Clustered Mutations in HIV-1 Gag Are Consistently Required for Escape from Hla-B27–Restricted Cytotoxic T Lymphocyte Responses

Kelleher, Anthony D.; Long, Chad; Holmes, Edward C.; Allen, Rachel; Wilson, Jamie; Conlon, Christopher P.; Workman, Cassy; Shaunak, Sunil; Olson, Katherine E.; Goulder, Philip; Berthou, Christian; Ogg, Graham S.; Sullivan, John S.; Dyer, Wayne B.; Jones, Ian M.; McMichael, Andrew J.; Rowland‐Jones, Sarah; Phillips, Rodney E.

doi:10.1084/jem.193.3.375

Cited by 416 publications

(434 citation statements)

References 52 publications

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“…Indeed HIV has been shown to escape from CTL immune surveillance by mutation at P2 [3,30], and this escape is mediated by immune selection pressure [31,32]. The viral capsid interactions between two neighboring p24 molecules are mediated by residues within the HIV epitope, and it appears that modification of the P6 leucine to methionine permits mutation of the P2 arginine without significant loss of viral fitness [31]. A P6 L-to-M mutation occurs prior to, [26] were based on the structure of the KIR2DL1-HLA-Cw4 complex [27].…”

Section: Discussionmentioning

confidence: 99%

“…or coincidentally with, mutation of the P2 arginine to threonine, lysine or aspartate [31,32]. Studies have shown that the M6 mutant retains full binding potential to the HLA-B*2705 groove [30,31], and the HLA-B*2705-HIV structure indicates that the P6 leucine side chain, being solvent-exposed, plays little role in stabilizing the HIV epitope's binding to HLA-B*2705.…”

Section: Eur J Immunol 2005 35: 341-351mentioning

confidence: 99%

“…Studies have shown that the M6 mutant retains full binding potential to the HLA-B*2705 groove [30,31], and the HLA-B*2705-HIV structure indicates that the P6 leucine side chain, being solvent-exposed, plays little role in stabilizing the HIV epitope's binding to HLA-B*2705. We predict the mutation of P6L to methionine would have little overall impact on the peptide conformation, as there is ample space to accommodate a slightly bulkier methionine side chain.…”

Section: Eur J Immunol 2005 35: 341-351mentioning

confidence: 99%

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Crystal structures and KIR3DL1 recognition of three immunodominant viral peptides complexed to HLA‐B*2705

et al. 2005

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We have solved the crystal structures of three HLA‐B*2705–peptide complexes with the immunodominant viral peptides: EBV EBNA3C 258–266 (RRIYDLIEL), influenza (flu) nucleoprotein NP383–391 (SRYWAIRTR), and HIV gag 264–273 (KRWIILGLNK). Long‐term non‐progression during HIV infection has been associated with presentation by HLA‐B*2705, and T cell recognition, of the highly immunodominant KRWIILGLNK peptide. The tight hydrogen‐bonding network observed between the HLA‐B*2705 B‐pocket and the peptide P2 arginine guanadinium anchor explains why mutation of this residue during HIV infection results in loss of peptide binding, immune escape and progression to AIDS. Prominent, solvent‐exposed structures within these peptides may participate in generating T cell responses to these immunodominant epitopes. In the HLA‐B*2705 complex with flu NP383–391, the amino acid side chains of residues 4, 7 and 8 are solvent‐exposed whilst in the HIV decamer, the main‐chain bulges into the solvent around P7. Thus, HLA‐B*2705 presents viral peptides in a range of conformations. Tetrameric complexes of HLA‐B*2705 with the HIV and flu but not EBV peptides bound strongly to the killer‐Ig‐like receptor (KIR)3DL1. Substitution of EBV P8 glutamate to threonine allowed recognition by KIR3DL1. In the HLA‐B*2705–EBV structure the P8 glutamate side chain is solvent‐exposed and may inhibit KIR3DL1 binding through electrostatic forces.See accompanying Commentary: http://dx.doi.org/10.1002/eji.200425875

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Section: Discussionmentioning

confidence: 99%

Section: Eur J Immunol 2005 35: 341-351mentioning

confidence: 99%

Section: Eur J Immunol 2005 35: 341-351mentioning

confidence: 99%

See 1 more Smart Citation

Crystal structures and KIR3DL1 recognition of three immunodominant viral peptides complexed to HLA‐B*2705

et al. 2005

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“…If escape occurs in variable viruses, it is highly epitope dependent, as is clear from detailed studies of HLA-B27-restricted epitopes in HIV [71][72][73]. Some of these epitopes may fall in regions that are 'constrained' or stable within the virus, due to conserved structure or function and multiple 'compensatory' mutations may need to accumulate, which does not occur readily.…”

Section: Success Versus Failure Of T Cell Responses: the Potential Romentioning

confidence: 99%

Cellular immune responses against hepatitis C virus: the evidence base 2002

Ward¹,

Lauer

Isba³

et al. 2002

Clinical and Experimental Immunology

136

102

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SUMMARYHepatitis C virus (HCV) is an RNA virus which is estimated to persistently infect about 170 million people worldwide. After acute infection, there is an initial period during which long-term outcome is decided. There is strong evidence that the cellular immune responses, involving both CD4 + and CD8 + T lymphocytes, are involved at this stage and it is their effectiveness which determines outcome. What is not understood is what determines their effectiveness. The most important component of this is likely to be some aspect of epitope selection, itself dictated by host MHC. Thus, to understand host immunity to HCV, we need to have a detailed understanding of the peptides involved in T lymphocyte responses. In this review, we discuss the peptide epitopes that have been identified so far, and their potential significance. We relate this to a scheme of host defence which may be useful for understanding natural and vaccine-induced immunity.

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“…Although the role of antigenic variation in HLA class I-restricted epitopes has been widely studied [18][19][20][21], work on the influence of HIV-1 antigenic variation on HLA class II-restricted CD4 T-cell responses has been limited, probably due to the difficulty of detecting these responses in HIV-1 infected individuals at any stage of infection. The objective of this study was to determine whether differences in the amino acid sequences of envelope glycoproteins from HIV-1 isolates of infected children would influence the ability to detect Env-specific Thelper cell responses.…”

Section: Introductionmentioning

confidence: 99%

Detection of Human Immunodeficiency Virus Type 1 Envelope Peptide- Stimulated T-helper Cell Responses and Variations in the Corresponding Regions of Viral Isolates among Vertically Infected Children

et al. 2004

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Although human immunodeficiency virus type 1 (HIV-1) specific CD4 T-helper cells are vital in mediating antiviral defence, little is known concerning the influence of HIV-1 antigenic variation on CD4 T-cell responses. In this study, the amino acid sequences of 5 synthetic HIV-1 envelope peptides used for in vitro stimulation (T2, P18 MN, P18 IIIB, T1 and TH4.1) were compared to the corresponding amino acid sequences of the gp 160 region of viruses isolated from HIV-1 infected children to determine whether variation in the envelope region of HIV-1 was associated with the ability to detect Env-specifice T-helper cell responses. Although the T2 region appeared to offer some evidence as to the role antigenic variation may have played in class II-restricted CD4 T-cell responses between those children who showed a detectable Env-stimulated T-helper cell response and those who did not, the other regions studied showed no evidence of being more conserved among those children who showed detectable responses. The combined amino acid variation across the specific peptide reions studied was not associated with peripheral levels of HIV-1, nor did the degree of amino acid variation dictate the clinical category into which the children had been classified, although there was a tendency towards HIV-1 isolates from the younger children showing a greater degree of amino acid variation than isolates from the older children. These results suggest that HIV-1 specific CD4 responses may be somewhat tolerant of viral variation, although further studies are required to fully elucidate the effect of antigenic variation on immune recognition.

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Clustered Mutations in HIV-1 Gag Are Consistently Required for Escape from Hla-B27–Restricted Cytotoxic T Lymphocyte Responses

Cited by 416 publications

References 52 publications

Crystal structures and KIR3DL1 recognition of three immunodominant viral peptides complexed to HLA‐B*2705

Crystal structures and KIR3DL1 recognition of three immunodominant viral peptides complexed to HLA‐B*2705

Cellular immune responses against hepatitis C virus: the evidence base 2002

Detection of Human Immunodeficiency Virus Type 1 Envelope Peptide- Stimulated T-helper Cell Responses and Variations in the Corresponding Regions of Viral Isolates among Vertically Infected Children

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