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microbial translocation during hyperacute SIV infection Adam Ericsen1,2, Michael Lauck3, Mariel Mohns3, Sarah DiNapoli4, James Mutschler5, Justin Greene3, Jason Weinfurter1, Gabrielle Lehrer-Brey5, Kristin Crosno5, Eric Peterson5, Matthew Reynolds1, Roger Wiseman1, Benjamin Burwitz6,7, Jonah Sacha6,7, Thomas Friedrich 5,8, Jason Brenchley4, David O'Connor 1,5 1 University of Wisconsin-Madison, Pathology and Laboratory Medicine, Madison, United States, 2 University of Wisconsin-Madison, Virology Training Program, Madison, United States, 3 University of Wisconsin-Madison, Madison, United States, 4 National Institute of Allergy and Infectious Disease, Laboratory of Molecular Microbiology, Bethesda, United States, 5 Wisconsin National Primate Research Center, Madison, United States, 6 Oregon Health & Sciences University, Vaccine & Gene Therapy Institute, Beaverton, United States, 7 Oregon Health & Sciences University, National Primate Research Center, Beaverton, United States, 8 University of Wisconsin-Madison, Pathobiological Sciences, Madison, United States viremia drives disease progression SIV RNA copies/ml 9 8 hypothesis 7 6 the composition of the gut or blood microbial community differentiates controllers from progressors. 5 4 3 2 0 7 14 21 28 35 42 days post-infection [y-axis is log 10-transformed] 49 56 63 70 77 84 91 98 105 112 119 126 133 140 but what drives viremia? SIV RNA copies/ml 9 hypothesis 8 7 the composition of the gut or blood microbial communities differentiates controllers from progressors. 6 5 4 3 2 0 7 14 21 28 35 42 days post-infection [y-axis is log 10-transformed] 49 56 63 70 77 84 91 98 105 112 119 126 133 140 study design intrarectal SIVmac239 -42 0 8 14 18 21 35 56 monitored into chronic infection days post-infection ‣ 8 macaques ‣ MHC-identical (HLA-A & HLA-B) 16S rDNA seq of stool 16S rDNA seq & qPCR of plasma flow cytometry PBMC (CD4+CCR5+) plasma analyte ELISA cynomolgus macaques rhesus macaques 16S rDNA copies/ml 6 5 4 3 2 1 -5 0 5 10 15 20 Day Post-Infection days post SIV infection 25 30 35 LPS-binding antibodies (EndoCAb) soluble CD14 frequency absolute count but does microbial translocation increase viremia? inducing microbial translocation in macaque elite controllers water with 0.5% dextran sulfate sodium (DSS) administered orally intrarectal SIVmac239 +1 year -35 -21 -14 -7 0 1 2 3 4 … days post-DSS treatment days post-dextran sulfate sodium (DSS) treatment monitored for 10 weeks inducing microbial translocation in macaque elite controllers Data 2 Data 2 simian immunodeficiency virus infection water with 0.5% dextran 7 sulfate sodium (DSS) administered orally 6 intrarectal SIVmac239 5 4 monitored for 8 weeks +1 year 3 -35 -21 -14 1 2 3 4 … days post-infection days post-DSS 0DSS 330 325 340 -5 320 335 80 120 160 200 240 280 -20 -15 -10 315 330 310 325 305 320 300 315 280 310 240 305 300 200 280 160 240 120 40 200 80 0 160 40 120 0 80 0 days post-DSS treatment 2 40 -7 DSS 6 water with 0.5% dextran sulfate sodium (DSS) administered orally intrarectal 5 SIVmac239 4 +1 year 3 -35 -21 -14 -7 0 1 2 3 4 … monitored for 8 weeks Dayssulfate Post-DSS days post-dextran sodium treatment 70 65 60 55 50 45 40 35 30 25 20 15 10 5 0 -5 -10 -15 -20 -25 2 -30 days post-DSS treatment -35 Log10 vRNA copies/ml plasma inducing microbial translocation in macaque elite controllers inducing microbial translocation in macaque elite controllers increased plasma levels of intestinal fatty-acid binding protein increased plasma water with 0.5%16S dextran rDNA load sulfate sodium (DSS) administered orally intrarectal SIVmac239 +1 year -35 -21 -14 -7 0 1 2 3 4 … days post-DSS treatment days post-dextran sulfate sodium treatment monitored for 8 weeks inducing microbial translocation in macaque elite controllers water with 0.5% dextran sulfate sodium (DSS) administered orally intrarectal SIVmac239 +1 year -35 -21 -14 -7 0 1 2 3 4 … days post-DSS treatment days post-dextran sulfate sodium treatment monitored for 8 weeks acknowledgements ‣ AIDS Vaccine Research Laboratory • • • • • • • Meghan Breitbach Ken Drinkwater Dawn Dudley Thomas Friedrich Samantha Gieger Michael Graham Justin Greene • • • • • • • Julie Karl Michael Lauck Gabrielle Lehrer-Brey Mariel Mohns James Mutschler David O’Connor Trent Prall ‣ Wisconsin National Primate Research Center • Kristin Crosno • Eric Peterson • Buddy Capuano ‣ NIAID • Sarah DiNapoli • Jason Brenchley • • • • • Eva Rakesz Mustafa Rasheed Matthew Reynolds Jason Weinfurter Roger Wiseman ‣ Oregon Health & Sciences University • Benjamin Burwitz • Jonah Sacha ‣ NCI • Jacob Estes ‣ Funding • NIH • T32 AI078985