Since my background is as an infectious disease specialist and an immunologist, I was primarily interested in looking at host factors involved in HIV from the very beginning, even before the virus had a name. My interest was in using the virus as a probe to study how the host reacts, as opposed to how a virologist approaches the disease, which is by studying the molecular makeup of the virus and what effect that has on the host. In other words, when people historically would look at viral infections, they would look at how the virus directly damages various organ systems—the brain, the heart, the GI tract, etc. And although the host response has always been important in any disease, we were noting from our own observations that these host factors were playing as much a role in the pathogenesis of HIV as was the direct effect of the virus. There was this very interesting interaction between host and microbe telling us about the complexity of the pathogenesis of HIV infection.

“There is certainly something about HIV that you do not see in other infections.”

In 1995 we had published an article on the role of lymphoid tissue in the propagation of HIV infection even in clinically latent disease, and that convinced me that we had accumulated enough information to write a review, tying together a decade of observations on what roles the host plays in the pathogenesis of the disease—lymphoid tissues, aberrant activation of the immune system, cytokine production, etc.—and how these factors impact the disease process. That is the reason why I entitled the paper "Host factors and pathogenesis of HIV-induced disease."

One of the things that this idea was based on was the question of why the virus continues to replicate even though we have what looked like a reasonable immune response. (Although we know now years later that it is by no means an adequate immune response.) So what is it about the human body, the host, that helps drive virus replication, and what is it that tries to block virus replication? And because of our work and work from other labs on various cytokines, like TNF-α and IL-6 and IL-1 beta, as well as the discovery the previous year of certain chemokines to suppress HIV replication, it looked like there was this delicate balance between stimulatory and inhibitory effects of host factors, particularly endogenous cytokines, on HIV replication. It was not just the virus operating in a vacuum. There was an important and complicated interaction with these host factors.

We happened to be very interested in cytokines, and particularly the cytokine microenvironment of lymphoid tissue; however, we needed a forum to tie all these ideas together. This was an important enough new concept that it needed a discussion in its own right, and since this was getting to be a very hot area, I did the review as an article for Nature. And because it was an important topic it was highly read and highly cited.

HIV brought special insight into it. There is certainly something about HIV that you do not see in other infections. Typically when a microbe enters the body, the immune system recognizes it and gets activated, and the activation of the immune system is almost exclusively a beneficial phenomenon for the host. The immune system responds appropriately to suppress whatever microbe we happen to be dealing with.

But HIV is a different story, because it is the activation of the immune system that provides a permissive milieu for the virus itself to replicate more efficiently. We know the virus replicates much more efficiently when we have this aberrant immune activation. That is a big, big difference between HIV and most other infections. It is a double-edged sword. We need the immune system to be activated enough to mount an adequate immune response, but it is the very activation of the immune system that paradoxically puts cells at even more risk of pathogenic damage because that is the way the virus likes to replicate. That was a new concept and a difficult one to accept.

To be honest with you, a couple of years earlier I wrote a similar type of review for Science, albeit not as advanced because the research was not as far along. So it was pretty simple: this time I decided to do Nature. Clearly, the audience I wanted to reach reads both of these journals.

In my mind this was an important turning point in our own laboratory’s direction and where the field was moving. When antiretroviral therapy came into play, there was hope among some people that if we could suppress the virus for a long enough period of time, we could actually wind up eradicating the virus. Many labs were looking at patients who had been on HAART (Highly Active Antiretroviral Therapy) for varying periods of time, in which there was no detectable virus in the plasma, and the question was whether this prolonged therapy would eradicate the virus. This paper was the first in a series that we wrote, in which we finally definitively proved that no matter what we do with antiretroviral therapy, we do not achieve eradication of HIV.

This was the first step, to take the cells of people who had prolonged undetectable plasma viremia because of this therapy and determine if we could extract a replication-competent virus from the cells of these people. If we could, then we had not eradicated the virus, even though we could not detect any virus in their plasma. We showed that that was the case, i.e., that the virus was not eradicated, and that is why this paper was so important.

In fact, this same finding was also published at almost the same time by two other laboratories: one was Bob Siliciano’s lab and the other was Doug Richman’s lab. We were all looking at the same sort of thing. It was one of those beautiful times in science, when a number of independent groups looked at the same question and came up with the exact same answer.

Then we followed this up with a series of experiments in which we ultimately treated patients with even more aggressive ways of activating the immune system and tried to "flush out" the virus. In some of these people, even when we did lymph node biopsies we could not find the virus; however, when we stopped the aggressive therapy, the virus rebounded right back to where it was before we started.

What we did was to try and get much more substantial evidence about why this virus does not completely get eradicated. When you have people on therapy they look well; they feel well; you do not detect any plasma viremia, and yet the virus is still replicating. So we harkened back to a point made in that review article in Nature and said, "Could it be that the normal type of subliminal stimulation that the immune system gets every day is actually triggering the virus to continually replicate?" In other words, our immune system is never completely at rest. It is continually receiving a variety of stimuli. I asked whether we could show at a molecular level that the virus, although undetectable in the plasma, is, in an almost subliminal way, continually replicating at extremely low levels. We could only show its replicating by doing things like lymph node biopsies and by examining the phylogenetic molecular evolution of the virus over time, showing that this evolution could only be explained by some degree of ongoing viral replication.

Then we asked, "If that is the case, what actually induces this level of replication? Could it be a self-propagating phenomenon: activation begets activation?" So we started studying the effect of the envelope protein of the virus on the induction of aberrant activating signals, and we found out that even at the very lowest level when just the lowest amount of virus replication is going on, it continues to induce a very low level of activation of the immune system. This almost subliminal cycle of viral replication and immune activation is responsible for the continual replenishment of the viral reserve that excludes eradication. So the reservoir never completely attenuates itself and never disappears completely. And what this means is that eradication does not seem possible given the present therapeutic regimens.

Now we are trying to figure out novel ways of blocking this low-level activation. We have been using the most sophisticated techniques, like gene expression microarrays, looking at the cells of people who are infected but without viremia, and we compare them to those of people with high levels of viremia, and we find that different genes are expressed in the viremic patients, different clusters of genes that are very permissive for activation of the virus. Even when we examine the lymph nodes of people in whom the virus seems to be quiescent, we still see this slight degree of gene activation in the cells that is hinting at some degree of ongoing virus replication. And we can see this, even when we cannot detect that the virus is replicating by the standard plasma viremia measurements. In this regard, we are doing much more research at a signal transduction level and at a gene expression level to continue to understand this propagation of activation and how we might eventually stop it.

I think it is partially a coincidence, but it is also partially that this was the time when tools were finally available that allowed us to ask the right questions and then answer those questions. It was beginning in the mid-1990s that we had the availability of antiretroviral therapy, which allowed us to study people whose virus was completely suppressed and compare them with people who had detectable viremia. That is how we were able to answer these questions about the persistence of viral replication.

Prior to this, when we studied people, they all had viremia. We had no control to use as a comparison. Now we could look at people before and after starting antiretroviral therapy. That all became available around 1996. It was also around that time that we learned to appreciate the complexity of host factors controlling HIV.

The chemokine connection was discovered in 1995; the kinetics of viremia were delineated that same year. Looking back, that was a time when we made a quantum leap in our understanding of the pathogenesis of HIV infection. It opened the door, and afterward we were able to ask the important questions and find some important answers.

Oh yes, I think the progress has been phenomenal, although a lot of the low-hanging fruit was picked early on. We had a much greater advance in the depth of our understanding early on, and we are not going to be able to have the same rate of productivity now, not in understanding the pathogenesis. The further we go, the more difficult the questions get and the much finer the granularity of the answers. For the most part, we do not have the big questions to answer anymore.

I think the biggest challenge is in the answer I just gave you. It is that we are at that stage that we know so much, that the only questions left to be answered are the toughest ones. What is the nature of protective immunity in HIV, for instance? Why do we not have protective immunity? This is the only infection we know of in which the body is consistently unable to adequately clear the virus from the body. That is befuddling all of us. Why is that? Is it because the virus does not induce an effective immune response as a result of the way it presents itself to the body? Is it because the virus is able to mutate so readily? Is it because the virus is able to integrate itself into the immune system and hide there? Is it all of the above? Those are the prevailing questions now, but they are not as easy to answer now as the equivalent questions were a decade ago.

There are multiple components in AIDS research and the answer depends on which ones we are talking about. The field of HIV pathogenesis will just get ever more refined, as we get ever more sophisticated questions and we push the limits of the technology. We will continue to understand at a finer and finer level the molecules that are involved in inhibiting or enhancing the replication of the virus.

Then there are the therapeutic areas, like developing new targets for drugs and better drugs for old targets. And then the vaccine field, which is a totally different scenario. We still do not know what the elements of protective immunity are. So a lot of the biggest question-mark areas are in the vaccine field. In pathogenesis, we fundamentally know about that, we just plod along at finer and finer granularity. In drug development, it is about picking new targets and developing drugs to go after them. The big intellectual challenge is with vaccines. We are just not sure what the roadmap to a successful vaccine looks like.

Yes.

Well, I am very passionate about my work. I love it, and I think I am pretty good at it. I surround myself with good people; I get good fellows. I work a lot and read a lot. And there is also a certain amount of personal sacrifice involved. I work preposterous hours. I work seven days a week. I get in at six-thirty in the morning and I leave, sometimes, at nine or ten o’clock at night. Then I go home and work a little bit more at home. I am not alone in this lifestyle; there are a lot of people who do this. The task at hand transcends the other things in life and allows you to make these sacrifices. And, fortunately, I have a very understanding family. They understand that if you want to make a difference in this world, you cannot necessarily do it by working just nine to five.

Anthony S. Fauci, M.D.
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, MD, USA