How HIV Uses T Cells to Hide in the Gut

Antiretroviral treatments for HIV (human immunodeficiency virus) have been extremely successful in extending life expectancy and reducing transmission. But one major challenge has so far prevented researchers from developing a cure: HIV likes to hide.

With consistent use, antiretroviral medications prevent HIV from infecting blood cells, largely keeping the virus out of circulation. However, in some parts of the body, primarily the gut, HIV hunkers down and evades immune system attack.

In a new study published in Immunity, Yale researchers figured out how.

They found that a strategy the body uses to form a strong immune defense in the gut—which protects us from pathogens we consume—also creates a perfect haven for HIV. The new findings give researchers a potential target for eliminating the virus all throughout the body.

The gut sees so many of the harmful things that come through the body, such as bacteria, fungi, and viruses. So stationed throughout are immune cells called T cells, with different versions for each of the major pathogens commonly passing through. There are T cells programmed to recognize Salmonella, for example, and others programmed to identify E. coli. When those pathogens come through, the T cells can target them immediately, minimizing the pathogens’ damage and clearing them from the body.

While there are a few places in the body where HIV accumulates, the vast majority of persistent virus resides in the gut, and in the T cells specifically. When the virus infects cells elsewhere in the body, immune cells notice and kill the infected cell, but that doesn’t happen in the gut.

To understand why, Yale researchers looked at gene regulation in gut cells. They found that a transcription factor—a protein that binds to DNA and influences what genes are activated or deactivated—plays a major role in turning short-lived T cells into long-lasting, persistent cells.

“This transcription factor called BACH2 does three things that are, normally, very protective,” says Ya-Chi Ho, MD, PhD, an associate professor of microbial pathogenesis at Yale School of Medicine and senior author of the study. “First, BACH2 tells T cells coming to the gut that they should stay there and not travel anywhere else. It then tells them to stick around for a really long time—forever, basically. And third, it tells these cells to stop throwing defensive, inflammatory weapons in order to keep the cells from harming the healthy, sensitive tissue sitting all around them.”

This establishes an essentially life-long protective barrier throughout the gut.

“But this is also perfect for HIV,” says Ho. “When it infects these long-lasting T cells, it has a really safe place to stay for a really long time.”

These findings make BACH2 an intriguing target for treating HIV. But there are challenges to that approach. BACH2 is found throughout the body, and it does perform a necessary function.

“So we can’t just target BACH2 and get rid of all of these long-lasting T cells,” says Ho. “We need to be specific and find a way to target only the T cells infected with HIV.”

In the meantime, Ho’s lab is digging deeper into HIV persistence.

“We’re using this approach to understand how HIV hides in other areas, such as in lymph nodes and in cancer cells,” says lead author Yulong Wei, PhD, a postdoctoral associate in Ho’s lab whose bioinformatics background enabled the multidisciplinary approach that made the study possible.

The researchers are also investigating what controls BACH2, looking at neighboring gut immune cells and how they talk to the T cells, as well as how gut microbes influence that communication.

“We want to understand how all of these cells talk to each other,” says Ho. “This could yield other targets for clearing HIV.”

The research reported in this news article was supported by the National Institutes of Health (awards R01AI174863, R01AI183430, R01AI141009, P01AI169768, BEAT-HIV Martin Delaney Collaboratory UM1AI164570, REACH UM1AI164565, CHEETAH U54AI170856, R01AI176601, R33DA047037, UM1 Y-SCORCH DA051410, U01 M-SCORCH DA053628, R01DA051906, and U01AI110434) and Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support was provided by the Natural Sciences and Engineering Research Council of Canada, the AIDS and Cancer Specimen Resource, the Yale Gruber Fellowship, the Robert I. Jacobs Fund of the Philadelphia Foundation, and the Herbert Kean, M.D., Family Professorship.