Researchers at Yerkes National Primate Research Center (YNPRC) have discovered a way to use cancer immunotherapy treatments to reliably shrink the size of the viral “reservoir” in simian immunodeficiency virus (SIV)-infected nonhuman primates treated with antiviral drugs.
In humans, antiviral drugs can suppress human immunodeficiency virus (HIV) to the point of being undetectable in blood, but the virus embeds itself in the DNA of specific immune cells (T cells). Each reservoir consists of T cells that continue to harbor the virus even during antiviral drug treatment.
According to the researchers, chronic viral infection and cancer produce similar states of “exhaustion.” T cells that could fight virus or cancer are present but unable to respond. In long-term HIV or SIV infection, T cells harboring the virus display molecules on the cell surface that make them targets for checkpoint inhibitors (cancer immunotherapy drugs designed to counteract the exhausted state).
In this study, researchers combined two cancer immunotherapy treatments to block the surface molecules CTLA-4 and PD-1 in nonhuman primates. In subjects that received both CTLA-4- and PD-1-blocking agents, researchers noted a stronger activation of T cells compared to only a PD-1 blockade.
“We observed that combining CTLA-4 and PD-1 blockade was effective in reactivating the (SIV) virus from latency and making it visible to the immune system,” said Mirko Paiardini, PhD, an associate professor of pathology and laboratory medicine at Emory University School of Medicine and a researcher at YNPRC.
In previous studies, shrinkage of the viral reservoir has been limited and inconsistent when researchers use single checkpoint inhibitors or other immune-stimulating agents. During this study, however, combination-treated animals showed a consistently measurable and significant reduction in the size of the viral reservoir.
Despite these findings, the combination treatment does not prevent or delay viral rebound once antiviral drugs are stopped. Paiardini suggested the approach may have greater potential if combined with other strategies, for example a therapeutic vaccine, or it could be deployed in a target-rich environment, for example during ART interruption when the immune system is engaged in intercepting and fighting the rebounding virus. Other HIV researchers have started to test those tactics, he indicated.
It is also noteworthy the equivalent combination of CTLA-4 and PD-1 blockade in humans has been tested in the context of cancer treatment, and while the two drug types can be more effective together, patients sometimes experience adverse side effects like severe inflammation, kidney damage or liver damage. Fortunately, the combination-treated animals in this study did not experience comparable events.
Finding a complete HIV cure is still critically important because problematic issues, like social stigma and the long-term toxicity and cost of antiretroviral drugs, remain.
To learn more about how NPRC scientists are working toward effective treatments—and ultimately a cure—visit this link.
