Identification of sequential viral escape mutants associated with altered T-cell responses in a human immunodeficiency virus type 1-infected individual.
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.
Geels
Mark J
MJ
Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Cornelissen
Marion
M
Schuitemaker
Hanneke
H
Anderson
Kiersten
K
Kwa
David
D
Maas
Jolanda
J
Dekker
John T
JT
Baan
Elly
E
Zorgdrager
Fokla
F
van den Burg
Remco
R
van Beelen
Martijn
M
Lukashov
Vladimir V
VV
Fu
Tong-Ming
TM
Paxton
William A
WA
van der Hoek
Lia
L
Dubey
Sheri A
SA
Shiver
John W
JW
Goudsmit
Jaap
J
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
D017931:DNA Primers; D000939:Epitopes