Decades later, BPRC's HIV research continues to yield new insights

More than thirty years after pioneering HIV research at BPRC, the work is still generating new scientific insights. A new PNAS study shows how HIV may influence the genetic composition of human populations over time.

No one could have imagined in the early 1990s that research launched in Rijswijk would still be generating new scientific insights more than thirty years later. Yet an international team of researchers is now building on HIV research that was carried out at BPRC for many years.

The researchers published their findings in the leading scientific journal Proceedings of the National Academy of Sciences of the United States of America (PNAS). Using genetic data and a computational model, they show that HIV can influence the genetic composition of a population over the long term.

People with immune genes that help control HIV more effectively are more likely to remain healthy for longer without treatment and to pass these protective genes on to future generations. Since the introduction of antiretroviral therapy, this natural selection pressure has been greatly reduced. As a result, a hypothesis developed decades ago, partly by researchers at BPRC, has gained new scientific support.

An enormous puzzle

In the early 1980s, a new and deadly disease emerged: AIDS. At the time there was no treatment, and for many years it remained unclear where the virus had originated. A major breakthrough came when researchers discovered that chimpanzees could naturally carry Simian Immunodeficiency Virus (SIVcpz), a virus closely related to HIV, and could also be infected with HIV itself. This made chimpanzees an important model for HIV research.

"Chimpanzees could be infected, but they became much less ill," says immunologist Petra Mooij. "One of the questions we wanted to answer was why chimpanzees did not become seriously ill while humans did."

BPRC therefore investigated not only the development of an HIV vaccine, but also how the immune system controls the virus. "By understanding how chimpanzees kept the virus under control, researchers hoped to better understand what is needed for humans to do the same," says immunologist Gerrit Koopman.

HIV's Achilles' heel

A key role is played by so-called cytotoxic T cells. These immune cells recognise and destroy cells infected with a virus. MHC molecules, known as HLA in humans, help by presenting small fragments of a virus to the immune system.

Meanwhile, HIV researchers had identified a small group of people who remained healthy for many years without treatment. These so-called long-term non-progressors were remarkably effective at keeping the virus under control.

"These people had specific immune cells that were very effective at suppressing the virus," Petra explains. "The next question was whether there was a similarity between these people and chimpanzees, which can also suppress the virus for a very long time."

HIV mutates rapidly, allowing it to escape immune responses. However, some parts of the virus are so essential for replication that they can hardly change.

"That is essentially HIV's Achilles' heel," says Gerrit. "If your immune response targets a part of the virus that it absolutely needs to reproduce, the virus cannot simply mutate that part," Petra explains. Which parts of the virus the immune system recognises depends in part on the MHC or HLA variants a person carries.

Why did chimpanzees become much less ill?

Researchers then asked why chimpanzees could control the virus so effectively while beneficial immune genes were relatively rare in humans. Immunogeneticist Natasja de Groot and her colleagues therefore studied variation in chimpanzee MHC genes. What they found was remarkable.

"Chimpanzees split from the human evolutionary lineage much earlier," Gerrit explains. "You would therefore expect them to have much greater genetic diversity. But that was not what we observed."

Specifically, the researchers found less variation than expected in the MHC genes involved in recognising viruses.

This led them to a possible explanation.

"Perhaps chimpanzees were exposed to this virus, or a very similar one, long ago," Gerrit says. "Many animals may have died, leaving mainly those chimpanzees that possessed the right MHC molecules to fight the virus."

According to this selective sweep hypothesis, a severe epidemic can result in animals with favourable immune genes surviving more often and producing more offspring, causing those genes to become increasingly common.

"You can never prove that with certainty," says Natasja, "but it fitted well with what we observed."

Thirty years later

For the new study, scientists analysed groups of mothers and children in KwaZulu-Natal, South Africa, both before and after antiretroviral therapy became widely available.

"The new study essentially shows what happens in the absence of antiretroviral therapy," Natasja explains. "You see much stronger selection for certain HLA variants."

Without treatment, people carrying protective HLA variants were better able to control HIV and remained healthy for longer. Using a computational model, the researchers calculated that these beneficial variants could become substantially more common within approximately 45 years, while less favourable variants would gradually decline.

The model therefore demonstrates that natural selection can become visible within just a few decades. The BPRC researchers recognised this as the same process they had long suspected in chimpanzees.

"After the introduction of antiretroviral therapy, you no longer see this selection," Natasja explains. HIV medication suppresses the virus so effectively that a person's HLA variants become much less important.

However, antiretroviral therapy does not eliminate HIV from the body.

"It is not a cure," Petra emphasises. "It suppresses the virus. As soon as treatment stops, the virus returns very quickly."

Still no vaccine

For the researchers, it is particularly rewarding to see work they contributed to decades ago continue to shape new scientific discoveries.

"It is wonderful to see this study build directly on research that was once carried out here with chimpanzees," says Natasja.

After chimpanzee studies came to an end, HIV vaccine research at BPRC continued for many years using other non-human primate species. According to the World Health Organization (WHO), an estimated 40.8 million people were living with HIV worldwide in 2024. Approximately 630,000 people died from HIV-related causes that same year.

Despite decades of scientific progress, there is still no effective vaccine, something Gerrit finds deeply frustrating.

"We spent around thirty years working on HIV and AIDS here, and there is still no vaccine," he says. "I still hope that one day there really will be one."