The unlikely path that Thumbi Ndung’u followed to become a world-class AIDS researcher began in a rural highland village in Kenya. Ndung’u grew up with five brothers and five sisters in a house with no running water or electricity. He picked coffee beans and milked the family cows when he wasn’t at school. By Kenyan standards, he was middle class, and his father was a hardworking teacher at a neighborhood school. It would take a series of lucky breaks for this gifted scientist to wend his way to the Ph.D. program at Harvard University, becoming the first scientist to clone HIV subtype C—the most prevalent strain of HIV in Africa and one long ignored by Western scientists.
This year Ndung’u, 43, was awarded the Howard Hughes Medical Institute’s International Early Career Scientist award, which gives him five years of funding to pursue his work on genes in the immune system that help to fight AIDS and may lead to a vaccine. He heads the HIV Pathogenesis Program at the University of KwaZulu-Natal, located in a corner of South Africa where HIV prevalence hovers at 39.5 percent, placing it among the hardest-hit populations in the world. With a broad smile and unshakable optimism, he mentors up-and-coming African scientists, whose thank-you notes line his modest office, which has just enough room to squeeze in a second chair.
Scientific American recently spoke with Ndung’u to understand the state of AIDS research in Africa and how the course of his life has shaped his scientific mission. Excerpts follow.
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Scientific American: While you were growing up in rural Kenya in the 1980s, do you remember the first time you heard about someone with HIV/AIDS? Ndung’u: I do remember particular people I knew had AIDS, although it was one of those things you never mentioned openly. But you heard rumors, and more often than not they did have it. There was such stigma and such fear of the disease. The suffering was horrendous because there were no antiretroviral drugs.
So was this at the back of your mind as you developed an interest in science?
I just developed an interest in science and mathematics from a young age because I was good at them and my father encouraged it. He was an English teacher at a neighborhood school. He always brought the newspaper home, and I read it religiously. I was very much aware of the greater world, even though I came from a small village.
I decided to get a degree in veterinary medicine. One of my lecturers from school introduced me to a professor at the University of Nairobi doing vaccine research on schistosomiasis, a parasitic disease that is common in developing countries. That experience fascinated me and set me on the path toward my Ph.D.
You didn’t just get your Ph.D. anywhere, of course. You studied at Harvard. How did that happen?
I was also very lucky because when I got that position studying schistosomiasis, the [U.S. Agency for International Development] provided a six-month training at the Harvard School of Public Health to learn some techniques for making monoclonal antibodies. My mentors encouraged me to pursue a career in science. Later, I enrolled for a Ph.D. and was fortunate to receive a full scholarship.
Was that the first time you made a visit to the U.S.?
That was my first time out of Kenya! When I arrived in Boston, someone was supposed to be waiting for me at the airport, but for whatever reason they didn’t show up. So I took a cab on my own. I just showed up at the door of the Harvard School of Public Health. I still remember I was hungry that particular afternoon, and the first thing I did was to look for a place where I could get a cup of coffee. I ended up at a Dunkin’ Donuts.
Did you feel you had a lot to learn in terms of the U.S. culture and Harvard culture?
It was overwhelming. I had never been to a proper research laboratory before. The resources in Nairobi were really at a minimum. It was very difficult to get reagents. And there is not a critical mass of scientists, so that most of the time you are working on your own or with two people.
To find myself in a place where there were books everywhere and reagents and bottles and the things we find typical in a well-functioning lab in the U.S. was incredible—really astounding to me. I had quite a lot to learn. I had never seen a flow cytometer, which I could use to count cells. Luckily, there were some very good people at the lab that I went to, and they helped me settle down quickly. They soon started encouraging me to apply to the Ph.D. program, which I did in 1995.
How did you make the decision to return to Africa?
I had a very tough time after my Ph.D. deciding what I wanted to do. Deep down in my heart, I always wanted to go back, but at the same time I had doubts as to whether I could succeed. I knew many people who had gone back and not had a positive experience. They went back but didn’t get the necessary support they needed to run a lab.
But my Ph.D. supervisor, Max Essex, helped to establish a lab in Botswana and suggested I should work there. It allowed me access to the resources that an institution like Harvard has, but at the same time it gave me an opportunity to work directly in Africa, where I wanted to make a difference. So it was an offer that I couldn’t refuse.
Much of your work has focused on the progression of HIV into full-blown AIDS. Can you explain that process?
AIDS is the immune deficiency syndrome caused by HIV. When you get infected with HIV, it doesn’t mean that you have AIDS. In fact, the hallmark of HIV infection is that it takes many years before the disease develops. So you can be infected for 10 years and not show any symptoms. What happens with HIV infection is that, slowly, the virus starts destroying the immune system, and then you start to get opportunistic infections that somebody with a normal immune system would normally not get. That’s when we say that you have AIDS. My research focuses on why the disease course varies so much in infected people.
Some people take one year to develop AIDS; others may take 20 years. What accounts for those differences?
What happens is that you start to have a progressive loss of the main cells of the immune system, called CD4 cells. The types of opportunistic infections you get differ from one person to the next based on where they are located. For example, we know that pneumocystis pneumonia, a typical indication of AIDS in the West, is not as common in African countries, perhaps because the environment is just different. Here in Africa the most common opportunistic infection is tuberculosis. Most important, we have evidence that genetic factors, the immune response and the nature of the virus itself combine to determine the outcome of infection.
Some people are also naturally resistant to catching these opportunistic infections.
That’s right. We have collaborations with four hospitals to try and understand which of those genetic, immunological and biological factors might be responsible for these differences we see in disease progression. Some people who have HIV don’t have AIDS or detectable virus, and their CD4 counts are completely normal. We know they are infected because they make antibodies to HIV. You can take cells from their blood and grow the virus in vitro, but in their body the virus is kept in check, probably by a potent immune system. That is what we are trying to understand.
You’ve found some particular immune proteins that play an important role.
Yes, the human leukocyte antigen proteins, or HLAs. They are like flags. They attach to virus proteins to alert the disease-fighting cells of the immune system of the presence of the virus. Then those immune cells will home in on human cells infected with the virus and kill them. These HLA proteins are the most diverse proteins of the body, and people in different populations have different types of these HLA molecules. Many studies, including our own, have shown that the type of HLA proteins a person has is the most important genetic determinant of who are HIV controllers and who are fast progressors. People with certain protective alleles [variants] have a viral load generally three times or more lower than that of others in the population.
How do these proteins do that?
It’s really about how those proteins influence our immune response and what HIV does in response to them. HIV evolves to escape recognition by these particular HLA proteins, but the virus becomes crippled by those changes. It’s no longer able to replicate as efficiently as it did before. We may be able to make a vaccine that targets those vulnerable regions of the virus.
What would be the next step in terms of developing an AIDS vaccine strategy?
Identifying those vulnerable regions of the virus using the assay we have in the laboratory. Then we can identify which other segments of the virus are vulnerable, and we can try to see whether we can use them in a vaccine construct that would cripple the virus. Obviously there might be other mechanisms of viral control. And we and others continue to investigate whether we can complement those mechanisms. By combining those kinds of strategies, we hope to come up with an effective vaccine construct.
Are there any other ways we can control the spread of HIV?
Yes. We know there are some people who can resist HIV infection. A good example is the CCR5-delta 32 mutation, which prevents HIV from entering cells and enables people to resist infection completely. We also know from studies in Nairobi and South Africa that some individuals may have other mechanisms of resistance. We hope it might be related to some human genes that HIV needs to replicate itself. HIV requires human proteins to complete its life cycle, but if those proteins are different, they may affect HIV replication. We have ongoing work on that aspect.
In addition to the possibility of a vaccine, antiretroviral therapy and protease inhibitors have already made HIV quite manageable in the West. How widespread are they in Africa today?
Antiretroviral drugs are available here in South Africa. In most cases, they are even available for free from the government. Certainly the situation differs from place to place, and we still do not have everybody in treatment who should be. And it tends to vary, depending on the political will within certain countries and their health care capabilities.
Right. Former South African president Thabo Mbeki was an AIDS denialist. How did his views affect the country’s effort to rein in AIDS?
It’s a very tragic story, and South Africa’s lack of response to the epidemic did slow down efforts to fight HIV/AIDS. The government then was not as committed as it is right now. It undoubtedly set South Africa back in the battle against the disease. Those who were in the forefront of that denial were very influential people, and so there were quite a lot of misconceptions.
But things now are much better. There is much more cooperation among the government, NGOs [nongovernmental organizations] and others involved in the fight against AIDS.
When you go back to your village in Kenya, are you a bit of a celebrity?
I’m not so sure that I’m a celebrity exactly, but they are very, very proud of me. I’m also very grateful to my family and my community for their support over the years.
This article was published in print as "Resistance Fighter."