Determinants of human immunodeficiency virus type 1 escape from the primary CD8+ cytotoxic T lymphocyte response.
CD8+ cytotoxic T lymphocytes (CTLs) play an important role in containment of virus replication in primary human immunodeficiency virus (HIV) infection. HIV's ability to mutate to escape from CTL pressure is increasingly recognized; but comprehensive studies of escape from the CD8 T cell response in primary HIV infection are currently lacking. Here, we have fully characterized the primary CTL response to autologous virus Env, Gag, and Tat proteins in three patients, and investigated the extent, kinetics, and mechanisms of viral escape from epitope-specific components of the response. In all three individuals, we observed variation beginning within weeks of infection at epitope-containing sites in the viral quasispecies, which conferred escape by mechanisms including altered peptide presentation/recognition and altered antigen processing. The number of epitope-containing regions exhibiting evidence of early CTL escape ranged from 1 out of 21 in a subject who controlled viral replication effectively to 5 out of 7 in a subject who did not. Evaluation of the extent and kinetics of HIV-1 escape from >40 different epitope-specific CD8 T cell responses enabled analysis of factors determining escape and suggested that escape is restricted by costs to intrinsic viral fitness and by broad, codominant distribution of CTL-mediated pressure on viral replication.
Jones
Nicola A
NA
Viral Immunology Group, The Edward Jenner Institute for Vaccine Research, Compton, Newbury, Berkshire RG20 7NN, England, UK.
Wei
Xiping
X
Flower
Darren R
DR
Wong
Mailee
M
Michor
Franziska
F
Saag
Michael S
MS
Hahn
Beatrice H
BH
Nowak
Martin A
MA
Shaw
George M
GM
Borrow
Persephone
P
D000595:Amino Acid Sequence; D017951:Antigen Presentation; D002860:Chromium Radioisotopes; D017931:DNA Primers; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D015750:Genes, gag / Q000235:genetics; D015756:Genes, tat / Q000235:genetics; D019302:HIV Envelope Protein gp160 / Q000235:genetics; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000821:virology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000821:virology*
D002860:Chromium Radioisotopes; D017931:DNA Primers; D018984:Epitopes, T-Lymphocyte; D019302:HIV Envelope Protein gp160; D007371:Interferon-gamma