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

Abstract

N-803 is a drug that boosts the immune cells involved in combating HIV/SIV infection. Here, we found that in SIV + rhesus macaques that were not on antiretroviral therapy, N-803 increased the proliferation and potential capacity for killing of the SIV-specific immune cells to a greater degree in animals that spontaneously controlled SIV than in animals that did not control SIV.

Mathematical modeling indicates that regulatory inhibition of CD8+T cell cytotoxicity can limit efficacy of IL-15 immunotherapy in cases of high pre-treatment SIV viral load

“…In this work, we updated our previous model of SIV infection and N-803 treatment [21] by separating the CD8 + T cell pool according to activation and SIV-specificity. This change allows the level of CD8 + T cell activation and regulatory inhibition to depend on both viral load and N-803, and it provides closer comparison to SIV-specific CD8 + T cell cytotoxic marker expression as a validation [9]. Our differential equations (Eq.…”

“…10) over a volume of distribution ( v d ), before being eliminated (rate constant k e ). In our pharmacodynamic model, N-803 increases CD8 + T cell proliferation [8, 10] and cytotoxic function [9, 15] based on multiplicative functions (Eq. 13-15) that reach half-saturation at a single concentration ( C 50 ).…”

“…This cohort had received vaccination against SIV prior to infection and had temporarily maintained undetectable SIV (<50 CEQ/mL) [60], and three of these macaques expressed an MHC allele associated with SIV control [61]. In the second cohort [9], fifteen rhesus macaques were infected with SIV mac 239M, which is a barcoded SIV mac 239 [62], and ten of these also received some type of prior vaccination. Of the fifteen NHPs, twelve had high viral loads (≈5-7 log CEQ/mL at the time of treatment).…”

“…Thus, only the twelve high viral load subjects were included in model calibration. We validated our model against measurements of Granzyme-B, a marker of cytotoxic function, on SIV-specific CD8 + T cells [9]. We also compare model predictions to healthy and SIV-infected NHP cohorts given intravenously administered N-803 [10].…”

“…In this study, we adapted and applied our computational model to simultaneously explain both the transient viral suppression in SIV Cohort 1 [8] and the lack of viral suppression in SIV Cohort 2 [9] after N-803 treatment. To this end, the mathematical model was simultaneously calibrated to SIV viral load and CD8 + T cell counts in both cohorts.…”