Quantifying the Impact of Human Immunodeficiency Virus-1 Escape From Cytotoxic T-Lymphocytes 英文参考文献.docVIP

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Quantifying the Impact of Human Immunodeficiency Virus-1 Escape From Cytotoxic T-Lymphocytes 英文参考文献.doc

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Quantifying the Impact of Human Immunodeficiency Virus-1 Escape From Cytotoxic T-Lymphocytes 英文参考文献

QuantifyingtheImpactofHumanImmunodeficiency Virus-1EscapeFromCytotoxicT-Lymphocytes UlrichD.Kadolsky*,BeccaAsquith DepartmentofImmunology,DivisionofMedicine,ImperialCollegeLondon,London,UnitedKingdom Abstract HIV-1 escape from the cytotoxic T-lymphocyte (CTL) response leads to a weakening of viral control and is likely to be detrimental to the patient. To date, the impact of escape on viral load and CD4 T cell count has not been quantified, + primarilybecauseofsparselongitudinaldataandthedifficultyofseparatingcauseandeffectincross-sectionalstudies.We use two independent methods to quantify the impact of HIV-1 escape from CTLs in chronic infection: mathematical modellingofescapeandstatisticalanalysisofacross-sectionalcohort.Mathematicalmodellingrevealedamodestincrease inlogviralloadof0.051copiesml21perescapeevent.Analysisofthecross-sectionalcohortrevealedasignificantpositive association between viral load and the number of ‘‘escape events’’, after correcting for length of infection and rate of replication. We estimate that a single CTL escape event leads to a viral load increase of 0.11 log copies ml21 (95% confidenceinterval:0.040–0.18),consistentwiththepredictionsfromthemathematicalmodelling.Overall,thenumberof escapeeventscouldonlyaccountforapproximately6%oftheviralloadvariationinthecohort.Ourfindingsindicatethat althoughthelossoftheCTLresponseforasingleepitoperesultsinahighlystatisticallysignificantincreaseinviralload,the biologicalimpactismodest.Wesuggestthatthissmallincreaseinviralloadisexplainedbythesmallgrowthadvantageof thevariantrelativetothewildtypevirus.EscapefromCTLshadameasurable,butunexpectedlylow,impactonviralloadin chronicinfection. Citation: Kadolsky UD, Asquith B (2010) Quantifying the Impact of Human Immunodeficiency Virus-1 Escape From Cytotoxic T-Lymphocytes. PLoS Comput Biol6(11):e1000981.doi:10.1371/journal.pcbi.1000981 Editor:RobJ.DeBoer,UtrechtUniversity,TheNetherlands ReceivedApril18,2010;AcceptedSeptember28,2010;PublishedNovember4,2010 C