8.6 David Baltimore — Bringing it to an End (And Where Are We Going?)

David Baltimore: [00:00:00] This has been a great event, and I'm honored to be part of it and having an opportunity to finish it up. It is impressive to see how much can be learned in 35 years of research, and how you take a challenge that's put up by [00:00:30] nature and apply science to it. Of course, it also reminds us that probably the greatest failure of modern molecular biology is that we haven't been able to control HIV and that we are still in the midst of an epidemic.

My own involvement in it came accidentally. It was that, [00:01:00] having discovered the reverse transcriptase and therefore been involved in retrovirus research, when HIV was discovered I took an interest in it and followed what was going on but wasn't involved myself. Then in 19, I guess, probably 1985, I was approached to head [00:01:30] a study by the National Academy of Sciences. That came about because it was understood in the scientific community that we weren't putting all of the effort that we could into trying to understand HIV for a lack of resources and a lack of visibility of the problem, largely held down by the unwillingness of [00:02:00] politicians at that time to even speak about HIV or gay men.

And so the National Academy of Sciences had decided that they would try to look into this situation. I was approached at a cocktail party at MIT by Walter Rosenblith (1913–2002), who was then in the [00:02:30] academy hierarchy, asking me whether I would be willing to be a co-chair of that with a clinical person, Shelly Wolff (1930–1994), as it turned out. I said it seemed to me that history had thrust me into a position that I couldn't get out of and that I certainly would do that. It was a very fast study one of the fastest the Academy has ever done. It was also, when we published Confronting AIDS [00:03:00] as a book, one of the best sellers of all the academy studies. (1) The best up to that time. I haven't followed it since then.

Two of the things we said in there are worth commenting about. One is that right at the end in the last session of the meeting of this group—and I don't [00:03:30] think any of you here were part of that group—Oh, yes, [Paul Volberding]. I said to the assembled group, "There's one thing lacking here. There's no number." I was, by that time, aware enough of politics to realize that numbers are what get headlines. We needed an amount of money [00:04:00] that we were asking for. I said that amount of money should be a billion dollars. A billion dollars in 19—it came out in 1986—was a lot of money. It's really interesting to see how it's been degraded in recent years by all of these billionaires. I took the [00:04:30] number out of my back pocket. It was nice and round and simple and eye-catching, because that was against an NIH research budget which I can't remember but it was a significant fraction of it. Everybody gasped and then recognized the political value of doing that and we all got behind it. It wasn't the number that we calculated on [00:05:00] any rational basis. It was impressive to see that a couple of years later we were spending a billion dollars on HIV research and that that study I think had a very important effect.

It had another effect on me because one of the things we called for in there was for people who had experience with retroviruses to at least move some of their research efforts to looking [00:05:30] at HIV. HIV, we knew by that time, was quite different than standard retroviruses. But these were people who had experience with thinking about the overall class of viruses and could make a contribution. I must say I have always been unhappy about how little response we got to that call from senior retrovirologists, but that's another story. [00:06:00] 

However, from my own point of view, it became clear to me that I had to listen to that admonition. And so we began to study HIV in my own laboratory, and over the years we've worked on many different aspects of it. I'm not going to try to review all of that, I don't think it's useful or necessary. We worked on Nef, on the effect of the virus on the host cell.

Audience 1: [unintelligible; laughter]

David: You only think you're driving.

Audience: [unintelligible; laughter]

We worked on models of latency years ago and we discovered NF-κB in 1986, actually [00:07:00] and showed very rapidly that it was key to the transcription of the viral genome, work of Gary Nabel who's gone on to be quite notable. I'm not going to try to show slides of that sort. This, I'm going to get to in a minute. But I do want to say that HIV probably is the best [00:07:30] understood virus on the planet today. That is because of the response of the federal government in devoting, like, 10% of the Infectious Disease budget to—or maybe the NIH budget, sorry—to HIV research for so many years. And it has given us the very wonderful people that we've heard [00:08:00] speak at this meeting and many others whose work has been supported and whose intelligence is able to be focused on this problem.

We now know that HIV is some funny artifact of the transmission of a monkey virus through a chimpanzee to humans. I say it's an artifact because it's mutated so ferociously in its attempt [00:08:30] to adapt to transmission in humans that's giving it characteristics like no other virus we know. It is not a natural virus like polio or measles which have such tightly focused structures. Even flu which is attempting to adapt all the time because it's young to our species, doesn't mutate with anywhere near the ferocity [00:09:00] of HIV. That's a perspective we just simply live with and it really dominates so much of the discussion we've had here.

It is also in another sense an artifact, it's an artifact of modern civilization with the various modes of transportation that have developed with the huge cities that we have today with just the various ways that humans interact [00:09:30] with each other. That's giving us lots more viruses and it's something we shouldn't forget. Zika, SARS, and the like are easier to deal with because they don't have that same ability to go under the radar for so long and to then appear the way HIV did.

Our challenge really is to put this genie back in [00:10:00] the bottle. It's to stop the spread of HIV and to control the virus in those who are infected already, so that we can let it die out. To do that—I think still and I said this the other night—I think we still have to make a vaccine that we can't stop our focus, and we're not on finding a way to make a vaccine even though the virus doesn't lend itself to control [00:10:30] by the natural immune system very well. We need to be able to treat all infected people well enough so that they won't transmit the virus.

A cure is a good thing to have but actually, I don't think is on the critical path to the control of a virus but the conundrum of the reservoir and how the reservoir can [00:11:00] ever be controlled is a great scientific challenge and it may turn out to be, as we saw in some calculations, an inexpensive way of—

[background conversation] [laughter][00:11:30]

The other side of it, of course, is the vaccine. And my feeling is that I'm a little more hopeful in hearing what we heard yesterday than I have been in a long time, but I still think we've got a long, long way to go and we don't know that we'll ever have [00:12:00] a standard vaccine. We're learning an enormous amount along the way about the balance between viral mutation rates and antibody diversification rates, which is fascinating immunology and is really going to be the core information from which all of vaccinology is going to draw in years of the future. It's, again, important [00:12:30] and terrific science. But I am still worried about whether it will get to where we need to be.

We've actually in the last years focused on whether there are other ways of approaching prevention other than standard vaccination, that is giving people a protein or an immunogen of some [00:13:00] sort, and allowing their immune system to do the work of preventing infection and whether we can in some way program the immune system to do what it is, we really want it to do and we know about that well enough, and that is to make monoclonal antibodies—to make antibodies of the quality of the monoclonal antibodies that are so effective in breadth and potency that have been [00:13:30] found in the last decade or so.

I want to show a couple of slides and that's what this is about and most of you will know that I know, that show one way to do this. And I mean, it is only one way to do this and encourage people to think about other ways and that's what we've called [00:14:00] [vectored] immunoprophylaxis or VIP, a form of presenting the genes for monoclonal antibodies to the body, which can prevent infection and experimental animals and which we are trying to get into clinical trials. I'll mention that last perspective to it in a minute, I'm just going to show a few slides.

We've focused on [00:14:30] AAV (adeno-associated virus) as a carrier for antibody genes because AAV is non-pathogenic in humans, it's actually non-integrating as a vector. It has excellent expression, it grows to high titers, it's easy to deal with and it has a history of using humans and it is the only approved gene therapy vector—approved in Europe actually not in the United States—by regulatory authorities [00:15:00] and I would predict it will get increased use over time.

Its negative characteristic is that it's very small, you can just—have to squeeze tight to get an antibody gene in there. But you can squeeze tight, and you can put an antibody gene into the vector, use it to a sequence between the heavy chain and light chain, provide other goodies and get a good [00:15:30] vector. That vector works best when it's directly injected into muscle and we've shown that in a variety of ways.

When it is injected into muscle, it will produce antibody or other proteins. It's not at all specific for antibodies, it's just that's what we care about and it will last for the lifetime of a mouse and there's evidence that it will last for a decade in humans, [00:16:00] and maybe longer. If you look at mechanistically, there's no reason why it shouldn't last forever in a human, because once it gets into the nucleus of a muscle cell, it sits there as a plasmid churning out RNA which then goes on and encodes relevant proteins.

If you inject it into a variety of mouse strains, some immunodeficient, some wild type, in all of them it grows up to [00:16:30] a titer the antibody goes up in the blood to a level of between 100 micrograms per mil and a milligram per mil, which is an enormous amount of a single monoclonal antibody. And so there's no question about its ability to encode at least in experimental animals sufficient antibody. [00:17:00] 

We showed in humanized mice, where we'd put in human PBMCs, that if you don't have antibody on board, you kill CD4 cells and if you do have antibody on board, you can totally protect CD4 cells using all the old b12 antibodies. In this case, we use other ones that are better [00:17:30] than that now. But this was effectively sterilizing immunity. We looked around for any nidus of infection which you can see if you express luciferase. But if you express the antibody, we couldn't find in any sections, any evidence that there was infection of any sort. It was non-detectable.

A number of other monoclonal antibodies that we studied in this particular case, all left detectable virus growing, [00:18:00] and in many cases that was mutant virus. So the B12 antibody, or in fact, any antibody that goes deeply into the CD4 binding site seems to give the sterilizing immunity.

We've done the same thing. And actually we weren't involved in this, but a group at the VRC (NIH Vaccine Research Center) where Gary Nabel was the director at the time [00:18:30] did this in non-human primates. (2) You have to do some tricks for a variety of reasons I can go into it, if anybody cares. But animals that are not protected get infected, animals that are protected don't get infected, except for one animal that actually had very low levels of antibody in its circulation. This works in non-human primates.

Just in summary, [00:19:01] you get robust production of antibody, it's long-lived, it goes to mucosal surfaces, we can show that, it protects against mucosal infection, we have shown that. You get precise tuning of the antibody concentration by a function of the dose of virus that's administered, you can get protection against HIV infection even with high dose challenges, and with relatively low vector doses [00:19:30] and as I said, it's effective in non-human primates.

So, it's obviously should be an object of clinical investigation. We've teamed up with the Vaccine Research Center at NIH to do that clinical evaluation. The FDA did approve a general trial design, but now has some issues. We have manufactured vector and that's complete by GMP manufacture [00:20:00] for a trial. We hope to be able to learn, whether we can make the kinds of antibody levels in humans that we can make in experimental animals, and to know whether it's safe or not. But it's gotten stalled. It's gotten stalled for reasons I don't fully understand, but it's driving me crazy. I'm just going to complain I'm not going to explain.

You can control other pathogens with VIP. VIP is an interesting platform. [00:20:30] Various people we've worked with on flu, malaria, hepatitis C, even on this funny situation of butyrylcholinesterase which hydrolyzes cocaine, and Steve Brimijoin showed that you can express that in a mouse and make the mouse immune to the effects of cocaine. That's a quick romp through that and a short complaint [00:21:00].

This is only one of other strategies that could be imagined. For instance, we talk about T cell control of the virus. And T cells obviously do a fabulous job of controlling the virus in the right circumstances. Could we use T cells? Could we engineer T cells? Well, in the cancer field, we're engineering [00:21:30] T cells all the time now. What we do is put in, for instance, a T cell receptor gene, or a CAR (chimeric antigen receptor), which are generally more effective for the moment, into a population peripheral T cells. They're expressed on the surface of those cells, and those cells then go and kill tumor cells. They can, in fact, provide a complete cure for tumors.

Could we do the same sort of thing? [00:22:00] Well, I think the answer is, we should be able to do that. The question is, what T cell receptor to use? We combined our efforts with those of Bruce Walker, who has shown that there are T cell receptors in elite controllers that are very specific for HIV peptides in the context of the MHC (major histocompatibility complex) of the controller, in particular B27, which is [00:22:30] a particularly favorable situation. I'm not going to show any slides for this. We've gotten out the T cell receptors from these patient cells. We can show in the context of B27 that we can kill cells in vitro. We, in this case, is Alok Joglekar, who's a postdoctoral fellow with me. [00:23:00] We've cloned it into a lentivirus vector. We studied that in humanized mice, and you get a pretty effective control of HIV in humanized mice. We're still in the midst of those experiments. We're going to try to move this into clinical investigation, with an understanding that it's a complicated way of going at the problem [00:23:30] because of the diversity of MHC in humans.

I can just point out that this is one example of one of the tremendous spin-offs from the HIV epidemic, which is the ability to use the vectors for gene therapy. Gene therapy is the form of control of [00:24:00] medical issues that is the most exciting today, at least to me, and really has benefited enormously from the understanding in-depth of HIV. As we were talking about earlier in the break, George Shaw's discovery of peptides from the 5' end is something we have to now take into account [00:24:30] in thinking about vectors.

That's a number of thoughts about where we might go in the future, and comments on where we have been. I want to thank the organizers for giving me the opportunity to speak but more importantly, for the effort to bring forward this meeting. It is really interesting to see how exciting it is to have a [00:25:00] presentation of these questions in their historic context rather than the usual meetings that we have, which started what was going on the day before and move forward from there.

Thank you.

[applause] 

Ashley Haase (moderator): Flossie. [00:25:30].

Flossie Wong-Staal: Thank you. This may not be directly related to what David talked about but I wonder if anyone can make a mathematical model, that if you can keep all the infected people at undetectable levels or even low enough so that they don't transmit the virus, how long it would take for the virus to disappear?

David Baltimore: It depends on what you assume about transmission. [00:26:00] If transmission were completely stopped—David, you want to—

David Ho: One generation.

David Baltimore: One generation, yes.

[laughter]

Flossie: Wouldn't that be a more feasible goal than something else?

David Baltimore: 37 million people have to die not of HIV but of time [00:26:30] and then it would be gone. I mean, you're right. That's exactly what would have to happen.

Paul Volberding: David, I'm Paul Volberding. I was the other person on that IOM committee. A couple of things. As I remember it, the $1 billion came in part because Shelly Wolff made some envelope calculation that we were spending about a billion dollars a year on the treatment of people with HIV at that time. As I remember it, [00:27:00] you said, "Well, then we should be spending a comparable amount on the research." I'm not sure that my memory is right or not. I also remember saying, "Gee, this is such an impressive committee. David Baltimore and all these people, how do I join this organization?" They looked at me and said, "You have to wait a while."

[laughter]

Ashley: Go ahead.

Monica Green: Thank you. What do we do for the next [00:27:30] HIV? The discourse about emerging--

David: Prayer. Pray there isn't one.

[laughter]

Monica: The historians' question is there has been a discourse about emerging diseases, as you know, since 1992. HIV has been the poster child of that. There's a lot of disease surveillance and so forth. What would you say is what can be done in terms of [00:28:00] scientific infrastructure that would have made anything go faster? Just the biological possibility of some new kind of pathogen arising. We don't even need to talk about the odds for that. What, in terms of scientific infrastructure, could be in place now that would be better prepared to deal with something that is as new as HIV [00:28:30] was as an organism?

David: I think the answer is surveillance. We have to continue to be aware of every new challenge that's put up by the natural world because there are tens of thousands of viruses out there any one of which could give us a surprise. Complacency is our worst enemy. [00:29:00] We don't have sufficient focus on public health issues on surveillance. Something which we've been talking about just among ourselves upfront here in the last day is the increasingly smaller cadre of students going into infectious disease research or infectious disease treatment even. That there are 100 [00:29:30] places for infectious disease fellows that are not being filled today because young medical students are just not interested in going that direction. That is a disaster in the making. We need that kind of expertise for the next epidemic. Nevermind for all the things that we face already.

The real hope, I think, [00:30:00]. is that HIV is a singularity. HIV, as I say, was under the radar screen for a long time. Maybe the evidence is for decades, before there was even a hint of it, and then once there was a hint it had already spread quite widely in the world. That's not true of things that SARS  and MERS  [00:30:30] and Zika  and whatever, and they're also quickly self-limiting diseases. Either they cause their awful effects or they don't, but they do it quickly.

I think most viruses are of that nature. The huge reservoir of flaviviruses, bunyaviruses that we know exist in Africa and elsewhere are [00:31:00] viruses that probably we would detect as they got into the human population because of their relatively dramatic symptomatology and because of the speed with which they work.

Ashley: Robin, one last comment/question before lunch.

Robin Weiss: David said it for me. HIV was unique and it had 60 years to get going below the radar. In the historical context, I think it's different. [00:31:30] Read Jacques Pepin's book on the history of AIDS. (3) It's one of the better ones.

[background conversation]

Susan Zolla-Pazner: I think that we learned something from the RV 144 (2003–2009) story and that was that within two years after the announcement of partial protection in RV144, there [00:32:00] was money out and research being done all around the world to figure out what the correlate was. The reason for that that we moved so quickly was that the money came from the Army, not from the NIH. The Army, the Armed Forces are in a position to move money quickly when there is a problem. All you have to do is look at what's going on with the funding for Zika this year [00:32:30] to know that that is definitely not the case for most public health issues. One answer is to give the NIH some sort of a slush fund with which to respond to true public health emergencies.

David: Protect the NIH from Congress.

[laughter]

[00:32:54] [END OF AUDIO]

Citations

1. Baltimore, David, Sheldon M. Wolff, and National Academy of Sciences. Confronting AIDS: Directions for Public Health, Health Care, and Research. Washington, D.C.: National Academy Press, 1986.
2. Saunders, Kevin O., Lingshu Wang, M. Gordon Joyce, Zhi-Yong Yang, Alejandro B. Balazs, Cheng Cheng, Sung-Youl Ko, et al. “Broadly Neutralizing Human Immunodeficiency Virus Type 1 Antibody Gene Transfer Protects Nonhuman Primates from Mucosal Simian-Human Immunodeficiency Virus Infection.” Journal of Virology 89, no. 16 (August 15, 2015): 8334–45. doi:10.1128/JVI.00908-15.
3. Pepin, Jacques. The Origins of AIDS. Cambridge: Cambridge University Press, 2011.

Index

• 1.4 Robin Weiss — Retrovirus History and Early Searches for Human Retroviruses
• 2.1 Paul Volberding — The First Patients
• 5.1 Flossie Wong-Staal — Discovery of Human Retroviral Transactivators
• 6.3 Bruce Walker — Role of T Cells in Controlling HIV Infection
• 8.2 David Ho — Unraveling of HIV Dynamics In Vivo
• adeno-associated virus (AAV)
• antibody, immunoglobulin (Ig)
• blood — banks, donors, plasma, screening, transfusions, clotting factors (factor VIII), PBMCs
• chimpanzee (Pan troglodytes)
• clinical trials (phases of clinical research)
• Congress, US
• disease surveillance
• drug safety
• epistemic object becomes the technical object
• Europe, European Union
• FDA (US Food and Drug Administration)
• Flavivirus
• funding and grants
• gay men, gay community
• Green, Monica H.
• hepatitis
• HIV vaccine
• humanized mouse
• immunology
• in vitro vs. in vivo
• infectious disease (medical specialty)
• influenza
• Joglekar, Alok
• lab vs. clinic
• luciferase
• major histocompatibility complex (MHC)
• malaria, Plasmodium
• measles
• mechanism
• medical school, residency, and fellowship
• memory
• MERS (Middle East respiratory syndrome)
• mice
• military service and "Yellow Berets"
• MIT (Massachusetts Institute of Technology)
• models (model systems, model organisms, modeling)
• molecular cloning
• monoclonal antibody
• Nabel, Gary J.
• National Institutes of Health (NIH)
• natural selection, evolutionary selection, evolutionary fitness
• nef
• NF-κB
• NIH Vaccine Research Center (VRC)
• non-human primates
• PNAS (Proceedings of the National Academy of Sciences)
• polio, polio vaccine 
• public health
• reverse transcriptase
• Rosenblith, Walter A. (1913–2002)
• RV 144 (2003–2009)
• SARS (Severe acute respiratory syndrome)
• sensitivity and specificity; false positive, false negative; biological specificity
• Session 7: Prospects for an HIV Vaccine
• spillover, zoonotic disease, xenotropic virus
• vectored immunoprophylaxis (VIP)
• Wolff, Sheldon M. (1930–1994)
• Zika