Abstract The IL-15 superagonist N-803 has been shown to enhance the function of CD8 T cells and NK cells. We previously found that in a subset of vaccinated, ART-naïve, SIV+ rhesus macaques, N-803 treatment led to a rapid but transient decline in plasma viremia that positively correlated with an increase in the frequency of CD8 T cells. Here we tested the hypothesis that prophylactic vaccination was required for N-803 mediated suppression of SIV plasma viremia. We vaccinated rhesus macaques with a DNA prime/Ad5 boost regimen using vectors expressing SIVmac239 gag, with or without a plasmid expressing IL-12, or left them unvaccinated. Animals were then intravenously infected with SIVmac239M. Six months after infection, animals were treated with N-803. We found no differences in control of plasma viremia during N-803 treatment between vaccinated and unvaccinated macaques. Furthermore, the SIV-specific CD8 T cells displayed no differences in frequency or ability to traffic to the lymph nodes. Interestingly, when we divided the SIV+ animals based on plasma viral load set-point prior to N-803 treatment, N-803 increased the frequency of SIV-specific T cells expressing ki-67+ and granzyme B+ in animals with low plasma viremia (&lt;10 4 copies/mL; SIV controllers) compared to animals with high plasma viremia (&gt;10 4 copies/mL;SIV non-controllers). In addition, Gag-specific CD8 T cells from the SIV+ controllers had a greater increase in CD107a+CD8+ T cells when compared to SIV+ non-controllers. Overall, our results indicate that N-803 is most effective in SIV+ animals with a pre-existing immunological ability to control SIV replication.

Control of SIV infection in prophylactically vaccinated, ART-naïve macaques is required for the most efficacious CD8 T cell response during treatment with the IL-15 superagonist N-803