?url_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Adc&rft.relation=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F39073%2F&rft.title=Identification+of+Circulating+Biomarkers+of+HIV+Disease+Progression&rft.creator=Stephenson%2C+Katrina&rft.description=Understanding+the+ability+of+Nonprogressors+(NP)+to+control+HIV+disease+progression+may+lead+to+novel+therapeutic+strategies+and+vaccines%2C+with+the+potential+to+make+a+significant+contribution+to+the+field+of+public+health.+A+small+percentage+of+HIV+infected+individuals+control+HIV+disease+progression+for+many+years+without+therapeutic+intervention%2C+defined+as+long-term+nonprogressors+(NP).+We+have+demonstrated+that+all+professional+antigen+presenting+cells+(APC)+(B+cells%2C+dendritic+cells+(DC)+and+macrophages)+from+NP+have+the+unique+inability+to+mediate+HIV+trans+infection+of+autologous+and+heterologous+CD4%2BT+cells.+We+have+linked+this+phenotype+to+alterations+in+cholesterol+metabolism+in+APC%2C+specifically+an+increased+activity+of+the+reverse+cholesterol+transporter+ABCA-1%2C+and+to+depletion+of+cholesterol+in+cell+membrane+lipid+rafts.+ABCA1+activity+could+be+modulated+by+transcriptional+or+post+transcriptional+factors.+Our+data+show+that+plasma+from+NP+elicit+higher+cholesterol+efflux+from+macrophages+in+males+and+females+than+Progressors+(PR).%0D%0AIt+was+also+our+aim+to+identify+soluble%2C+circulating+biomarkers+that+could+modulate+ABCA1+activity%2C+thus+being+associated+with+control+of+HIV+disease+progression.+A+bioactive+fatty+acid+screen+was+performed+on+a+subset+of+NP+and+PR+samples+that+have+been+well-characterized+by+testing+for+APC+mediated+trans+infection.+Analysis+by+liquid-chromatography-mass+spectrophotometry+identified+metabolites+present+at+a+higher+level+in+NP+than+PR%2C+specifically+5-+oxo-eicosatetranoic+acid+(5-Oxo-ETE).+Preliminary+data+of+5-oxo+show+that+treatment+of+APC+at+5%CE%BCM+reduces+the+efficiency+of+HIV+trans+infection+of+CD4%2BT+cells.+A+second+molecule+that+was+tested+was+25-Hydroxycholesterol+(25HC)%2C+which+interferes+with+virus-cell+membrane+fusion+and+reduces+inflammatory+factors+and+cytokines.+Serum+from+HIV+infected+individuals+was+tested+for+25HC+content+by+ELISA%2C+and+preliminary+data+show+that+25HC+levels+are+slightly+higher+in+NP+than+PR%2C+but+more+samples+need+to+be+analyzed.+A+trans+infection+assay+in+the+presence+of+25HC+was+also+performed+and+it+was+found+that+treatment+of+B+cells+with+25HC+in+culture+strongly+inhibits+HIV+trans+infection.%0D%0AGenetic+factors+have+been+identified+that+contribute+to+cholesterol+efflux+capacity+in+men+and+women.+SNPs+were+identified+by+Villard+et.al.+that+affect+the+ability+of+macrophages+to+efflux+cholesterol+and+were+implicated+in+atherosclerotic+development.+These+SNPs+were+tested+in+our+HIV+NP+and+PR+cohorts.+Two+SNPs+were+found+to+be+significantly+associated+with+the+male+NP%2C+contributing+to+differences+in+cholesterol+metabolism+and+homeostasis+in+male+and+female+NP+and+PR.&rft.date=2020-07-30&rft.type=University+of+Pittsburgh+ETD&rft.type=PeerReviewed&rft.format=application%2Fpdf&rft.language=en&rft.identifier=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F39073%2F1%2FStephensonKatrina_MSThesis_April2020.pdf&rft.identifier=++Stephenson%2C+Katrina++(2020)+Identification+of+Circulating+Biomarkers+of+HIV+Disease+Progression.++Master's+Thesis%2C+University+of+Pittsburgh.++++(Unpublished)++