Abstract

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.

Public Health Relevance

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI124923-02
Application #
9540789
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sharp, Gerald B
Project Start
2017-08-08
Project End
2019-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205