Ourlong-termgoalistoidentifybioactivelipidmetabolitesthataredysregulatedinHIV-infectedindividualsand to gain a fundamental understanding of these lipid metabolites in liver disease pathogenesis and the developmentofliver-relatedcomplications.TheoverallobjectiveistoutilizeHIV/HCV-coinfectionasamodelto probeforunderlyingmechanismsofacceleratedliverfibrosisanddiseaseprogressionwiththeoverallpremise that there is a common final pathway of liver injury that is metabolic in nature. Our central hypothesis is that dysregulation of bioactive lipid metabolism reports on a common mechanism by which HIV-infection, antiretrovirals,andviralco-infectionsinteracttomodulatefibrogenesis.BasedonevidencethatHCVdramatically modulateshostcelllipidmetabolismandHIV-infectionandantiretroviralsalsoperturblipidpathways,wepropose that accelerated fibrogenesis in HIV is due, at least in part, to additive hits on lipid metabolism and excess accumulationofdetrimentallipidmetabolites,likeceramide.Thus,weusedamulti-targetedlipidomicsplatform to investigate bioactive lipids as predictors of liver fibrosis stage. Our preliminary studies indicate that (1) expressionofbioactivelipidscorrelateswithhistopathologicstageofliverdiseaseinpatientswithHIV/HCVand HCV infections, and (2) clearance of HCV using DAA regimens results in rapid changes in lipid homeostasis pathways.TheproposedworkwilltestourhypothesisthatdysregulationofbioactivelipidmetabolisminHIV- infectionplaysakeyroleinprogressiveliverdisease,aswellasthecorollaryhypothesisthatvariationsinlipid expression can be used as noninvasive assessments of liver disease complications. We will accomplish the objectiveoftheapplicationbypursuingthefollowingSpecificAims:(1)Discoverandvalidatespecificexpression patternsofcirculatingbioactivelipidmetabolitesthatarepredictiveofend-stageliverdiseasecomplicationsin patients with HIV/HCV-coinfection;? (2) Determine unique patterns of circulating bioactive lipid metabolite expression for patients with HIV-infection including those with and without HCV co-infection and non-virally mediatedmetabolicliverdisease(NAFLD/NASH);?(3)Identifyspecificbioactivelipidmetaboliteexpressionthat ismodifiedbyDAAtreatment-inducedHCVclearanceandstatininitiationinHIV/HCVco-infectedpatients.The impactofthisproposalwillbetofundamentallychangeourunderstandingofthemetabolicmechanismsofliver diseaseinpeoplelivingwithHIV.Wewilldevelopanovel,noninvasiveassessmentofend-stageliverdisease complicationsthatwillhaveimmediateclinicalutility.Wewillalsoapplythisvalidated,noninvasivemetabolite profile as a tool to dissect lipid dysregulation related to HCV infection and other etiologies of liver disease includingHIVpersistenceandlong-termantiretroviraltoxicitywhichcouldinformfuturemechanisticstudiesand identifypotentialtherapeutictargetsoffibrogenesis.
This R01 application is highly relevant to the health of the American Public, as it seeks to understand the pathogenesisofacceleratedliverdiseaseinHIV/HCVco-infectedpersons,aUSpopulationthatcomprisesover 250,000 Americans. Co-infected patients experience more rapidly progressive hepatic fibrogenesis, cirrhosis, anddecompensatedliverdiseasethanmatchedHIV-uninfected/HCV-infectedpatientsandamongHIV-infected persons HCV co-infection is associated with higher all-cause mortality. This proposal seeks to address responsive topics within this RFA including (1) define mechanisms by which HIV-infection accelerates liver fibrosisanddiseaseprogressioninmono-HIVandco-infectionwithHCVand(2)developmentofnoninvasive meansofassessmentofliverdiseaseandfibrosisinHIV-infectedindividuals.Byincreasingourunderstanding ofwhyHIV/HCVdualinfectionsresultingreaterhumandiseasewecanidentifypathwaysandtherapeutictargets thatcansloworreversediseaseprogression.
| Naggie, Susanna; Clement, Meredith; Lusk, Sam et al. (2018) Using Stepwise Pharmacogenomics and Proteomics to Predict Hepatitis C Treatment Response in Difficult to Treat Patient Populations. Proteomics Clin Appl :e1800006 |
| Chan, Austin; Patel, Keyur; Naggie, Susanna (2017) Genotype 3 Infection: The Last Stand of Hepatitis C Virus. Drugs 77:131-144 |
| Zuckerman, Autumn; Chastain, Cody A; Naggie, Susanna (2017) Retreatment Options Following HCV Direct Acting Antiviral Failure. Curr Treat Options Infect Dis 9:389-402 |
