Seattle Children’s researchers show that one way HIV survives antiretroviral treatment is by disrupting genes that control cell proliferation.

In 2014, Seattle Children’s researchers demonstrated that HIV hangs on at low levels during antiretroviral therapy (ART) because HIV-infected cells continue to replicate. They discovered that the HIV-infected cells that continue to replicate are more likely to have HIV integrated into genes that normally limit cell proliferation. These genes are often linked to cancer.

“HIV randomly inserts into the human genome, but we think infected cells proliferate more when the virus integrates into particular genes,” says Dr. Thor Wagner, who co-led the study with Dr. Sherry McLaughlin of the University of Washington. “It helps explain why HIV is such a long-lasting infection and may open new paths toward cures.”

How HIV Survives

When patients first started taking ART in the 1990s, it suppressed HIV so well that researchers thought all the infected cells would die off, resulting in a cure. Instead, HIV has shown a remarkable ability to survive and come roaring back as soon as patients stop taking ART.

Wagner and McLaughlin suspected that HIV’s survival may be fueled by proliferation of HIV-infected cells. Their research team – which included investigators from the University of Washington and Fred Hutchinson Cancer Research Center – developed an assay to pinpoint where HIV inserts into the human genome. Then they sequenced HIV integration sites from three patients who had been taking ART for more than a decade.

The aha moment came when the researchers analyzed the integration sites and saw that the virus repeatedly embedded in genes that normally put a check on cell proliferation. Cell growth increases when the normal function of genes is disrupted. This is what allows many cancers to flourish, and it may do the same for HIV-infected cells. Wagner’s team published their results in a study in Science.

“HIV disrupts these genes when it integrates into them and that may help the infected cells keep proliferating instead of dying off,” Wagner says.

Immunotherapy for HIV?

Now the researchers are working to unravel each step in this disruption, with hopes it will give them clues that lead to a cure. Their first step is to piece together how long it takes HIV to insert into these specific genes.

“It might be possible to eradicate HIV if we can treat patients before the virus gets into these specific genes,” Wagner says.

The researchers are also investigating new ways to attack HIV-infected cells. Wagner envisions a future where doctors can use immunotherapy to kill HIV-infected cells.

“We think we might be able to borrow technology from oncology to find ways to kill the HIV-infected cells that hang around during antiretroviral treatment,” Wagner says.

“HIV medications have been an amazing success, but the most common question we get from children with the virus is ‘Can I ever stop taking pills?’” Wagner says. “Those kids motivate our research and many of them have been eager participants in our studies.”

It might be possible to eradicate HIV if we can treat patients before the virus gets into these specific genes.
– Dr. Thor Wagner