Abstract

The2015UNAIDSreportestimatesthatover35millionpeopleareinfectedwithHIV.Despitethelack ofasterilizingcure,antiretroviraldrugtherapies(ART)effectivelysuppressviralreplicationininfected individuals.However,only17millioninfectedindividualshaveaccesstoART.Additionally,ARTisa life-longtherapythatrequiresdailyadministrationandisassociatedwitharangeofunwantedside effects.Broadlyneutralizingantibodies(bNAbs)maybeabletosupplementorreplaceART.Several suchantibodieshavealreadyshownpromiseinhumanclinicaltrials,whereasingledosecandecrease viremiainHIV-1infectedindividuals.However,viralreboundoccursrapidlyduringtreatmentasthe bNAbconcentrationdecreasesandresistantvariantsareselected.Adeno-associatedvirus(AAV) vectorscanexpressbNAbsforyearsatconcentrationscapableoflimitingviralevolutionand maintainingviralsuppression.However,weandothergroupshaveshowntheemergenceofanti-drug antibodies(ADA)toexpressedbNAbsthatcanlimittheirexpression.InthisK99/R00proposal,Iwill addressthreekeyquestionsassociatedwiththeuseofAAV-deliveredbNAbsinafunctionalcure.1) WhichbNAbshavebiophysicalandneutralizationpropertiesconsistentwithsuppressingan establishedinfection?2)CanvectorandAAVcapsidoptimizationincreasebNAbexpressionandhelp limitthehostADAresponse?3)CanAAV-deliveredbNAbssuppressanestablishedSHIVinfectionin rhesusmacaques,obviatingtheneedforART?Byansweringthesequestions,wewilldeterminehow besttouseAAVvectorstotreatanAAVinfection,andprovideinsightforinvestigatorsusingAAVin otherclinicalcontexts.MyresearchwithAAVandHIV-1systemsandmydevelopmentofnon-human primateprojectsasaRuthL.KirschsteinFellowhaveprovidedmewiththetrainingnecessaryto completetheseaims.TSRIprovidesanoutstandingresearchenvironmentforcollaborativescience, especiallyintheHIVfield.Moreover,IwillattendcoursesofferedatTSRIandColdSpringHarborthat willprovidefurthertrainingonbecominganindependentinvestigator.Mymentor,Dr.Farzan,along withmyScientificAdvisoryCommitteeconsistingofDrs.RonDesrosiers,SusanaValenteandHyeryun Choe,arecommittedtoprovidingmewithanexcellenttrainingindevelopingmyresearchgoalsand improvingmygrantwritingskillsforfutureR01submissions.TheskillsIacquireduringthetraining phasewillserveasafoundationformyownresearchprogramduringtheindependentphase,withthe specificgoalsofdevelopingnewgene-therapyvectorsandapplyingthesevectorstohumandiseases.

Public Health Relevance

Althoughtheuseofantiretroviraltherapy(ART)hasallowedHIV-1infectedindividualstolivewithout detectablevirus,ARTcancauseundesirableside-effects,isexpensivetodistributeinresource-poor settings,andrequiresregularcompliance.Adeno-associatedvirus(AAV)vectorscanprovidelong-term expressionofHIV-1broadlyneutralizingantibodies(bNAbs),possiblyreplacingdailyadministrationof ART.HereweapplynovelandestablishedtechnologiestooptimizeAAV-mediatedexpressionof bNAbs,anddetermineifthesebNAbscanestablishafunctionalcureinrhesusmacaques.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Career Transition Award (K99)
Project #
5K99AI138860-02
Application #
9996523
Study Section
Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
Program Officer
Conley, Tony J
Project Start
2019-08-16
Project End
2021-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost

  Institution

Name
Scripps Florida
Department
Type
DUNS #
148230662
City
Jupiter
State
FL
Country
United States
Zip Code
33458