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Clustered mutations in HIV-1 gag are consistently required for escape from HLA-B27-restricted cytotoxic T lymphocyte responses.

Kelleher AD, Long C, Holmes EC, Allen RL, Wilson J, Conlon C, Workman C, Shaunak S, Olson K, Goulder P, Brander C, Ogg G, Sullivan JS, Dyer W, Jones I, McMichael AJ, Rowland-Jones S, Phillips RE - J. Exp. Med. (2001)

Bottom Line: In each case, R264K was tightly associated with a leucine to methionine change at residue 268.Its occurrence was associated with a glutamic acid to aspartic acid mutation at residue 260.Outgrowth of CTL escape viruses required high viral loads and additional, possibly compensatory, mutations in the gag protein.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council Human Immunology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom. kelleher@worf.molbiol.ox.ac.uk

ABSTRACT
The immune response to HIV-1 in patients who carry human histocompatibility leukocyte antigen (HLA)-B27 is characterized by an immunodominant response to an epitope in p24 gag (amino acids 263-272, KRWIILGLNK). Substitution of lysine (K) or glycine (G) for arginine (R) at HIV-1 gag residue 264 (R264K and R264G) results in epitopes that bind to HLA-B27 poorly. We have detected a R264K mutation in four patients carrying HLA-B27. In three of these patients the mutation occurred late, coinciding with disease progression. In another it occurred within 1 yr of infection and was associated with a virus of syncytium-inducing phenotype. In each case, R264K was tightly associated with a leucine to methionine change at residue 268. After the loss of the cytotoxic T lymphocyte (CTL) response to this epitope and in the presence of high viral load, reversion to wild-type sequence was observed. In a fifth patient, a R264G mutation was detected when HIV-1 disease progressed. Its occurrence was associated with a glutamic acid to aspartic acid mutation at residue 260. Phylogenetic analyses indicated that these substitutions emerged under natural selection rather than by genetic drift or linkage. Outgrowth of CTL escape viruses required high viral loads and additional, possibly compensatory, mutations in the gag protein.

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Related in: MedlinePlus

Maximum likelihood phylogenetic trees depicting the evolutionary relationships of viruses from patients (a) RT, (b) 007, and (c) 777. The tree is unrooted but the direction of mutations can be inferred by assuming that the oldest sampled sequences are ancestral. All branch lengths are drawn to scale. The labels on each branch correspond to the time point at which the viral sample was taken (years after diagnosis), followed by the amino acid (single letter code) found at positions 260, 264, and 268, respectively. The positions of all putative changes involving amino acids E to D at position 260, R and K at position 264, and M to L at position 268 are indicated with arrows. Note that designation of amino acid changes is difficult inpatients 007 and 777 because viruses from the first sampling time point do not form a single group and are dispersed across the phylogeny. Genbank accession numbers for sequences used to construct phylogenetic trees are available from Genbank/EMBL/DDBJ under accession nos. RT, AF319258, AF319259, AF319260, AF319261, AF319262, AF319263, AF319264, AF319265, AF319266, AF319267, AF319268, AF319269, AF319270, AF319271, AF319272, AF319273, AF319274, AF319275, AF319276, AF319277, AF319278, AF319279, AF319280, AF319281, AF319282, AF319283, AF319284, AF319285, AF319286, AF319287, AF319288, AF319289, AF319290, AF319291, AF319292, AF319293, AF319294, AF319295, AF319296, AF319297, AF319298, AF319299, AF319300, AF319301, AF319302, AF319303, AF319304, AF319305, AF319306, AF319307, AF319308, AF319309, AF319310; 007, AF319174, AF319175, AF319176, AF319177, AF319178, AF319179, AF319180, AF319181, AF319182, AF319183, AF319184, AF319185, AF319186, AF319187, AF319188, AF319189, AF319190, AF319191, AF319192, AF319193, AF319194, AF319195, AF319196, AF319197, AF319198, AF319199, AF319200, AF319201, AF319202, AF319203, AF319204, AF319205, AF319206, AF319207, AF319208, AF319209, AF319210, AF319211, AF319212, AF319213, AF319214, AF319215, AF319216, AF319217, AF319218, AF319219, AF319220, AF319221, AF319222, AF319223, AF319224, AF319225, AF319226, AF319227, AF319228, AF319229, AF319230, AF319231, AF319232, AF319233, AF319234, AF319235, AF319236, AF319237, AF319238, AF319239, AF319240, AF319241, AF319242, AF319243, AF319244, AF319245, AF319246, AF319247, AF319248, AF319249, AF319250, AF319251, AF319252, AF319253, AF319254, AF319255, AF319256, AF319257; and 777, AF319311, AF319312, AF319313, AF319314, AF319315, AF319316, AF319317, AF319318, AF319319, AF319320, AF319321, AF319322, AF319323, AF319324, AF319325, AF319326, AF319327, AF319328, AF319329, AF319330, AF319331, AF319332, AF319333, AF319334, AF319335, AF319336, AF319337, AF319338, AF319339, AF319340, AF319341, AF319342, AF319343, AF319344, AF319345, AF319346, AF319347, AF319348, AF319349, AF319350, AF319351, AF319352, AF319353, AF319354, AF319355, AF319356, AF319357, AF319358, AF319359, AF319360, AF319361, AF319362, AF319363, AF319364, AF319365, AF319366, AF319367, AF319368, AF319369, AF319370, AF319371, AF319372, AF319373, AF319374, AF319375, AF319376, AF319377, AF319378, AF319379, AF319380, AF319381, AF319382, AF319383, AF319384, AF319385, AF319386, AF319387, AF319388, AF319389, AF319390, AF319391, AF319392, AF319393, AF319394, AF319395, AF319396.
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Figure 2: Maximum likelihood phylogenetic trees depicting the evolutionary relationships of viruses from patients (a) RT, (b) 007, and (c) 777. The tree is unrooted but the direction of mutations can be inferred by assuming that the oldest sampled sequences are ancestral. All branch lengths are drawn to scale. The labels on each branch correspond to the time point at which the viral sample was taken (years after diagnosis), followed by the amino acid (single letter code) found at positions 260, 264, and 268, respectively. The positions of all putative changes involving amino acids E to D at position 260, R and K at position 264, and M to L at position 268 are indicated with arrows. Note that designation of amino acid changes is difficult inpatients 007 and 777 because viruses from the first sampling time point do not form a single group and are dispersed across the phylogeny. Genbank accession numbers for sequences used to construct phylogenetic trees are available from Genbank/EMBL/DDBJ under accession nos. RT, AF319258, AF319259, AF319260, AF319261, AF319262, AF319263, AF319264, AF319265, AF319266, AF319267, AF319268, AF319269, AF319270, AF319271, AF319272, AF319273, AF319274, AF319275, AF319276, AF319277, AF319278, AF319279, AF319280, AF319281, AF319282, AF319283, AF319284, AF319285, AF319286, AF319287, AF319288, AF319289, AF319290, AF319291, AF319292, AF319293, AF319294, AF319295, AF319296, AF319297, AF319298, AF319299, AF319300, AF319301, AF319302, AF319303, AF319304, AF319305, AF319306, AF319307, AF319308, AF319309, AF319310; 007, AF319174, AF319175, AF319176, AF319177, AF319178, AF319179, AF319180, AF319181, AF319182, AF319183, AF319184, AF319185, AF319186, AF319187, AF319188, AF319189, AF319190, AF319191, AF319192, AF319193, AF319194, AF319195, AF319196, AF319197, AF319198, AF319199, AF319200, AF319201, AF319202, AF319203, AF319204, AF319205, AF319206, AF319207, AF319208, AF319209, AF319210, AF319211, AF319212, AF319213, AF319214, AF319215, AF319216, AF319217, AF319218, AF319219, AF319220, AF319221, AF319222, AF319223, AF319224, AF319225, AF319226, AF319227, AF319228, AF319229, AF319230, AF319231, AF319232, AF319233, AF319234, AF319235, AF319236, AF319237, AF319238, AF319239, AF319240, AF319241, AF319242, AF319243, AF319244, AF319245, AF319246, AF319247, AF319248, AF319249, AF319250, AF319251, AF319252, AF319253, AF319254, AF319255, AF319256, AF319257; and 777, AF319311, AF319312, AF319313, AF319314, AF319315, AF319316, AF319317, AF319318, AF319319, AF319320, AF319321, AF319322, AF319323, AF319324, AF319325, AF319326, AF319327, AF319328, AF319329, AF319330, AF319331, AF319332, AF319333, AF319334, AF319335, AF319336, AF319337, AF319338, AF319339, AF319340, AF319341, AF319342, AF319343, AF319344, AF319345, AF319346, AF319347, AF319348, AF319349, AF319350, AF319351, AF319352, AF319353, AF319354, AF319355, AF319356, AF319357, AF319358, AF319359, AF319360, AF319361, AF319362, AF319363, AF319364, AF319365, AF319366, AF319367, AF319368, AF319369, AF319370, AF319371, AF319372, AF319373, AF319374, AF319375, AF319376, AF319377, AF319378, AF319379, AF319380, AF319381, AF319382, AF319383, AF319384, AF319385, AF319386, AF319387, AF319388, AF319389, AF319390, AF319391, AF319392, AF319393, AF319394, AF319395, AF319396.

Mentions: Phylogenetic trees were constructed for the viral sequences obtained from three of the patients: RT, 007, and 777 (Fig. 2, a–c) to study the evolutionary processes contributing to the accumulation of mutations clustered around codon 264. In the tree constructed for patient RT, there is a long branch separating the sequences sampled 0.9 yr after enrolment from those collected at later time points (2.4–2.8 yr after enrolment). Two amino acid changes have occurred on this branch: E260D and R264G. It is striking that these two changes are in such close proximity in the amino acid sequence and that they are fixed in all later samples (Fig. 1 d, and online supplemental Table SI). This suggests that either both represent escape mutants, or that one is favored by selection and that the other has been pulled to fixation by genetic linkage.


Clustered mutations in HIV-1 gag are consistently required for escape from HLA-B27-restricted cytotoxic T lymphocyte responses.

Kelleher AD, Long C, Holmes EC, Allen RL, Wilson J, Conlon C, Workman C, Shaunak S, Olson K, Goulder P, Brander C, Ogg G, Sullivan JS, Dyer W, Jones I, McMichael AJ, Rowland-Jones S, Phillips RE - J. Exp. Med. (2001)

Maximum likelihood phylogenetic trees depicting the evolutionary relationships of viruses from patients (a) RT, (b) 007, and (c) 777. The tree is unrooted but the direction of mutations can be inferred by assuming that the oldest sampled sequences are ancestral. All branch lengths are drawn to scale. The labels on each branch correspond to the time point at which the viral sample was taken (years after diagnosis), followed by the amino acid (single letter code) found at positions 260, 264, and 268, respectively. The positions of all putative changes involving amino acids E to D at position 260, R and K at position 264, and M to L at position 268 are indicated with arrows. Note that designation of amino acid changes is difficult inpatients 007 and 777 because viruses from the first sampling time point do not form a single group and are dispersed across the phylogeny. Genbank accession numbers for sequences used to construct phylogenetic trees are available from Genbank/EMBL/DDBJ under accession nos. RT, AF319258, AF319259, AF319260, AF319261, AF319262, AF319263, AF319264, AF319265, AF319266, AF319267, AF319268, AF319269, AF319270, AF319271, AF319272, AF319273, AF319274, AF319275, AF319276, AF319277, AF319278, AF319279, AF319280, AF319281, AF319282, AF319283, AF319284, AF319285, AF319286, AF319287, AF319288, AF319289, AF319290, AF319291, AF319292, AF319293, AF319294, AF319295, AF319296, AF319297, AF319298, AF319299, AF319300, AF319301, AF319302, AF319303, AF319304, AF319305, AF319306, AF319307, AF319308, AF319309, AF319310; 007, AF319174, AF319175, AF319176, AF319177, AF319178, AF319179, AF319180, AF319181, AF319182, AF319183, AF319184, AF319185, AF319186, AF319187, AF319188, AF319189, AF319190, AF319191, AF319192, AF319193, AF319194, AF319195, AF319196, AF319197, AF319198, AF319199, AF319200, AF319201, AF319202, AF319203, AF319204, AF319205, AF319206, AF319207, AF319208, AF319209, AF319210, AF319211, AF319212, AF319213, AF319214, AF319215, AF319216, AF319217, AF319218, AF319219, AF319220, AF319221, AF319222, AF319223, AF319224, AF319225, AF319226, AF319227, AF319228, AF319229, AF319230, AF319231, AF319232, AF319233, AF319234, AF319235, AF319236, AF319237, AF319238, AF319239, AF319240, AF319241, AF319242, AF319243, AF319244, AF319245, AF319246, AF319247, AF319248, AF319249, AF319250, AF319251, AF319252, AF319253, AF319254, AF319255, AF319256, AF319257; and 777, AF319311, AF319312, AF319313, AF319314, AF319315, AF319316, AF319317, AF319318, AF319319, AF319320, AF319321, AF319322, AF319323, AF319324, AF319325, AF319326, AF319327, AF319328, AF319329, AF319330, AF319331, AF319332, AF319333, AF319334, AF319335, AF319336, AF319337, AF319338, AF319339, AF319340, AF319341, AF319342, AF319343, AF319344, AF319345, AF319346, AF319347, AF319348, AF319349, AF319350, AF319351, AF319352, AF319353, AF319354, AF319355, AF319356, AF319357, AF319358, AF319359, AF319360, AF319361, AF319362, AF319363, AF319364, AF319365, AF319366, AF319367, AF319368, AF319369, AF319370, AF319371, AF319372, AF319373, AF319374, AF319375, AF319376, AF319377, AF319378, AF319379, AF319380, AF319381, AF319382, AF319383, AF319384, AF319385, AF319386, AF319387, AF319388, AF319389, AF319390, AF319391, AF319392, AF319393, AF319394, AF319395, AF319396.
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Figure 2: Maximum likelihood phylogenetic trees depicting the evolutionary relationships of viruses from patients (a) RT, (b) 007, and (c) 777. The tree is unrooted but the direction of mutations can be inferred by assuming that the oldest sampled sequences are ancestral. All branch lengths are drawn to scale. The labels on each branch correspond to the time point at which the viral sample was taken (years after diagnosis), followed by the amino acid (single letter code) found at positions 260, 264, and 268, respectively. The positions of all putative changes involving amino acids E to D at position 260, R and K at position 264, and M to L at position 268 are indicated with arrows. Note that designation of amino acid changes is difficult inpatients 007 and 777 because viruses from the first sampling time point do not form a single group and are dispersed across the phylogeny. Genbank accession numbers for sequences used to construct phylogenetic trees are available from Genbank/EMBL/DDBJ under accession nos. RT, AF319258, AF319259, AF319260, AF319261, AF319262, AF319263, AF319264, AF319265, AF319266, AF319267, AF319268, AF319269, AF319270, AF319271, AF319272, AF319273, AF319274, AF319275, AF319276, AF319277, AF319278, AF319279, AF319280, AF319281, AF319282, AF319283, AF319284, AF319285, AF319286, AF319287, AF319288, AF319289, AF319290, AF319291, AF319292, AF319293, AF319294, AF319295, AF319296, AF319297, AF319298, AF319299, AF319300, AF319301, AF319302, AF319303, AF319304, AF319305, AF319306, AF319307, AF319308, AF319309, AF319310; 007, AF319174, AF319175, AF319176, AF319177, AF319178, AF319179, AF319180, AF319181, AF319182, AF319183, AF319184, AF319185, AF319186, AF319187, AF319188, AF319189, AF319190, AF319191, AF319192, AF319193, AF319194, AF319195, AF319196, AF319197, AF319198, AF319199, AF319200, AF319201, AF319202, AF319203, AF319204, AF319205, AF319206, AF319207, AF319208, AF319209, AF319210, AF319211, AF319212, AF319213, AF319214, AF319215, AF319216, AF319217, AF319218, AF319219, AF319220, AF319221, AF319222, AF319223, AF319224, AF319225, AF319226, AF319227, AF319228, AF319229, AF319230, AF319231, AF319232, AF319233, AF319234, AF319235, AF319236, AF319237, AF319238, AF319239, AF319240, AF319241, AF319242, AF319243, AF319244, AF319245, AF319246, AF319247, AF319248, AF319249, AF319250, AF319251, AF319252, AF319253, AF319254, AF319255, AF319256, AF319257; and 777, AF319311, AF319312, AF319313, AF319314, AF319315, AF319316, AF319317, AF319318, AF319319, AF319320, AF319321, AF319322, AF319323, AF319324, AF319325, AF319326, AF319327, AF319328, AF319329, AF319330, AF319331, AF319332, AF319333, AF319334, AF319335, AF319336, AF319337, AF319338, AF319339, AF319340, AF319341, AF319342, AF319343, AF319344, AF319345, AF319346, AF319347, AF319348, AF319349, AF319350, AF319351, AF319352, AF319353, AF319354, AF319355, AF319356, AF319357, AF319358, AF319359, AF319360, AF319361, AF319362, AF319363, AF319364, AF319365, AF319366, AF319367, AF319368, AF319369, AF319370, AF319371, AF319372, AF319373, AF319374, AF319375, AF319376, AF319377, AF319378, AF319379, AF319380, AF319381, AF319382, AF319383, AF319384, AF319385, AF319386, AF319387, AF319388, AF319389, AF319390, AF319391, AF319392, AF319393, AF319394, AF319395, AF319396.
Mentions: Phylogenetic trees were constructed for the viral sequences obtained from three of the patients: RT, 007, and 777 (Fig. 2, a–c) to study the evolutionary processes contributing to the accumulation of mutations clustered around codon 264. In the tree constructed for patient RT, there is a long branch separating the sequences sampled 0.9 yr after enrolment from those collected at later time points (2.4–2.8 yr after enrolment). Two amino acid changes have occurred on this branch: E260D and R264G. It is striking that these two changes are in such close proximity in the amino acid sequence and that they are fixed in all later samples (Fig. 1 d, and online supplemental Table SI). This suggests that either both represent escape mutants, or that one is favored by selection and that the other has been pulled to fixation by genetic linkage.

Bottom Line: In each case, R264K was tightly associated with a leucine to methionine change at residue 268.Its occurrence was associated with a glutamic acid to aspartic acid mutation at residue 260.Outgrowth of CTL escape viruses required high viral loads and additional, possibly compensatory, mutations in the gag protein.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council Human Immunology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom. kelleher@worf.molbiol.ox.ac.uk

ABSTRACT
The immune response to HIV-1 in patients who carry human histocompatibility leukocyte antigen (HLA)-B27 is characterized by an immunodominant response to an epitope in p24 gag (amino acids 263-272, KRWIILGLNK). Substitution of lysine (K) or glycine (G) for arginine (R) at HIV-1 gag residue 264 (R264K and R264G) results in epitopes that bind to HLA-B27 poorly. We have detected a R264K mutation in four patients carrying HLA-B27. In three of these patients the mutation occurred late, coinciding with disease progression. In another it occurred within 1 yr of infection and was associated with a virus of syncytium-inducing phenotype. In each case, R264K was tightly associated with a leucine to methionine change at residue 268. After the loss of the cytotoxic T lymphocyte (CTL) response to this epitope and in the presence of high viral load, reversion to wild-type sequence was observed. In a fifth patient, a R264G mutation was detected when HIV-1 disease progressed. Its occurrence was associated with a glutamic acid to aspartic acid mutation at residue 260. Phylogenetic analyses indicated that these substitutions emerged under natural selection rather than by genetic drift or linkage. Outgrowth of CTL escape viruses required high viral loads and additional, possibly compensatory, mutations in the gag protein.

Show MeSH
Related in: MedlinePlus