Background
The RV550 clinical trial assessed whether the IL-15 superagonist (IL-15SA) N803 administered alongside ART during acute HIV infection could enhance antiviral immunity and reduce viral persistence. We designed a parallel nonhuman primate study to assess the effects of IL-15SA on viral dynamics and SIV-specific T cell responses in tissues.
Methods
TwelveMamu A*01+ rhesus macaques (RM), divided into 2 balanced groups (n=6 each), were inoculated intravenously with SIVmac239M (5000 IU) before starting daily ART (TDF, FTC, DTG) 9 days post-infection (dpi). Six RM received subcutaneous IL-15SA (100 ug/kg) at 11, 32 and 53 dpi. Blood, cerebral spinal fluid (CSF), lymph node (LN), bone marrow (BM) and spleen were collected longitudinally prior to necropsy at study endpoint (15±1 weeks). SIV viral loads were measured by ddPCR and cellular immune dynamics by flow cytometry.
Results
IL-15SA treatment transiently increased frequencies of total memory CD8+ and SIV Gag CM9-specific CD8+ T cells in blood (p=0.009 and p=0.002), LN (p=0.009 and p=0.04), BM (p=0.002 and p=0.004), spleen (p=0.002 and p=0.03) and CSF (p=0.009 and p=0.2), respectively, compared to controls. Similar increases in memory CD4+ T cells and NK cells were also observed in response to IL-15SA. Despite this, SIV RNA levels in plasma and CSF were not significantly different between IL-15SA-treated RM and controls. At necropsy, while frequencies of memory CD8+ T cells in blood were similar across both groups, levels remained elevated in LN (p=0.009) and spleen (p=0.004), suggesting some effects of IL-15SA persisted. However, cell-associated SIV DNA and RNA in PBMC, LN and frontal lobe were also not significantly different between treatment groups.
Conclusions
Consistent with RV550, we found that IL-15SA administered with ART during acute infection was safe and enhanced the expansion of SIV-specific CD8+ T cells in blood and lymphoid tissues. However, IL-15SA alone, in the absence of additional adjuvant therapies, was insufficient to significantly reduce SIV persistence in blood or tissues.
Table or Figure
