- In a new study, researchers found that by targeting a type of protein, they were able to suppress replication of HIV in certain cells.
- This is a potential step toward complete elimination of the virus.
- Experts caution that more study is needed.
A new study published this week in Cell Chemical Biology suggests a path forward for eliminating the so-called viral reservoir cells in people with HIV.
By targeting a type of protein called the Nef protein, researchers at the University of Pittsburgh School of Medicine were able to suppress the replication of HIV in target cells, a potential step toward complete elimination of the virus.
The Nef protein helps HIV-infected cells avoid detection by a person’s immune system.
The Nef protein was long considered “undruggable” because it provides few ways for any antiviral drugs to bind.
Previous Nef inhibitors, which only bind to those proteins, can block some of its functions but were unable to disrupt others that are essential for HIV infection. If a person has stopped taking antiretroviral drugs but reservoir cells remain because the Nef protein is helping them hide, the reservoir cells can eventually reactivate and start producing new virus again.
Dr. Lori Emert-Sedlak, Ph.D., a research associate professor in the Department of Microbiology and Molecular Genetics at the University of Pittsburgh School of Medicine and one of the study’s authors, told Healthline that their approach to targeting Nef proteins was based on a type of drug called PROTAC drugs that have been successful in attacking cancer cells.
“PROTAC stands for proteolysis targeting chimeras, which are ‘two-headed’ small molecules; one end binds selectively to the drug target (HIV Nef in our case) and the other end binds to a cellular machine…that marks the target protein for degradation. The PROTAC, therefore, acts as a bridge between the target protein and this cellular machine,” Emert-Sedlak said.
The research for this latest discovery has been in the works for a long time, she added.
“Discovery and development of small molecules that bind selectively to Nef took us about 10 years, and extending the work to the targeted degrader approach required another 3 years,” Emert-Sedlak said.
Researchers “synthesized more than 500 unique compounds for this project, all of which had to be screened for activity in a battery of biophysical, biochemical, and virological tests,” Emert-Sedlak said. “PROTACs are not trivial compounds for chemists to make and no clear ‘rules’ exist to predict which ones will work in advance. So, each analog must be tested individually, which takes time.”
Experts caution that there will need to be more testing and that the implementation of PROTACs for the treatment of HIV is still a long way off.
The next step would be testing the approach using animal models before any human trials can begin. Dr. Tom Smithgall, Ph.D., a professor at the Department of Microbiology and Molecular Genetics at the University of Pittsburgh School of Medicine and another author of the study, told Healthline that the data behind their research are promising, but there’s still a lot more testing to be done.
“Our results suggest that treatment of an HIV-positive individual with a Nef PROTAC would not only suppress viral growth like existing antiretroviral drugs but also keep the infected cells ‘visible’ to the immune system for elimination,” Smithgall said. “This effect may prevent seeding of a reservoir early in the infection, and therefore might help to eliminate the virus entirely.”
Smithgall said more testing will be needed to verify this is a safe and effective treatment. But if this ends up being a way to treat HIV, it could help eliminate the need for lifelong antiretroviral therapy.
Dr. Monica Gandhi, MPH, a professor of medicine at the University of California San Francisco’s Division of HIV, Infectious Diseases, and Global Medicine, told Healthline that achieving a widespread application of PROTAC drugs could be a huge leap forward in the search for a cure for HIV.
“The maintenance of the viral reservoir is our key barrier to achieving HIV cure among individuals living with HIV infection and we have not been able to find strategies yet that could eliminate the reservoir. This new Nef-destroying strategy represents a major advance and could be the ‘holy grail’ we have been looking for in terms of HIV cure,” Gandhi said. “However, there is still a lot of work to be done prior to testing in humans, including testing this strategy in animal models of HIV infection.”
One additional potential benefit to developing Nef PROTAC drugs would be applying the mechanics to other viruses — including COVID-19, which also utilizes some of its proteins to
“In theory, PROTACs against such proteins may work in combination with existing antivirals and vaccines to help the immune system control the virus, thereby limiting the severity of infection,” Smithgall said.
Smithgall also points out that first, researchers have to find the right molecule to target, which can take a long time. “However, this ‘warhead’ molecule needs only to bind selectively to its target, not inhibit it directly, to construct a PROTAC. In theory, the PROTAC approach can render any protein ‘druggable’ even if it lacks an active site like many targets for current drugs.”
A new study by scientists at the University of Pittsburgh School of Medicine shows promise for PROTAC drugs that can disrupt HIV “reservoirs” — groups of HIV-infected cells that can hide the virus from the body’s immune system.
Over a 10-year period, researchers developed a way to target a type of protein which aid HIV in hiding and can prompt a return of the virus if a person stops taking antiretroviral drugs.
There is still a significant amount of testing and research to be done before PROTACs can be implemented in humans.