By Casey Ostheimer, WNPRC editorial intern
Dec. 19, 2022
Wisconsin National Primate Research Center scientists have long been working to improve our understanding of human immunodeficiency virus (HIV) pathology and advance therapies for the disease. Recently, Shelby O’Connor, professor of pathology and laboratory medicine at the University of Wisconsin–Madison, and her research team have been evaluating the drug N-803, which may be virologically and immunologically beneficial in treating HIV under certain circumstances.
Olivia Harwood and Shelby O’Connor had summarized in a September 2021 review in Viruses that the drug N-803 (Anktiva™) was being studied as a way to enhance the innate and adaptive cellular immune responses to HIV and its primate analog, simian immunodeficiency virus (SIV), by improving CD8+ T cell recognition and killing of virus-infected cells. It may also direct immune cells to mucosal sites and lymph nodes, the primary sites of virus replication. The drug, trademarked by the company ImmunityBio, received Fast Track and Breakthrough Therapy designations from the U.S. Food and Drug Administration (FDA) in 2017 and 2019, respectively, as a potential therapeutic for BCG-unresponsive non-muscle-invasive bladder cancer carcinoma in situ.
With Primate Center and National Institutes of Health funding (NIH R01AI108415), O’Connor and her team have studied this drug’s effectiveness in the context of various immune states and concurrent therapies in a SIV model using both rhesus and cynomolgus monkeys. Her previous research has shown that N-803 could lead to a quick and transient reduction in blood plasma virus copies and an increase in cytotoxic CD8+ T-cells in a subset of monkeys that had not undergone antiretroviral treatment for SIV. Following more experimental testing, they found that the viral load (number of virus copies) in the plasma could affect the immune response to N-803 treatment. This testing involved unvaccinated or vaccinated primates undergoing an SIV infection and then treatment with N-803 six months later. The vaccinated primates all received the SIV
Gag vector, which leads to an SIV Gag-specific immune response, and then half of the vaccinated animals also received an immune cell stimulator.
Interestingly, there were no significant differences in control of viral load between the vaccinated and unvaccinated primates during N-803 treatment. The distinction in N-803 responsiveness was associated with the viral load before treatment. In primates with low viral copies, known as SIV spontaneous controllers, N-803 increased the frequency of SIV-specific T-cells, improving their proliferation and cytotoxicity, or ability to kill SIV. Additionally, in experiments looking at cells from the primates, the Gag-specific CD8+ T-cells of the SIV controllers exhibited an increase in CD8+T-cells expressing CD107a, a marker of immune cell activation and cytotoxicity. Further, increased responses to Gag have been associated with reduced viral loads and stronger antiviral activity.
Compared to the spontaneous controllers, the animals that expressed a higher viral load in their plasma did not see the same increase in CD8+ T-cells expressing CD107a. Instead, these non-controllers showed chronic activation of T-cells resulting in immune “exhaustion.” This can leave the SIV specific cells unable to fight viral infection even with N-803 treatment. These results support the conclusion that this drug is most effective in SIV+ animals with a natural pre-existing immunological ability to control SIV replication. Future experiments in the O’Connor lab will address the mechanism of how N-803 might function differently in individuals that control HIV/SIV (for example, individuals on antiretroviral therapy or spontaneous controllers), compared to settings where HIV/SIV is not controlled. This could impact the efficacy of N-803 use in the field of HIV cure research.
Newer work done in the lab focuses on the effect of N-803 as a CD8+ T cell booster accompanied by vaccination with Gag immunogens following completion of antiretroviral treatment. This combination may create and recall Gag-specific CD8+ T-cells. The results supported this finding, as vaccination induced a high frequency of the Gag-specific CD8+ T-cells, which were then boosted by N-803 to a similar extent as the natural CD8+ T-cells had been. The results revealed that N-803 treatment enhanced the frequency and proliferation Gag-specific CD8+ T-cells, which have been shown previously to protect the immune system from loss of CD4+ T-cells and thus lower HIV viral loads.
Because HIV is a complex disease and antiretroviral therapy can only suppress HIV replication rather than cure it, a functional cure will most likely involve a combination of different therapies. Therefore, the discovery of N-803 and its effects generating and recalling immune responses will have broad implications in the field of HIV cure research.
O’Connor lab references:
Harwood OE, Balgeman AJ, Weaver AJ, Ellis-Connell AL, Weiler AM, Erickson KN, Matschke LM, Golfinos AE, Vezys V, Skinner PJ, Safrit JT, Edlefsen PT, Reynolds MR, Friedrich TC, O’Connor SL. Transient T Cell Expansion, Activation, and Proliferation in Therapeutically Vaccinated Simian Immunodeficiency Virus-Positive Macaques Treated with N-803. J Virol. 2022 Nov 15:e0142422.
Ellis-Connell AL, Balgeman AJ, Kannal NM, Hansen Chaimson K, Batchenkova A, Safrit JT, O’Connor SL. IL-15 Superagonist N-803 Enhances IFN-γ Production of MAIT Cells in SIV+ Macaques. Infect Immun. 2022 Oct 3:e0025922.
Ellis-Connell AL, Balgeman AJ, Harwood OE, Moriarty RV, Safrit JT, Weiler AM, Friedrich TC, O’Connor SL. Control of Simian Immunodeficiency Virus Infection in Prophylactically Vaccinated, Antiretroviral Treatment-Naive Macaques Is Required for the Most Efficacious CD8 T Cell Response during Treatment with the Interleukin-15 Superagonist N-803. J Virol. 2022 Oct 3:e0118522.
Harwood O, O’Connor S. Therapeutic Potential of IL-15 and N-803 in HIV/SIV Infection. Viruses. 2021 Sep 2;13(9):1750.