HIV Research at a Crossroad?
An interview of Robert Gallo, Director of the Institute of Human Virology at the University of Maryland School of Medicine in Baltimore, USA
Over the years, Professor Gallo and his co-workers achieved a series of visionary discoveries in the fields of human blood cells biology and human retroviruses. They first discovered IL-2 in 1976, then the first human retrovirus, HTLV1, in 1980 and, one year later, HTLV2. Pr Gallo and his colleagues also independently discovered HIV, and provided the first results to show that HIV was the cause of AIDS. They also developed the HIV life saving blood test. In 1986, Pr Gallo and his co-workers discovered HHV-6 and, in 1995, the first endogenous inhibitor of HIV, the beta chemokines.
In 1996, after 30 years at the National Cancer Institute (NCI) of NIH, Gallo left to form the Institute of Human Virology (IHV) of the University of Maryland School of Medicine in Baltimore, where he is still the Director.
Pr Gallo is the recipient of numerous scientific honors and awards, including the Albert Lasker Prize, the World Health Award, and more recently Israel’s top prize, the Dan David Award.
Alain Lafeuillade: it looks like the terms ‘HIV sterilizing cure’ and ‘HIV functional cure’ are no longer ‘dirty’ words for scientists. What is the main gap in our knowledge about HIV persistence that should be resolved before we can envision new strategies to reach these goals?
Robert C. Gallo: The answer is clearly demonstrating the precise cell types that are the source of persisting HIV. This means cells that go beyond the common memory T cells that currently are chiefly studied, and demonstrating that by so-called “purging” these cells by activation mechanisms will lead to death of these cells. At the moment this is the assumption.
AL: Do you think that the concept of long-term HIV drug-free remission is realistic or pipe dreams?
RCG: Well I can only answer that with the current, available information. At the moment, I don’t know that anyone who feels totally secure in stopping drugs for a long period of time and maintaining remission. I would not feel so. However, this does not mean it is not doable. Therefore, in some sense it is not a “pipe dream,” it is an idea that one day might come to fruition. If I had to bet, I bet we are not going to see this any time soon. I would pay more attention to Jacques Leibowitch’s results that therapy may be needed only a few days a week rather than daily.
AL: At the last IHV Meeting in Tropea, Carl June showed a strategy using a population of HIV-resistant immune cells to reconstitute a reservoir of healthy and uninfectable T-cells in already infected individuals. Do you think that we can fight only on the immune depression front without getting rid of persistent viremia, inflammation, etc…?
RCG: No I do not.
AL: On the cytokine front, some researchers hope to use IL-7 to both reconstitute a potent immune system and flush out HIV from latent reservoirs. What are your feelings about the therapeutic promises of IL-7?
RCG: I think the idea is logical and people are presenting some encouraging findings in this direction. However, as you may know, I always have some reservation about the entire strategy. My reservation is that it is based on two assumptions: 1) That when we purged, the infected cell releasing virus will die and 2) that the antiviral agents will block virtually all of the released virus. If these assumptions are not completely sure, the virus could spread to the brain and the infected cells in some cases may still be around.
AL: Others put their faith in anti-latency agents, like HDAC inhibitors, to purge the reservoir. In a recent editorial in AIDS, Janice Clements calls for a pause, arguing that these drugs could put the HIV brain reservoir beyond control. Would you also say ‘pause’ or ‘let’s do it and see’?
RCG: I would say lets do it in monkeys and see. And if the monkey experiments pan out properly, I would go forward.
AL: With the financial crisis, is it possible to fund both access to care in poor countries, research for a cure and research for a vaccine, or has a choice to be made?
RCG: I am not sufficiently smart in regards to economics and sociology and I would be a very bad person to give advice in such matters. However, at a minimum I can say with certainty that we have to bring therapy to Africa and some of the other developing nations as priority number one. And after that, hosted by governmental agencies and foundations we can keep up the other needed research. Certainly we must find money for vaccine research.
AL: You were quite a pessimist a few years back about HIV vaccine research. Your Institute is currently working hard on it: what caused the change, and what is the agenda, if you can tell?
RCG: Well I never thought it was impossible to get an HIV vaccine. The proof of that is that I’ve been working on it since the field began – admittedly on again, off again.
The pessimism was because some of the candidates chosen to go into trials were not built on science and should not have gone forward.
My second concern was that there were not a sufficient number of available primates (monkeys) for research studies and that the studies took a long time to contain any kind of conclusive result.
The third reason for some lack of enthusiasm was the fact that HIV integrates and this fact demands we achieve real blockade early, presumably by antibodies, and that we keep the antibodies lasting a long time because an integrating virus doesn’t allow us time to develop an appropriate immune response, a consideration that has not received enough appreciation.
I am, in recent years, more optimistic because at IHV we can now see a pathway toward an HIV preventive vaccine.
I am, in recent years, more optimistic because at IHV we can now see a pathway toward an HIV preventive vaccine....We have obtained the most interesting results in the past three or four years. I am hoping we will be in clinical trials soon and I can at least promise that the approach is logical, and based on scientific results.
We are actively working on our approach through the support of the US National Institutes of Health (NIH) and especially the Bill and Melinda Gates Foundation. We have obtained the most interesting results in the past three or four years. I am hoping we will be in clinical trials soon and I can at least promise that the approach is logical, and based on scientific results. What is IHV’s approach? It is based on attenuated gp120 envelope protein. The modification is in linking gp120 to the region of CD4 that binds gp120. This interaction stabilizes the otherwise mobile gp120 which makes targeting critical regions of gp120 difficult. It also “opens” gp120 so there is more exposure of sites, such as the CCR5 co-receptor binding areas of gp120, that are functionally required for HIV to infect its target cells. Importantly, these sites are conserved, i.e. they are not variable, so there is not so much the problem of escaping antibodies due to HIV stain variability.
Key words: HIV cure, HIV reservoirs, HIV vaccine