A global, multi-disciplinary initiative is trying a completely new strategy for curing HIV. The group, known as the HIV Obstruction by Programmed Epigenetics (HOPE) Collaboratory, will be led by researchers at Gladstone Institutes, Scripps Research Florida, and Weill Cornell Medicine. Their approach, which aims to both silence and permanently remove HIV from the body, takes advantage of knowledge about how other viruses have become naturally inactivated over time.
“This is a fundamentally different approach to targeting HIV than what everyone else has been trying,” says Melanie Ott, M.D., Ph.D., director of the Gladstone Institute of Virology, and the program director and a principal investigator of the HOPE Collaboratory. “If cells infected with latent HIV could be solidly silenced, we could take patients off their entire antiretroviral therapy regimens and the virus would not reappear,” she says.
In 2020, more than 35 million people were living with HIV around the world. While there are treatments to control the disease and even prevent transmission, there is no drug yet that cures HIV.
A big challenge is that this virus can hide in a latent state in immune cells. This doesn’t cause overt symptoms or full-blown AIDS, but can lead to long-term health complications and can’t be targeted with standard antiretroviral therapy. Moreover, a lapse in daily therapy can lead to a rapid rebound of the infection.
Most attempts at curing HIV have centered around purposefully reactivating the latent virus in order to flush it out in the presence of antiretroviral therapy—an approach called “shock and kill.” But researchers have struggled to reactivate every copy of the virus in the body, or at least, to do so without severe undesirable side effects. And even a small remaining reservoir of latent virus means that someone living with HIV must remain on daily treatments.
The researchers involved in the HOPE Collaboratory are calling their new, alternative tactic “block-lock-excise,” and it targets latent HIV in new ways, without reactivating it.
The inspiration for the “block and lock” part of their strategy comes from ancient viruses that have integrated themselves into the human genome over millions of years of evolution. HIV also integrates into the genome of a person living with HIV. However, unlike HIV, the ancient viruses remain in a silenced state or are defective.
Researchers have found that these ancient inactive viruses are missing several genetic elements that HIV contains. Two particular elements—a sequence of DNA at the start of HIV’s genetic code and a protein called Tat—are needed for latent HIV to reactivate and begin replicating.
“We have shown that blocking Tat with certain drug-like small molecules can lock HIV in its dormant stage, and this block stays in place for some time, even if antiretroviral therapy is interrupted,” says Susana Valente, Ph.D., one of the principal investigators of the HOPE Collaboratory and associate professor of immunology and microbiology at Scripps Research in Florida. “With the ‘block and lock’ approach, we basically want to push HIV into becoming like a harmless, ancient virus.
The consortium includes members from 12 institutions around the world, and will also work with three pharmaceutical companies with insight into the development of potential therapeutics from the drugs studied in their labs.
Over the first two years of the five-year grant, they plan to complete feasibility studies and further investigate a handful of potential drugs. Once those initial studies are complete, the group can re-evaluate and, if needed, shift their approach.
“We cannot be satisfied with the status quo, which is lifelong therapy for people living with HIV,” says Ott. “We need to continue pushing for a cure—and that’s exactly what we intend to do through the HOPE Collaboratory.”
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