Over the last 40 years, HIV has shifted from a deadly and mysterious virus to one that can be controlled with daily drugs. But attempts to completely eliminate the virus from the bodies of people living with HIV, curing them for good, have failed.
Now, with a $26.5 million grant from the National Institutes of Health (NIH), a multidisciplinary group of researchers from institutions around the world 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 and Weill Cornell Medicine, and will include investigators on the Ithaca campus. 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,” said Dr. Melanie Ott, director of the Gladstone Institute of Virology, and the program director and a principal investigator of the HOPE Collaboratory. “I think it’s extremely important for us to explore a broad range of scientific approaches to find the best cure for people living with HIV, as quickly as we can.”
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.
Targeting latent HIV in novel ways
HIV is notorious for its ability to hide in a latent state in immune cells; while latent viruses don’t cause overt symptoms or full-blown AIDS, they can lead to long-term health complications for those living with HIV and can’t be targeted with standard antiretroviral therapy. Moreover, a lapse in this 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 with 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.
“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 of the HOPE Collaboratory and professor of molecular biology and genetics at Cornell’s College of Agriculture and Life Sciences.
Feschotte’s lab studies the biology of these so-called endogenous retroviruses, which make up 8% of our DNA. Unlike HIV, however, they are no longer capable of infection because they are disabled and permanently silenced. His team’s goal is to identify the precise molecules (proteins) used by our own cells to lock endogenous retroviruses.
“Armed with this knowledge, and inspired by these natural defenses, we will combine our expertise to that of other HOPE participants to engineer 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 cells.”
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,” 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.”
Using drugs to block the elements needed for the virus to reactivate could shift HIV from a transient latent state to a robustly silenced one. The drugs would not only impede the Tat protein, but also alter the three-dimensional structure of the HIV genetic material, making it harder for other proteins to access the HIV genes and turn them on. This dual strategy, the HOPE team thinks, could lock HIV into a silent state for good, without continuous 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 to the host or to others,” Valente said.
“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,” said Ott.
Genome editing opens new doors
The “excise” component of the HOPE Collaboratory’s approach takes advantage of recent advances in genome editing. The development of the CRISPR/Cas9 genome-editing technology has given researchers inroads into altering the DNA of human cells. This means that the latent HIV inserted in the DNA of immune cells could be edited.
The team plans to test the utility of a number of gene-editing approaches in changing the DNA of latent HIV to such an extent that the virus would be destroyed. This step, they say, could follow the “block-and-lock” treatment that silences the virus, or it could be an alternative path depending on the effectiveness and cost of each approach.
“We have not yet been able to achieve a cure for HIV because the virus finds a way to hide out in reservoirs of cells in the body,” said Dr. Lishomwa Ndhlovu, a principal investigator of the HOPE Collaboratory and a professor of immunology in medicine in the Division of Infectious Diseases at Weill Cornell Medicine. “The HOPE grant will allow us to test whether a ‘block-lock-and-excise’ approach can achieve long-term silencing of HIV in all relevant tissue sanctuaries so it cannot be released from cells. Coupled with permanent removal of any remnants of the silenced virus, we hope this will prevent the rebound of HIV when antiviral drugs are stopped, and lead to a cure.”
A collaborative approach
The collaboratory 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 the labs. In addition, clinical groups will help provide data and samples from people living with HIV in Africa and Brazil.
With community partner San Francisco AIDS Foundation, the HOPE team will also involve people living with HIV in their research agenda. Discussion panels will bridge researchers and the community to help ensure that any HIV therapeutics are welcomed – and understood – by 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.”
Individually, the principal investigators of the HOPE Collaboratory have already been working on HIV latency, retroviruses and Tat inhibitors for many years, so they’re ready to hit the ground running as a team, they say.
Over the first two years of the five-year grant, they plan to complete feasibility studies and further investigate a handful of potential drugs. The collaboratory nature of the grant means that, 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,” said Ott. “We need to continue pushing for a cure – and that’s exactly what we intend to do through the HOPE Collaboratory.”
Sarah C.P. Williams is a freelance writer for Gladstone Institutes.