PROTAC Drug Candidates Help Eliminate Viral Reservoir Cells, Show Potential in Suppressing HIV Replication

In a new study, researchers suggest a path forward for eliminating viral reservoir cells in people with HIV. By targeting a type of protein called the Nef protein, they could suppress the replication of HIV in target cells. This could be a potential step toward the complete elimination of the virus.

(Photo: Wikimedia Commons/ CDC/ C. Goldsmith, P. Fiorino, E. L. Palmer, W. R. McManus)

Role of Nef Protein in HIV Replication

Nef (negative regulatory factor) is a small myristoylated protein essential in viral pathogenesis. Nef protein helps HIV-infected cells avoid detection by a person's immune system. It was long considered "undruggable" because it allows antiviral drugs to bind.

Previous Nef inhibitors only bind to those proteins, blocking some of their functions. However, they are unable to disrupt others, which are also vital for HIV infection. If a person has stopped taking antiretroviral drugs, the reservoir cells remain because the Nef protein helps them hide. Eventually, the reservoir cells can reactivate and start producing new viruses again.

PROTAC-Mediated Degradation of HIV

Led by Dr. Lori Emert-Sedlak from the Department of Microbiology and Molecular Genetics at the University of Pittsburgh School of Medicine, the research team targets Nef proteins based on PROTAC drugs, which have successfully attacked cancer cells.

PROTAC (proteolysis targeting chimeras) are 'two-headed' small molecules, with one end binding selectively to the drug target and the other binding to a cellular machine. This marks the target protein for degradation. In other words, PROTAC acts as a bridge between the target protein and this cellular machine.

According to Emert-Sedlak, the team spent about ten years searching for and developing small molecules that bind selectively to Nef. Then, another three years were needed to extend the work to the targeted degrader approach.

In a recent study, the experts synthesized over 500 unique compounds, all of which had to be screened in a series of virological, biochemical, and biophysical tests. PROTACS are not trivial compounds for scientists to make, and there are no existing clear rules to predict which ones will work in advance. This means that each analog needed to be tested individually.

The study's results suggest that treating an HIV-positive individual with a Nef PROTAC would not only suppress viral growth like existing antiretroviral drugs, but it can also keep the infected cells 'visible' to the immune system for elimination. Such an effect may prevent the seeding of a reservoir early in the infection, helping to eliminate the virus.

The researchers noted that more testing will be needed, and the implementation of PROTACs for HIV treatment is still a long way off. For the next step, the team plans to test the approach using animal models before starting any human trials. If this approach is effective in treating HIV, it could help eliminate the need for lifelong antiretroviral therapy.

Maintenance of the viral reservoir is the critical barrier to achieving HIV cure among individuals living with HIV infection, and researchers have not been able to find methods that can eliminate the reservoir. According to Dr. Monica Gandhi from the University of California San Francisco, the new Nef-destroying strategy represents a major advance in terms of HIV cure.