HIV Positive, and Deadly

Dr David Baltimore speaking on the occasion of the third annual Nelson Mandela Science Lecture at Wits University in Johannesburg, South Africa

Pigs with blue ears, Italians with an African infection, birds dying by the millions, beehives collapsing worldwide, 40 million people living with chimpanzee’s infection—what do all these have in common. They all show that viruses are not stable parts of our ecology; they show that viruses mutate continually and can change their properties dramatically. They show that all species, but especially humans, are at risk of infections with viruses that explode out of nature with little warning. This is my topic today, how viruses move around continually, presenting the world with one of its greatest challenges.

You may be disappointed to hear that I am going to talk about viruses. After all, this is the Nelson Mandela Lecture and he is such an extraordinary personal hero, such a deep thinker, such a committed man. Shouldn’t a lecture in his name say something about the world condition or about personal heroism or about bringing peace to the world?

My job here is to convince you that viruses are a threat to peace in the world, a threat to economic development, a threat requiring selfless devotion to our communities. And in particular HIV is threat to all nations that do not mount an offensive to counter the virus. There is hope but only if we recognize the nature of our enemy. I think it is a topic worthy of being considered in the name of Nelson Mandela.

But to do this I need to make sure that we all understand what a virus is. So I will start there and then broaden out my concerns with a special focus on human immunodeficiency virus, HIV, the cause of AIDS.

A virus is the simplest form of life that can exist. It is a tiny object, pared down to only the essentials for living. It is so simple that it cannot carry out any life process on its own, it must find its way into a living cell where it commandeers the machinery it needs to multiply itself. Our bodies are made of cells and each cell has a set of instructions encoded in DNA that runs the cell. A virus is really nothing more than an alternative set of instructions that can take over the cell and make the cell into a virus-producing factory. As in our own DNA, the instructions are broken up into genes. Because viruses put such a premium on being small, the virus’s genes are notably compact but also notably changeable. The rapid change means that a virus can readily adapt itself to new circumstances. All cells have viruses that grow in them.

In my lexicon, viruses come in two forms; I call them equilibrium viruses and non-equilibrium viruses. The equilibrium viruses are highly adapted to a particular species and grow only, or mainly, in that species. In humans, polio, smallpox, measles and mumps are examples of equilibrium viruses. All of these grow solely in humans; that is why they are candidates for elimination: they have no animal reservoir so if we eliminate transmission among humans, there is no virus left on earth. We have done this for smallpox; for polio we are close although we presently seem to be losing the battle.

Equilibrium viruses are dependent on a single host species and therefore it is not in their interests to kill off the species. That fact is thought to be behind the relatively temperate nature of such viruses—many cause no disease at all and none are highly lethal. Even the worst, smallpox and polio, were only rarely lethal.

It is the non-equilibrium viruses that are the most dangerous ones. These are viruses that can infect members of a particular species but are not highly adapted to that species. They are equilibrium viruses of one species but have the ability to cross to another species and in this non-equilibrium setting, they can wreak havoc. Most of the time, when a virus jumps species it will burn itself out without adapting to its new host. But occasionally a virus has the ability to maintain itself in the new species and that’s when the trouble starts. In its new host, the virus many have no interest in being temperate, if I can speak anthropomorphically. So it may be very lethal. What are examples?

Ebola virus is a good case to think about first. It seems to be an equilibrium virus of bats. But humans have enough contact with bats that occasionally it infects a human. The person gets very sick very quickly and usually dies, but can sometimes pass the infection to close associates or medical personnel. Then the virus is said to have “emerged”. Ebola emerges every few years in places like the Congo—it has recently emerged there and is still spreading although it may be largely contained. A virus like this responds well to quarantine because an infected person gets sick before he or she begins to spread the infection. So isolation of sick people can stop the spread. This is presently the strategy in the Congo and it seems to be working.

SARS is a very similar case. It emerged in China in 2003, again probably from bats but with civet cats as an intermediate host, and spread widely in the world because infected people traveled abroad, carrying the infection. The lack of transparency on the part of Chinese officials let it get out of hand. But when quarantine procedures were finally instituted, the infection rapidly burned itself out and has not reappeared except for infection from a laboratory working on the virus. It was fairly lethal but killed fewer than 1000 people worldwide.

Influenza virus is a contrast. Known affectionately as flu, it is an equilibrium virus of migratory birds that infects humans poorly and rarely. But it is poised to change into a virus that can be efficiently spread among humans. This happens with some frequency, often by infection of domestic birds on farms and then passage of the virus, perhaps through pigs, to humans. This virus then spreads widely and is not stopped by quarantine because it can spread from person to person before the spreader gets overtly sick. Viruses like this are major threats if they also are highly lethal. We believe that in 1918, just such a highly lethal flu strain emerged and caused perhaps 20 million deaths. We are now worried that a lethal flu in birds is preparing to jump again to humans and the world is taking action to respond to this threat.

This is not the only case an emerging virus that takes hold in people: West Nile virus, for instance, a virus that is spread by mosquitoes, has spread from Africa recently and now is endemic in much of the world—luckily it is usually not fatal. Its prevalence in the United States now is remarkable considering that it was unknown a few years ago. And a virus with the difficult Swahili name of Chikungunya has caused 160 cases of disease in Italy this summer and may spread further in the future. It may be a case of global warming allowing a mosquito vector to live in a new environment to transmit this disease.

And humans are not alone in being threatened by viruses. Bees are dying throughout the world, apparently of a virus infection that was first detected in Israel but may have originated in Australia. And pigs in China are dying with blue ears in huge numbers, raising the price of pork. Again, this seems to be a spreading virus. There are continual unexplained die-offs in particular species, often birds, that probably involve other viruses but people don’t spend the time and money to find the cause.

I have related these horror stories because I want this to be the background for understanding the emergence of HIV. It is important to understand that HIV is just another virus that has emerged from an animal reservoir. I think people tend to believe that HIV is some special and unique plague of the human race. It is not, it is a relatively small virus. It has characteristics that make it particularly dangerous but these should be seen in the context of the many infectious diseases with which we contend. Let me tell you what is known now about where HIV originated.

HIV was originally a chimpanzee virus. We know that because scientists have isolated a very similar virus from chimpanzee. The most convincing experiments are come from a huge collaborative group lead by Dr. Beatrice Hahn in Birmingham, Alabama. In this work, Africans collect the feces of chimps living in the wild. These samples are then preserved and sent to the United States where Dr. Hahn isolates the genetic material of the chimps and their viruses. She can sequence the chimp virus and show that it is a very close relative of HIV. She can also identify the chimp who left the droppings, know it is a chimp and not, for instance, a gorilla and identify it again if a second sample is from the same animal. The best isolations have been done in Camaroon, in West Africa. These isolations strongly suggest that Camaroon or a near neighbor is the place where HIV emerged.

Actually, the emergence of HIV took place as many as 8 decades ago but we did not become aware of the disease until the early 1980’s. The earliest sample from which virus was isolated dates to 1959 in the Congo. What took the virus so long to spread? The answer seems to be that HIV is transmitted slowly and inefficiently. The first isolate was probably in 1959. My guess would be that it emerged often before that but burned out before it adapted to humans and found a fertile ground for transmission. It seems likely that modern transport played a significant role in its spread.

How did HIV emerge from its chimpanzee origin? That is hard to answer but chimps, as bushmeat, are human food in West Africa, so a likely scenario is that the virus was passed to humans during the preparation of bushmeat.

Interestingly, chimps can be infected for many years with no evidence of disease. In laboratories, chimps can be infected with HIV and, although the virus grows well, it rarely causes symptoms. This remains a mystery; why should it be pathogenic in one species and benign in a closely related one? This is not a unique occurrence, a related virus in monkeys causes no pathology in the species where it naturally resides but can cause an AIDS-like syndrome in other monkeys.

The virus itself has an idiosyncratic internal structure but is basically similar to other viruses.

Once HIV emerged in West Africa, it must have been spread slowly to other parts of Africa and finally to Europe and the US. Infected people moving by car, truck or airplane seem the most likely vectors. There is a famous story of a gay airline cabin attendant who may be been responsible for a lot of the early spread. Gay men were likely the main spreaders out of Africa because they are so promiscuous but AIDS is no more a specifically gay disease than any sexually transmitted disease. Sex is convenient way for pathogens to spread among humans and many viruses and bacteria use this route of spread. For HIV, sex and sharing of injection needles has proved a very effective mode of spread. There are now some 40 million people worldwide living with HIV infections and 3.1 million die each year.

Now let’s turn to those characteristics that make HIV so deadly. The main characteristic is one we recognized very early, that HIV causes a chronic disease in which the virus is present at high concentration in the blood for many years. This shouldn’t happen. In most chronic viral diseases, the virus hides away, often in nerve cells, and is not in the blood. Our bodies have a powerful immune system designed to kill pathogens that do not hide away—the most remarkable fact about HIV is that unlike other viruses, it is not cleared by the immune system.

Lets look more closely at the immune system. For those of you who know a lot of immunology, I will admit that I am simplifying the picture and only talking about the adaptive immune system, not the innate one. For others in the audience, you can ignore that sentence. The immune system has three arms. One is B cells, which make antibodies. These are proteins that circulate in the blood, bind to viruses and kill the viruses. They are our main defense against viruses. The second arm of immunity involves cells called killer T cells: they carry receptors on their surface that recognize when cells are infected and kill those cells. They do this because an infected cell puts a flag on its surface that says, I’m infected, kill me. There is a third arm called helper T cells; they help the B cell make antibody and the T cells to kill. They are quite critical because without them the B cells and killer T cells are not very effective.

Now I can tell you about HIV. It has evolved to be largely resistant killing by antibody. It does this in number of ways but the simplest is that carries a coat of sugar that hides the virus from immune attack. If an antibody does appear that could kill HIV, the virus just changes its structure a little and eludes the antibody. It is sensitive to killer T cells but they are unable to totally clear it. And finally, HIV kills the helper T cells, so the whole immune system is compromised.

It is actually unprecedented that a tiny virus can so completely neuter the immune system. But because of this, the only way to control an HIV infection is with drugs that stop the virus from growing. And as you know, many very effective anti-HIV drugs have been developed by the pharmaceutical industry and they are now available worldwide. But better than treating HIV infections would be to prevent them, so let me turn to efforts at prevention. The best prevention we have today is education.

The medical community’s optimum method of preventing viral infection, one we use all the time, is immunization with a vaccine. What we do is give people a surrogate viral infection and thus stimulate the immune system. Then, when the real virus comes along, the immune system is primed and reacts quickly and strongly and prevents any harm from occurring. We have made vaccines against many of the viruses that infect humans like polio, smallpox, mumps and measles. The equilibrium viruses are generally quite sensitive to vaccines. Vaccines can also control some non-equilibrium viruses.

So how about HIV? Well I’ve told you that HIV is not controlled by the immune system so it should come as no surprise that making an HIV vaccine has been very hard. Most vaccines work by stimulating antibodies and as I said earlier, HIV is particularly insensitive to antibodies. This hasn’t prevented scientists from trying to make an antibody-based vaccine but they have been notably unsuccessful after years of effort.

But there is a second arm of immunity, the killer T cells. Maybe they could stimulate to provide protection. This idea has been the leading idea in HIV vaccine research for the last decade. It is very difficult because there is no precedent for a killer T cell-based vaccine but it sounds possible. Remember that killer T cells look for flags on infected cells and kill them. So to make a vaccine that will stimulate the killer we need a surrogate way to put the flags on cells. We have that because the flags are actually made of small pieces of the virus and so we need to have infection of cells to make the flags. These flags are actually little pieces of viral proteins and like all proteins their synthesis is controlled by DNA. So to make a vaccine we need to get the DNA that encodes these flags into the cells of the body. We can do that by methods of gene therapy and actually all vaccines for stimulating T cells are a form of gene therapy in which viruses carry potentially protective DNA into the body’s cells. This is one of the only good things that viruses do for us.

The Merck pharmaceutical company has made such a vaccine by using a common cold virus, called an adenovirus, to carry the DNA that encodes the flags and they hoped that they could raise immunity to HIV in this way. They got very promising results with such a vaccine in mice and then in monkeys so they took it to human testing.

Last week Merck announced the results of first clinical trial of this idea. To the horror of all of us who were hoping that the vaccine would show at least a little efficacy in humans, it proved to be totally ineffective. Actually, more infections occurred in the group that received the vaccine than in those who got an ineffective placebo. And the amount of virus circulating in the vaccinated people was not different than in the unvaccinated ones. Merck was starting trials in Africa but they have put those plans on hold.

This is huge setback for the HIV vaccine field and therefore a huge setback for humanity. I do not have to tell you how desperately the world needs an HIV vaccine, a way to prevent the spread of the virus. There are other vaccine candidates in the pipeline that are a little different from the Merck vaccine but tests of them are now on hold while the full results from the Merck experience are analyzed. I believe that one new vaccine concept will be tried next year but it is difficult to expect that it will give a qualitatively different result. Of course, even a glimmer of efficacy would be wonderful because it might tell us in which direction to go.

I have been involved with work on an HIV vaccine for more than 20 years. At all times I have said that a vaccine is at least 10 years away. I am sorry to say that I still have the same opinion.

The implication for South Africa is that our only hope to blunt the spread of HIV at this time is education. I am quite aware that the topic of AIDS is controversial here but as a scientist and someone who has devoted much of the last 2 decades to this problem I can only tell you what I believe to be true. Transmission of HIV can be reduced but it will take action on the part of every individual at risk. It is virus spread in two ways, by sexual contact and by contaminated blood. People need to protect themselves by using condoms during sexual intercourse because we have no other protection today. Maybe one day we will have a microbicide so that women can protect themselves. And we must avoid giving injections to multiple people with the same syringe meaning we need to provide free syringes to intravenous drug users. These are not difficult or even very expensive actions. However, they take honest educational advice, spread to everyone in the population and having the imprimatur of the highest authorities in the country. This works, as shown particularly by the massive drop in HIV infections in Thailand. At the moment, and probably for at least 10 years more, this is all science has to offer.

But lets look at the question of what science might do to change this perspective. Conventional ways to make an antibody-based vaccine have failed but might there be unconventional ways to approach the problem. One T-cell vaccine has failed but maybe there other ways to approach the problem. Actually, a number of years ago I was already feeling very glum about the prospects of an HIV vaccine coming from any on-going research. And I started saying to anyone who would listen that we needed to think about unconventional ways to approach the problem. I got very little response from anywhere except from my own head, which started thinking about what an unconventional approach might be. What I realized was that that we had neglected to bring into the battle the best weapon we had.

For the last 50 years, led by America, the world has seen a revolution in the biological sciences. In 1950 we had no idea how biological systems work, in 2007 we know a lot about how they work. We know that they are controlled by the molecule DNA, we know about many of the little machines that make things move, that generate biological energy and that control the growth and function of cells. We have learned that cancer is a disease rooted in the misbehavior of a cell’s genes and know many of the culprit genes. All of this knowledge came about from new technologies—every year that I have been involved in research new technologies have appeared that made research easier, faster and more powerful. And not only has this generated a revolution of understanding, it has spawned an industry, the biotechnology industry, that turns biological knowledge into agents that help to fight disease. Today the biotechnology industry is producing the majority of new drugs that get regulatory approval; the old pharmaceutical industry is much less innovative and less effective, in spite of spending many billion of dollars on research. This was the weapon we had not been using, the weapon of biotechnology. And why had we neglected it. Because vaccination did not seem like something that biotechnology could improve much. Maybe biotech could make new vaccines but as far as we could see, they would still have to work in the same way. But there is a new way, and I touched on it before. It is gene therapy, the one good thing that viruses can do. And interestingly, the virus that is a natural for this role is HIV itself. It is a retrovirus: that means it gets into it a cell, makes a DNA copy of itself and then integrates that DNA with the cell’s DNA. It is designed to bring genes into cells. So, what genes might be good ones? Remember we said that the immune system is a natural enemy of viruses but HIV can elude its attack. That suggests that maybe we could design in the laboratory new genes that could make the immune system stronger, able to cope with HIV. So, we are doing just that. In fact, I am in South Africa because the Gates Foundation has brought together many of its grantees to report on progress and they are funding my idea.

I want to end this talk with a reminder. HIV is awful but the natural world harbors on untold number of viruses anyone of which could be as bad. We need to be ever vigilant, watching out for new emerging viruses that could take hold in the human population and cause more misery. Africa is the cradle of human evolution but it is also the cradle of evolution of many other organisms. So Africa has a special responsibility to be alert to any new disease. That is hard when so much of Africa is poorly developed and its people are therefore prone to so many diseases. The world is willing to help but that means being open to public health officials who want to protect the world from the next Ebola, the next flu and the next HIV. Asian counties have not been a good example—particularly the Chinese who held back important information, unnecessarily allowing SARS to spread.

Emerging viruses can be so devastating that they can represent a threat to established society. The great plague was that in the Middle Ages and our modern plague of HIV is another reminder. But we have the ability to counter this threat if we combine openness, rigorous analysis and international cooperation. Dr. Margaret Chan, the new Director General of the World Health Organization said in her first annual report that new infectious diseases are emerging at an “unprecedented rate”. She goes on, “Given today’s universal vulnerability to these threats, better security calls for global solidarity. The new watchwords are diplomacy, cooperation, transparency and preparedness.” [Reported by Elizabeth Rosenthal in the NY Times of Aug. 27, 2007, pg. A9.]

Meanwhile, we in the developed world have a special responsibility—to use our prowess in biotechnology to benefit the whole world. We have not been forthcoming, generally making medicines so expensive that only the wealthy can benefit. And we have focused biotechnology on diseases of the developed world because that is where the profits are. This is changing some, especially because of the involvement of very rich individuals like Bill Gates, Warren Buffitt and others. Governments of Northern countries are also realizing that they have a responsibility to fund research that will benefit the whole world. Ultimately, the skills of science and technology must be disseminated throughout the world so that each country can make its own contributions and benefit in its own way from the great knowledge being produced by our universities. The internet is making that easier but the limiting factors will be trained people, focused institutions and financial capital. The latter takes time to amass but when corruption drains off a country’s resources, it steals from the people the opportunity to advance. The former, the people trained to utilize high technology, can only be products of great educational institutions—the generation and maintenance of such institutions seems to me a very high priority for any country that wants to advance economically.

In closing, I want to thank Wilmot James for the invitation to speak with you today. It is one of the honors of my life to be associated in any way with Nelson Mandela and I only hope that in a very small way I have honored him with my comments.