IndividualsinfectedwithHepatitisCvirus(HCV)willeithercleartheirinfection(becomeHCV RNAnegative)ordeveloppersistentinfectionwithinthefirsttwoyearsofinfection.HIVinfection leadstoimmunedysfunctionandismanifestedindecreaseratesofspontaneouscontrolof HCVinfectioninHIV/HCVcoinfectedindividuals.Highlyactiveantiretroviraltherapies(HAART) effectivelysuppressHIVreplicationresultinginimmunereconstitutionwhichmayaffect spontaneouscontrolofHCVinfection.Afewcasereportsandourpreliminarydatademonstrate thatspontaneouscontrolofHCVinfectioncanoccurinHIV/HCVcoinfectedindividuals chroniciallyinfectedwithHCVforupto21yearsfollowingeffectiveHAART(HIVRNA>40 copies/ml).Thus,weproposetodeterminetheprobabilityofspontaneouscontrolofchronic HCVinfectionfollowingeffectiveHAARTandidentifyassociatedimmunecorrelates. Inourstudy,wewillinvestigateHAART-mediatedspontaneousHCVclearanceusingthree largeHIVcohorts:MulticenterAIDSCohortStudy,Women?sInteragencyHIVStudy,andAIDS LinkedtotheIntraVenousExperiencestudy.ComprehensiveHCVvirologicaltestingwillbe usedtoaccuratelyidentifyspontaneousclearanceevents.Weexpecttoobservespontaneous controlofHCVviremiainatleast15%ofHIV/HCVcoinfectedsubjectsfollowingeffective HAART.Pre-HAART,post-HAARTandpost-HCVclearancesamplesfromcase(Clearance) subjectsandtime-matchedspecimensfrommatchedcontrol(Chronic)subjectswillbeselected forfurtheranalysis.HostfactorswillbeassessedfortheirassociationwithHAART-mediated spontaneouscontrolofchronicHCVinfection.
In Aim2, HCV-specificTcellresponsesincase andcontrolPBMCspecimenswillbeassessedusingELISpotanalysis.Weexpectthatthe breadth(#ofpositivepeptidepools)andmagnitude(#ofspotformingcolonies)ofHCV-specific Tcellresponseswillbegreaterincasescomparedtocontrols.
In Aim3, HCV-specific neutralizingantibody(nAb)responseswillbemeasuredusingalibraryofHCVpseudoparticles. Weexpecttodemonstrateanincreasedbreadth(#ofHCVppneutralized)andmagnitude(titer) incasescomparedtocontrols. Withsuccessfulcompletionofthisstudywewillbegintounderstandimmuneprocessesthatare restoredbyHAARTandalsoimportantincontrolofHCVinfection.Identificationofimmune correlatesassociatedwithHAART-mediatedspontaneousHCVclearancewillleadtofurther clinicalandbasicscienceinvestigationsintoHIVsuppressionofHCVimmuneresponsesand mayhighlightpotentialtargetsfordevelopmentofanHCVvaccine.
HIV infection has deleterious effects on anti-HCV immune responses as demonstrated by a decreased rate of spontaneous control of HCV infection in HIV/HCV coinfected individuals. Previous case reports and our preliminary data suggest that spontaneous clearance in chronically-infected individuals can occur following HAART-mediated suppression of HCV replication. These data will provide insight into HAART-mediated immune reconstitution and may be applicable to research into the development of an HCV vaccine.
