Direct visualization of HIV-1-specific cytotoxic T lymphocytes during primary infection

Wilson, Jamie; Ogg, Graham S.; Allen, Rachel; Davis, Charles E.; Shaunak, Sunil; Downie, Jean C.; Dyer, Wayne B.; Workman, Cassy; Sullivan, Susan M.; McMichael, Andrew J.; Rowland‐Jones, Sarah

doi:10.1097/00002030-200002180-00003

Cited by 152 publications

(78 citation statements)

References 27 publications

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“…Another explanation for the delay in the appearance of detectable anti-SL9 responses may reside in the subdominance of HLA-A*0201-restricted responses to other HLA allele-restricted responses, such as HLA-A3-and -B27-restricted responses, during acute HIV infection (30,65). It is interesting that studies conducted in vaccinees suggest that HLA-B57 ϩ individuals as well as HLA-B27 ϩ volunteers can generate anti-HIV CD8-mediated responses more frequently than individuals expressing other HLA alleles (66).…”

Section: Discussionmentioning

confidence: 99%

Absence of Immunodominant Anti-Gag p17 (SL9) Responses among Gag CTL-Positive, HIV-Uninfected Vaccine Recipients Expressing the HLA-A*0201 Allele

Ferrari

Neal

Ottinger

et al. 2004

The Journal of Immunology

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According to a number of previous reports, control of HIV replication in humans appears to be linked to the presence of anti-HIV-1 Gag-specific CD8 responses. During the chronic phase of HIV-1 infection, up to 75% of the HIV-infected individuals who express the histocompatibility leukocyte Ag (HLA)-A*0201 recognize the Gag p17 SLYNTVATL (aa residues 77–85) epitope (SL9). However, the role of the anti-SL9 CD8 CTL in controlling HIV-1 infection remains controversial. In this study we determined whether the pattern of SL9 immunodominance in uninfected, HLA-A*0201 HIV vaccine recipients is similar to that seen in chronically HIV-infected subjects. The presence of anti-SL9 responses was determined using a panel of highly sensitive cellular immunoassays, including peptide:MHC tetramer binding, IFN-γ ELISPOT, and cytokine flow cytometry. Thirteen HLA-A*0201 vaccinees with documented anti-Gag CD8 CTL reactivities were tested, and none had a detectable anti-SL9 response. These findings strongly suggest that the pattern of SL9 epitope immunodominance previously reported among chronically infected, HLA-A*0201-positive patients is not recapitulated in noninfected recipients of Gag-containing canarypox-based candidate vaccines and may be influenced by the relative immunogenicity of these constructs.

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Section: Discussionmentioning

confidence: 99%

Absence of Immunodominant Anti-Gag p17 (SL9) Responses among Gag CTL-Positive, HIV-Uninfected Vaccine Recipients Expressing the HLA-A*0201 Allele

Ferrari

Neal

Ottinger

et al. 2004

The Journal of Immunology

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“…Furthermore, an immunodominant CD8 + T cell response directed toward the conserved p24 Gag epitope KRWIILGLNK (KK10; residues 263-272) appears to contribute substantially to this protective association at a mechanistic level (1). The KK10-specific CD8 + T cell population is generated during the early stages of infection (5,6) and persists as the immunodominant epitope-specific response until the emergence of immune escape late in disease (1,7). Importantly, however, the magnitude of this response is not associated with viral load (1).…”

Section: Cd8mentioning

confidence: 99%

“…Staining of cryopreserved PBMCs with pMHCI multimers was performed as described previously (22). At each time point, responses to both WT (KRL) and variant (KRM) peptide sequences of KRWII(L/M)GLNK were studied using pMHCI multimers with the corresponding peptide loaded into HLA-B*2705 molecules (5). For the purposes of this analysis, the cognate epitope was designated as the major variant present in plasma virus sequence at each time point; the minor variant was entitled alternate.…”

Section: Sequencing Of Viral Rnamentioning

confidence: 99%

Persistent Survival of Prevalent Clonotypes within an Immunodominant HIV Gag-Specific CD8+ T Cell Response

Bockel

Price

Munier

et al. 2011

The Journal of Immunology

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CD8+ T cells play a significant role in the control of HIV replication, yet the associated qualitative and quantitative factors that determine the outcome of infection remain obscure. In this study, we examined Ag-specific CD8+ TCR repertoires longitudinally in a cohort of HLA-B*2705+ long-term nonprogressors with chronic HIV-1 infection using a combination of molecular clonotype analysis and polychromatic flow cytometry. In each case, CD8+ T cell populations specific for the immunodominant p24 Gag epitope KRWIILGLNK (KK10; residues 263–272) and naturally occurring variants thereof, restricted by HLA-B*2705, were studied at multiple time points; in addition, comparative data were collected for CD8+ T cell populations specific for the CMV pp65 epitope NLVPMVATV (NV9; residues 495–503), restricted by HLA-A*0201. Dominant KK10-specific clonotypes persisted for several years and exhibited greater stability than their contemporaneous NV9-specific counterparts. Furthermore, these dominant KK10-specific clonotypes exhibited cross-reactivity with antigenic variants and expressed significantly higher levels of CD127 (IL-7Rα) and Bcl-2. Of note, we also found evidence that promiscuous TCR α-chain pairing associated with alterations in fine specificity for KK10 variants could contribute to TCR β-chain prevalence. Taken together, these data suggest that an antiapoptotic phenotype and the ability to cross-recognize variant epitopes contribute to clonotype longevity and selection within the peripheral memory T cell pool in the presence of persistent infection with a genetically unstable virus.

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“…Indeed immunodominant HLA-B*2705-restricted epitopes have been identified and characterized for several human viral infections. HLA-B*2705 has been associated with long-term non progression in chronic HIV infection [3], and a single peptide from the p24 antigen -KRWIILGLNK (HIV) -presented by HLA-B*2705 is recognized by up to 5% CD8 + Tcells [4][5][6]. Mutation of the P2 arginine anchor of the HIV epitope has been closely correlated with progression to AIDS, implicating this epitope in controlling viral replication and delaying disease progression.…”

Section: Introductionmentioning

confidence: 99%

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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Direct visualization of HIV-1-specific cytotoxic T lymphocytes during primary infection

Cited by 152 publications

References 27 publications

Absence of Immunodominant Anti-Gag p17 (SL9) Responses among Gag CTL-Positive, HIV-Uninfected Vaccine Recipients Expressing the HLA-A*0201 Allele

Absence of Immunodominant Anti-Gag p17 (SL9) Responses among Gag CTL-Positive, HIV-Uninfected Vaccine Recipients Expressing the HLA-A*0201 Allele

Persistent Survival of Prevalent Clonotypes within an Immunodominant HIV Gag-Specific CD8+ T Cell Response

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

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