title: Identification of sequential viral escape mutants associated with altered T-cell responses in a human immunodeficiency virus type 1-infected individual.
abstract: Control of viremia in natural human immunodeficiency virus type 1 (HIV-1) infection in humans is associated with a virus-specific T-cell response. However, still much is unknown with regard to the extent of CD8(+) cytotoxic T-lymphocyte (CTL) responses required to successfully control HIV-1 infection and to what extent CTL epitope escape can account for rises in viral load and ultimate progression to disease. In this study, we chose to monitor through full-length genome sequence of replication-competent biological clones the modifications that occurred within predicted CTL epitopes and to identify whether the alterations resulted in epitope escape from CTL recognition. From an extensive analysis of 59 biological HIV-1 clones generated over a period of 4 years from a single individual in whom the viral load was observed to rise, we identified the locations in the genome of five CD8(+) CTL epitopes. Fixed mutations were identified within the p17, gp120, gp41, Nef, and reverse transcriptase genes. Using a gamma interferon ELIspot assay, we identified for four of the five epitopes with fixed mutations a complete loss of T-cell reactivity against the wild-type epitope and a partial loss of reactivity against the mutant epitope. These results demonstrate the sequential accumulation of CTL escape in a patient during disease progression, indicating that multiple combinations of T-cell epitopes are required to control viremia.
authors: Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Mark J
authors: MJ
authors: Geels
authors: Marion
authors: M
authors: Cornelissen
authors: Hanneke
authors: H
authors: Schuitemaker
authors: Kiersten
authors: K
authors: Anderson
authors: David
authors: D
authors: Kwa
authors: Jolanda
authors: J
authors: Maas
authors: John T
authors: JT
authors: Dekker
authors: Elly
authors: E
authors: Baan
authors: Fokla
authors: F
authors: Zorgdrager
authors: Remco
authors: R
authors: van den Burg
authors: Martijn
authors: M
authors: van Beelen
authors: Vladimir V
authors: VV
authors: Lukashov
authors: Tong-Ming
authors: TM
authors: Fu
authors: William A
authors: WA
authors: Paxton
authors: Lia
authors: L
authors: van der Hoek
authors: Sheri A
authors: SA
authors: Dubey
authors: John W
authors: JW
authors: Shiver
authors: Jaap
authors: J
authors: Goudsmit
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D017931:DNA Primers; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry; D005814:Genes, Viral; D015658:HIV Infections / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D017386:Sequence Homology, Amino Acid; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014779:Virus Replication / Q000276:immunology
chemical_list: D017931:DNA Primers; D000939:Epitopes