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Infectious disease

Researchers home in on how some people’s immune cells keep HIV in check

People who naturally fight off HIV do so with the help of immune cells that don’t kill the virus but hobble its ability to replicate

by Alla Katsnelson
December 19, 2019

A colorized transmission electron micrograph of HIV.
Credit: James Cavallini/Science Source
People who naturally fight off HIV (virus shown at 690,000 X magnification) do so with the help of immune cells that hobble its ability to replicate.

Most people infected with HIV must take multiple antiretroviral drugs for the rest of their lives to prevent the virus from overtaking their immune system. But less than 1% of people with HIV somehow naturally keep the infection in check. Since scientists first identified these so-called elite controllers in the 1980s, they have hoped to understand how these people’s immune system performs this feat to devise a therapy that mimics it.

Researchers have generally believed that in elite controllers, immune cells called CD8+ cells kill HIV-carrying cells by squirting them with toxic enzymes. But a new study suggests the process works differently (Sci. Transl. Med. 2019, DOI: 10.1126/scitranslmed.aax4077).

“We think that elite controllers are controlling HIV replication through a suppression mechanism, not a cytotoxic mechanism,” says Michael Betts, an immunologist at the University of Pennsylvania who led the work. “They are not eliminating the HIV-infected cells directly but they are preventing the cells from making more virus.”

CD8+ cells are known to kill pathogen-infected cells — that’s generally how they fight infections in the body. And researchers previously have shown that CD8+ cells from people who are infected with HIV and don’t naturally control the virus are less effective at killing HIV-infected cells than are CD8+ cells from healthy people. So Betts and his colleagues set out to test whether the CD8+ cells in elite controllers’ lymph nodes — part of the lymphatic system where HIV replicates — are better killers than CD8+ cells in people who don’t naturally control the virus but who have not yet taken antiretroviral drugs.

They took lymph node tissue from 12 elite controllers, 8 non-controllers who had not yet taken antiretroviral drugs, and 8 non-controllers who had. First, they confirmed that CD8+ cells from elite controllers’ lymph nodes do indeed control viral levels better than the cells from the other two groups. But these cells turned out not to express the cell-busting enzymes. Even when the researchers stimulated the cells by exposing them to HIV, they could not coax them to kill infected cells.

When the researchers studied individual CD8+ cells, they found that those from elite controllers expressed a set of 11 genes differently than do CD8+ cells from the two groups of non-controllers. Some of those genes have previously been found to counter HIV—not through cytotoxicity, but by preventing the virus’s entry into cells, interfering with replication, and other mechanisms. They also found that elite controllers’ CD8+ cells have a heightened ability to respond to the virus, and to make proteins known to suppress HIV activity.

Researchers working on HIV therapies have tried to find ways of boosting CD8+ cells’ killer instincts. “But this study shows that you actually don’t need to do that,” Betts says. “There’s no evidence that this is actually going to keep the virus in check.”

“This is really very novel insight into the mechanism by which elite controllers are actually able to control their HIV infection,” says Daniel Kuritzkes, an HIV researcher at Harvard University who was not involved in the study. When researchers first started studying the role of CD8+ cells in HIV infection, their understanding of how these cells behave was much more limited, and cytotoxicity was the easiest property to measure, he says.

Identifying exactly how elite controllers’ special CD8+ cells block the virus’s replication may open up new avenues for HIV therapy, Betts says. “If we can harness this, we would potentially have a strategy that would allow immunological control — not a cure, yet, but control — possibly without the need to take [antiretroviral] drugs.”


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