Antiretroviral therapy (ART) effectively suppresses HIV in the blood, but a latent reservoir of the virus persists, necessitating lifelong treatment. New research suggests that pembrolizumab, a cancer drug known as Keytruda, may help flush HIV out of these hidden reservoirs. The study, published in Science Translational Medicine, examined 32 patients with both cancer and HIV, revealing pembrolizumab's potential to revive the immune system and target latent HIV.
Pembrolizumab's Dual Action
HIV targets white blood cells (T cells), weakening the immune system. While ART can prevent viral replication and allow immune recovery, it cannot eliminate latent HIV. Exhausted T cells, characterized by the presence of programmed death 1 (PD1), contribute to immune suppression and viral latency. PD1 silences the virus and puts it in a latent form, leading to the persistence of latent viruses inside cells that express PD1.
Pembrolizumab, approved by the FDA in 2014 for advanced melanoma, binds to PD1, removing its suppressive effect on the immune system. In cancer treatment, this action stimulates the immune system to destroy tumor cells. Researchers hypothesized that pembrolizumab could similarly disrupt HIV's ability to hide, potentially offering a "double whammy" effect.
Study Design and Findings
The study focused on individuals already undergoing ART for HIV and receiving pembrolizumab for cancer treatment. Patients received pembrolizumab infusions every three weeks for up to 105 weeks. Researchers monitored HIV genetic material levels in the blood throughout the treatment period.
Following the initial pembrolizumab infusion, HIV genetic material was detected in the patients' blood, suggesting the drug was forcing the virus out of its latent state. However, pembrolizumab alone was insufficient to completely eliminate the HIV reservoir. According to Sharon Lewin, an HIV researcher at the University of Melbourne and the senior author on the study, "It released the brakes on the virus, and now they’re visible to the immune system... Anti-PD1 on its own repeatedly didn’t get rid of the reservoir."
Implications and Future Directions
Despite not eradicating HIV entirely, the findings represent a significant advancement. Steven Deeks, a professor of medicine at the University of California, San Francisco, emphasized that the study provides a "road map" for exploring strategies to manipulate the immune system and target the latent HIV reservoir. This includes investigating lower doses and alternative approaches within the same pathway.
However, experts caution that further research is crucial to determine the optimal use of pembrolizumab in HIV treatment. Shyam Kottilil, an infectious disease physician and professor at the Institute of Human Virology at the University of Maryland School of Medicine, highlighted the safety concerns associated with pembrolizumab in individuals without cancer, given its potential for severe toxicity. Studies are underway to assess the effects of low-dose pembrolizumab in HIV-positive individuals without cancer. Lewin suggests that the presence of cancer in the initial study may have influenced the drug's impact on HIV, warranting further investigation in different patient populations.
