIDS vaccine trial in the US to test ADVAX, a DNA vaccine based on subtype C virus developed by his research team. Ho recently spoke to IAVI Report editor Simon Noble about that trial, the Chinese AIDS Initiative and the current awareness of the burgeoning epidemic in China.

[Noble] In addition to your long and distinguished track record in HIV research, you’ve recently entered the field of SARS research. Do you think that the SARS epidemic in China and surrounding countries has improved the public health programs in these states, their accountability and transparency?

[Ho] The SARS outbreak has had a dramatic impact on China because it shook the whole country up in early 2003. I think we all would agree that China did not handle the early part of the epidemic very well. But starting from April, China reversed its course, became much more transparent in handling the outbreak and, I think, to everyone’s amazement brought the epidemic under control, even in rural areas, by July. Their effort in the latter part, certainly, was very commendable. I had the occasion of visiting China and Hong Kong multiple times throughout the period and I was impressed. They not only took action for SARS but they also committed lots of funds. In speaking to academic leaders and leaders within the Ministry of Health, it was clear to me that SARS was a wake up call, and it was also clear to me that it was a great opportunity to have the Chinese government focus on HIV/AIDS, which in reality is a much, much larger problem.

I think now the Chinese leaders realize how important public health and proper health care infrastructure are to their future prosperity, so I have seen nothing but positive changes in terms of the attitude of the Chinese leadership toward AIDS as a consequence of SARS.

Do you think this wake-up call has filtered or will filter through to HIV/AIDS surveillance and recognition of the problem?

I think at the top level, that is, at the State Council with the Vice Premier and at the level of the Ministry of Health and its leadership, it most definitely has. We’ve also been doing our advocacy work and it’s probably a combination of many events, including SARS, that has improved the political will to do something about HIV/AIDS in China. Certainly, we saw the symbolic gesture that the Chinese Premier made on World AIDS Day by visiting HIV patients.

But even more important than that, Vice Premier Wu Yi spent several days visiting villages with severe AIDS problems in the central province of Henan and this was done quietly, under the radar screen. I just came back from there recently, and it is clear that the government is restructuring their AIDS effort so that it reports to the State Council, elevating the status of this office. So I see a lot of changes but, of course, China is a huge country and a lot of the high-level commitment will take some time to trickle through the system.

Do you think there’s a change of attitude towards AIDS in China within the general populace, that it’s not seen just as a problem in marginalized communities?

There has been some improvement, although there’s a lot more that has to be done. I think the leadership is aware of the situation and will be making the right decisions. But unfortunately, if you speak about the Chinese population in general, I think most do not know anything about HIV/AIDS; most do not care. Most consider it a foreign disease or a disease that affects ‘strange’ populations. So there’s now a disconnect between what the leadership knows and would like to do, and the general population. And I think that will require tremendous educational and outreach effort.

You mentioned your advocacy work, were you referring to your own Chinese AIDS Initiative?

Yes, we’ve been organizing a consortium to help China address its HIV/AIDS problem because we wanted to approach the problem in a very comprehensive manner, with prevention at the center, including testing. Of course, this is prevention outside the vaccine research agenda. But we have also realized that there are multiple other components that will impact on this primary agenda of prevention; that is, we have to deliver care and services and, importantly, antiretroviral (ARV) therapy to help bring people into the prevention effort. The ARV component we have been doing together with the Clinton Foundation.

As for advocacy, it’s actually broader than that—it’s advocacy, outreach and education and also involves issues related to legal reform and policy changes. We’ve been working with the schools of journalism, law and public policy at Tsinghua University in Beijing, the leading educational institution in China. We have a series of things in mind including training of the Chinese political leadership and media with courses done at Tsinghua.

We’re going to make documentaries and public service announcements and at the end of last year, November 10th, we organized a high-profile conference that involved former President Bill Clinton. It was a very successful event that immediately preceded all these positive changes with the Chinese leadership. AIDS was prominent on the agenda for the Chinese for weeks, so I suspect it all had a pretty positive influence.

How are AIDS vaccine trials viewed in China, and are they something that your initiative and other Chinese groups are gearing up towards?

The Chinese government has always emphasized science and technology, so they welcome taking vaccines to China for testing. There are internal efforts underway by various Chinese investigators, particularly in collaboration with European scientists.

We’ve been speaking to the Ministry of Health and the State Drug Administration for some time now. They know that our two vaccine candidates are derived from a strain from southwest China, the Yunnan province, and that we have taken them through laboratory testing, some animal testing and now one is approved [for investigational use] by the FDA and another one will be submitted soon.

Which vaccine candidates are those?

Our first vaccine consists of two DNA vaccines mixed together, which will express five HIV proteins; Gag, Pol, Env, Nef and Tat [called ADVAX]. We’ve done the in vitro evaluation, the immunogenicity studies in animals, and this was taken to the FDA last year and approved [for study in humans]. We launched the clinical trial here in New York late last June, and we’ve just finished enrolling two dose schedule arms, and we have a third dose coming up, probably in May.

So that vaccine is well on the way. In terms of the regulatory aspect, we’ve been speaking to the Chinese State Drug Administration and working with a vaccine production facility in China to think about the next step in production there. We need to finish the Phase I here, then we will take this initial product to China.

The second product is a modified vaccinia Ankara (MVA), which contains the same five genes from the same subtype C strain of HIV from southwestern China. For this one, we’ve done the laboratory evaluation and animal testing, and we have a GMP-grade product that’s now in preclinical testing. We’re also doing some QA/QC (Quality Assurance/Quality Control) studies and we plan to submit it soon to the FDA. We believe this is one of the best vaccinia vaccines out there—it’s stable, it expresses well, it’s easy to grow, easy to produce to high titers. So, fortunately, we haven’t had the technical problems that have plagued others in MVA development. It’s gone well and we’re anxious to get it into the clinic. And once again, we’ll be testing in New York.

The work on both of these vaccines was made possible by support from IAVI, which has been absolutely vital to our vaccine effort. We had some internal funds that got the project off to a good start but IAVI stepped in fairly early and supported us for the past three years, and that’s been great, to be able to take it from the bench to the clinic in that short period of time. But it isn’t just financial support. Especially in the past year, IAVI also provided clinical research expertise that complemented our basic scientists here, particularly with respect to development issues and regulatory concerns. If it weren’t for that, we’d be struggling. So it’s been a very successful partnership and we certainly appreciate that.

What’s your opinion of the current state of Chinese research in general and HIV research in particular? Is there a new funding commitment from the government?

In general, China has put in a lot of money to support biomedical research, and they have created many new institutes and many positions within the leading universities. They’ve made a very impressive financial commitment and they’re beginning to attract some of the very best people to return.

More than 90% of the people who came to the US [from China] to study, stayed in the US. Now we’re seeing the return of some of the very best because living conditions are better, at least in the major urban areas, and they’re also making offers to some of the very best that are difficult to refuse. When I visit the various institutes and science parks in Beijing and Shanghai, it becomes very clear what China is trying to do to draw them back.

Now, in the HIV/AIDS area, I don’t quite see that yet. Although there is a deeper commitment on the part of the government, I don’t think it has trickled through the system to be relevant for AIDS in China right now. So there isn’t a lot of basic HIV research in China, in fact there’s almost none. But people are beginning to be more interested in more practical issues in treatment, vaccine development, prevention work and the clinical and epidemiological front.

How reliant is Chinese science on training in the US and Europe? And how is that now being affected by the recently imposed tougher visa restrictions?

The short answer is it’s impacted a great deal on training in the US and Europe. Since the late ‘70s, when Deng Xiao Ping and Jimmy Carter opened up the new relationship, there has been a massive outpouring of talent, to the US primarily but to Europe as well. Hundreds of thousands of some of China’s very best have been trained.

I think it’s really a shame that the post 9/11 changes in visa requirements and immigration laws are keeping out very talented scientists who could come and contribute to—not just learn from, but contribute to—American science. I’ve had a number of potential post-docs from China, some that I painstakingly selected, only to have them turned away at the visa office in Beijing or some other city in China.

What is the current state and the potential future use of vaccine manufacturing facilities in China?

Actually, unlike other developing countries, China has got a tremendous set-up for making vaccines or recombinant proteins. It has at least a dozen such facilities. The one we’ve been dealing with in Kunming City in Yunnan Province, for example, was built by the Dutch and the GMP conditions would match those in Europe. It makes all of China’s polio and hepatitis A vaccine. I know the IAVI experts went there not so long ago and were impressed with this particular site. So China really has a fair amount of capability in that area.

What about manufacturing facilities for ARVs? Is making their own generic ARVs an important pursuit of the government and public health bodies?

Yes, there are some pharmaceutical companies involved that are government- owned or government-backed. The Northeast Pharmaceutical Group, for example, has made several generic drugs. And now the private sector is trying to do more. There is a company in Shanghai called Desano [Bio-pharmaceutical Co.] that has made four generic drugs— AZT, ddI, D4T and nevirapine. These are now approved in China and they’re fairly cheap. I think some studies remain to be done to demonstrate bioequivalence to the western drugs, but at least part of the therapeutic arsenal is being synthesized in China.

We also have to keep in mind that China has for some years now had an active, not pharmaceutical, but a chemistry effort to make the basic components that are the precursors for ARV drugs. We hear so much about Cipla in India or the Brazilian effort, but we have to keep in mind that these places get their basic components from China, they have played a role through that particular function. Now they are trying to expand the process and go on to make the actual drugs. I think it will happen, I’m hearing more and more about other, mostly private companies trying to join the effort.

However, to date China has been respectful of World Trade Organization regulations with respect to intellectual property. So Desano and the Northeast Group have just made generics or drugs that are off patents or not covered by patents, they have not gone on to make 3TC, for example, which is patent-protected in China.

What do you think are the most important goals for China in terms of its AIDS epidemic in the next five years?

The most important goal is to make sure the projected numbers of people infected with HIV do not come true. By 2010, the World Health Organization and UNAIDS have suggested that China will have 10-20 million infected, going from approximately one million today. That’s a frightening prediction. So the most important goal is to make sure that doesn’t happen, and for our own Chinese AIDS Initiative, we want to reduce it by several-fold.

But to achieve that goal, I think the most important thing is to get the information out to the public. You know, here, really, more than anywhere else, knowledge is power and we have to educate the populace about HIV/AIDS and about prevention.

To switch gears a bit and go on to more scientific issues, what do you consider are currently the most pressing scientific challenges for HIV research?

I would say development of a protective vaccine is the highest priority in AIDS research. That’s mine, and I think many would agree with me.

Aside from a vaccine, I think that developing better drugs is still an important priority. It’s clear that combination therapy has been great for American and European patients, but the drugs still need to be improved; there’s development of resistance in some patients, and these people need other options. We need drugs that have fewer side effects and are easier to take. So there should be continued incremental development in the therapy side.

The greatest challenge on the therapy side is whether a cure could be obtained or not. There’s always a lot of debate on that. I think we all know that it will be exceedingly difficult, given the fact that the virus is now known to be hiding in a subset of CD4+ T cells. How to purge the virus from that subset will be extremely difficult, but probably not impossible, and so [research] groups have to continue to try. But right now, I can tell you, we can’t think of too many things to do along that front. If we could think of something that was reasonable, we would be jumping on it and pursuing it.

Also, there’s still a lot of molecular biology that needs to be defined. Recently, we’ve learned quite a bit about innate cellular factors that restrict HIV replication, and these things are wonderful, such as the APOBEC3G story or the TRIM5a story that came out only a few weeks ago. These things are wonderfully revealing about the basic biology of the virus and about how the host fights various pathogens.

But that said, the most important thing is to make sure we develop a vaccine to curtail the further spread of this epidemic. The vaccines that are fairly advanced in development have failed, and now we’re looking at vaccines mostly at early stages of development. We could optimistically think that these might offer partial protection, as we’re seeing in monkeys with some of the vaccine candidates. Will they be the home run that everyone is looking for? I wouldn’t be overly optimistic about that. So I think the next three to five years will be most interesting to see this whole series of DNA or viral vector vaccines advance to efficacy trials.

Do you think there are any basic immunological questions that should be addressed immediately, that are currently being ignored? We still haven’t defined the correlates of protection.

Well, you answered the question yourself. We are able to protect using, say, live attenuated virus vaccine, but in that system the correlates were never worked out, despite some attempts. But we measure what we know how to measure, and it would seem to some of us who have been in this field for some time that maybe the correlate is in something that we haven’t measured well up till now, like innate immune responses, or we haven’t been measuring the cellular responses in the proper way with the proper assays.

The standardization of assays is all focusing on ELISPOTs and interferon (IFN)-g, but it’s still not known if that’s a good surrogate marker for anything functional in protection. Do you think that’s an important issue that needs to be sorted out?

I think we need to sort all these things out. We tend to gravitate toward things that are quantitative and easy to do. In general there’s a rough correlation between those ELISPOTs and, say, protection results in monkeys, so that’s somewhat reassuring. But we don’t know whether ELISPOT, the way we measure it using IFN-g , is the right parameter. Maybe IFN-g  plus another cytokine—IFN-g  and Tumor Necrosis Factor (TNF)-a, or IFN-g  and interleukin-2 or -12, whatever—would give a better correlation with the killing ability of these CD8+ T cells. What do we need to actually measure? Maybe it’s that killing ability. Until it is well defined, we tend to just do whatever is easy to do. But we are just taking a snapshot when the real situation is more dynamic and one needs to integrate it over time.

You mentioned innate immunity, is it being realized now that perhaps we haven’t looked closely enough at the innate immune response in the context of HIV infection?

Yes, from the molecular field we now realize that there are molecules like APOBEC3G that reside inside the cell and have a way of mutating and degrading viral DNA so that the pathogen cannot survive. We’ve known about IFN-a and IFN-g in other viral systems such as hepatitis infection. They play a very important role, seemingly, in protection.

We’ve known since 1996 about the b chemokines, and these are probably, in a non-discriminatory way, shutting down HIV that uses particular receptors. And I suspect there are more that could play a very important role. Now, we may not be able to elicit those responses using the old vaccine strategies, because all of those are directed toward acquired immunity. So to induce the proper innate responses would be very difficult, but I have no doubt that the innate immune system is contributing to the control of HIV in every infected person.

Do you see these new targets, like APOBEC3G and TRIM5a, as being amenable to manipulation?

Yes, I think some of these are amenable for development of drugs, small molecule inhibitors. We know about Vif and APOBEC3G; could that be exploited for drug development? We know about TSG 101 and Gag-p6 for budding. So there are new targets for therapeutic development. So I’m hopeful, and I know there are people who are concentrating their drug development on these new targets.

How’s the ADARC trial going with ADVAX? You said earlier you’ve almost completed enrollment.

It’s going quite well. There are three dose groups, fifteen subjects per group, being done at two sites; here at Rockefeller University and at the University of Rochester in upstate New York. Within each blinded group there are 12 volunteers who receive vaccine and three who receive placebo. The first dose group began late last year. All of them have gotten their third shot already. They’re doing fine, no adverse events, that’s why we are allowed to move the dose group. Dose two has been enrolled, and that’s going well.

In terms of immunogenicity, those samples are just being shipped to IAVI’s core lab for testing. A few weeks from now, we may have some read out from the early periods, from dose one.

The concern was whether we would fully enroll, but it’s going very well. We got over 400 phone calls from people volunteering to participate in our trial when we only had 49 spots. So it bodes well for not only the third group that we have to enroll, but also the next [MVA] study. We think we could go back to the same pool of volunteers.

Is that particular to New York City or did you have a similar reaction in Rochester?

Rochester has a long history of vaccine testing, not just for HIV/AIDS, and they have built up a great program there to attract volunteers. New York, I think, is unique. We have so many people whose lives have been affected by HIV/AIDS, and almost every single one of our volunteers comes to us because of altruism, and not because of the reimbursement fee we give to participants. So we’ve been particularly moved by the spirit exhibited by our volunteers. It’s been phenomenal.

*Simon Noble, Ph.D., is editor of the IAVI Report