GSE184495
IFNalpha-blockade during ART-treated SIV infection lowers tissue vDNA, rescues immune function, and improves overall health
The induction of type I interferons during acute viral infections drives local and systemic anti-viral responses. However, in chornic virus infection these type I interferon driven responses can be detrimental and can be characterized impaired immune responses (greater T cell exhaustion) and an overall decline in health outcomes. To parse out the role of type I IFN and assess the therapeutic impact of blocking type I IFN, we administered IFN-a blocking antibody to a cohort of SIV-infected ART treated Maccaca mulata. After 9 weeks of treatment (1 injection per week), we observed a significant reduction in the SIV-DNA levels in the lymphnode. This reduced SIV reservoir was seem with a systemic increase in immune cell subset signatures associated with better CD8 T cell function and lower plasma levels of TGF-beta. In addition, upon interruption of ART (16 weeks after ART initiation and after 16 rounds of anti-IFNa infusion), we observed that the non-human primates that underwent type I interferon blockade maintained better overall health and hemoglobin levels. Overall design: 12 female Rhesus Macaques (4-5 years of age) were intravenously challenged with SIVmac251 after testing negative for simian retrovirus, simian T-lymphotropic virus, hepatitis B, and helminthic infections. At 8 weeks p.i., NHPs commenced an ART treatment regimen of L-612 (RAL, 150 mg PO BID, Merck), emtricitabine (FTC, 30 mg/kg/day, Gilead), tenofovir (PMPA, 20 mg/kg/day, Gilead), and darunavir (DRV, 400 mg PO BID, Tibotec) until ATI at 36 weeks p.i. After 12 weeks of ART (20 weeks p.i.), 6 NHPs received anti-IFN? humanized Ab AGS-009 i.v. at 10-11 mg/kg and the other 6 control NHPs received an irrelevant Ab (an anti-hepatitis B antibody, prepared by Keith Reimann) weekly for 16 weeks. AGS-009 and control Ab were administered i.v. in 50 ml saline solution, with an injection rate of 2.5-8 ml/min. Peripheral blood, rectal pinch biopsies, and peripheral lymph node biopsies were sampled to evaluate VL, CD4+ T cell counts, immune phenotype and function, and transcriptional and serological signatures.