Abstract
To investigate possible mechanisms behind HIV-1 escape from CTL, we performed detailed longitudinal analysis of Gag (SLYNTVATL)- and RT (ILKEPVHGV)-specific CTL responses and plasma epitope sequences in five individuals. Among those with CTL against consensus epitope sequences, epitope mutations developed over several years, invariably followed by decay of the CTL targeting the consensus epitopes. The maturation state of the CTL varied among individuals and appeared to affect the rate of epitope mutation and CTL decay, despite similar IFN-gamma production. Escape mutations were oligoclonal, suggesting fitness constraints. The timing of escape indicated that the net selective advantage of escape mutants was slight, further underscoring the importance of understanding factors determining selective pressure and viral fitness in vivo. Our data show surprisingly consistent decay of CTL responses after epitope escape mutation and provide insight into potential mechanisms for both immune failure and shifting CTL specificities.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adult
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Amino Acid Sequence
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / pathology
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CD8-Positive T-Lymphocytes / virology
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cytotoxicity, Immunologic* / genetics
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Epitopes, T-Lymphocyte / genetics*
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Epitopes, T-Lymphocyte / immunology
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Evolution, Molecular
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Gene Products, gag / genetics
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Gene Products, gag / immunology
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Gene Products, pol / genetics
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Gene Products, pol / immunology
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Genetic Variation / immunology
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HIV Seropositivity / genetics
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HIV Seropositivity / immunology
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HIV Seropositivity / virology
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HIV-1 / genetics*
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HIV-1 / immunology*
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Humans
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Interferon-gamma / biosynthesis
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Lymphocyte Count
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Male
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Molecular Sequence Data
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Mutation*
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Peptide Fragments / genetics
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Peptide Fragments / immunology
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Phylogeny
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Sequence Alignment
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T-Lymphocytes, Cytotoxic / immunology*
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T-Lymphocytes, Cytotoxic / pathology
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T-Lymphocytes, Cytotoxic / virology*
Substances
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Epitopes, T-Lymphocyte
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Gene Products, gag
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Gene Products, pol
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Peptide Fragments
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Interferon-gamma