A new collaborative effort aims to cure HIV using a novel “block-lock-excise” approach and is backed by a $26.5 million grant from the National Institutes of Health. The multidisciplinary group of researchers, known as the HIV Obstruction by Programmed Epigenetics Collaboratory, is being led by scientists at Gladstone Institutes, Scripps Research, and Weill Cornell Medicine.
The biggest hurdle to curing HIV has been the virus’s ability to hide a reservoir of latent copies within immune cells. Up to now most viable cure efforts have aimed at reactivating that virus reservoir in order to kill it with antiretroviral therapy — an approach called “shock and kill” or “kick and kill.” Unfortunately, those approaches haven’t been able to wake every single copy of the latent virus (at least not without also bringing about severe side effects).
The HOPE Collaboratory is taking “a fundamentally different approach to targeting HIV than what everyone else has been trying,” Dr. Melanie Ott, director of the Gladstone Institute of Virology and program director for the collaboratory, explained in a press statement.
The new alternative tactic, “block-lock-excise,” targets latent HIV without reactivating it. The inspiration for this tactic arose from the fact that researchers have found ancient viruses that are integrated into the human genome but are no longer active or viable.
“The central concept behind [this] strategy is inspired by the way our cells naturally cope with the remnants of ancient retroviruses that have integrated into our genetic material during evolution,” said Cedric Feschotte, one of the investigators and professor of molecular biology and genetics at Cornell’s College of Agriculture and Life Sciences.
Feschotte studies these so-called endogenous retroviruses, which make up about 8 percent of modern humans’ DNA.
Identifying which proteins are used by our immune cells to lock up endogenous retroviruses opens the way to developing “new repressive molecules that can target HIV and lock it permanently,” Feschotte said. “The concept is exciting, and it makes sense. We want to accelerate what evolution has already achieved with thousands of relatives of HIV previously defeated and buried in every human[’s] cells.”
The researchers have also found that these ancient inactive viruses are missing several elements that HIV contains. They’ve identified two elements in particular, one a sequence of DNA and the other a protein called Tat, which are necessary for latent HIV to reactivate and begin replicating again.
“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,” said Susana Valente, also a principal investigator and associate professor of immunology and microbiology at Scripps Research. “With the ‘block and lock’ approach, we basically want to push HIV into becoming like a harmless, ancient virus.”
The pharmaceutical solution would block the Tat protein and alter the structure of the virus, making it harder for other proteins to access the HIV genes and potentially turn them on. This could prevent the virus from awakening and reactivating. That would keep HIV from returning even after someone goes off antiretroviral treatment.
“The idea is not only to lock HIV so it cannot replicate without using drugs, but essentially to throw away the key, keeping it locked away forever, unable to do any more harm,” Valente said.
The “excise” part of the new approach uses recent advances in genome editing. By employing CRISPR/Cas9 genome-editing technology, researchers could delete the remnant HIV hiding in the DNA of immune cells. That would eliminate all traces of HIV and any chance of the virus rebounding.
The collaborators are drawn from 12 institutions around the globe, three pharmaceutical companies, clinical groups in Africa and Brazil providing data and samples from people living with HIV, and the San Francisco AIDS Foundation, which will bring insights and perspectives from people living with HIV.
“It’s absolutely key that this is a multi-institutional and multidisciplinary approach,” said Gladstone’s Danielle Lyons, program manager for the HOPE Collaboratory. “Bringing together this diverse group of people with expertise across various disciplines is what will really drive the discovery of a cure for HIV.”
The HOPE Collaboratory is one of 10 groups awarded a five-year grant under the Martin Delaney Collaboratories program, the flagship program on HIV cure research at the NIH.