Antiretroviral Drug Therapy Alters the Profile of Human Immunodeficiency Virus Type 1-Specific T-Cell Responses and Shifts the Immunodominant Cytotoxic T-Lymphocyte Response from Gag to Pol

Karlsson, Annika C.; Chapman, J.N.; Heiken, Brandon D.; Hoh, Rebecca; Kallas, Esper G.; Martin, Jeffrey N.; Hecht, Frederick M.; Deeks, Steven G.; Nixon, Douglas F.

doi:10.1128/jvi.00779-07

Cited by 14 publications

(15 citation statements)

References 46 publications

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“…Thus, a large fraction of potential responses might fail to be raised because of immunodominance (30). This also agrees with our previous findings showing failure to raise immune responses against many well identified HLA-restricted epitopes in subjects carrying a particular HLA allele (8,35). This analysis illustrates how immunodominance factors will place an upper limit on the success rate of epitope discovery projects.…”

Section: Discussionsupporting

confidence: 91%

Interdisciplinary Analysis of HIV-Specific CD8+ T Cell Responses against Variant Epitopes Reveals Restricted TCR Promiscuity

Hoof

Pérez

Buggert

et al. 2010

The Journal of Immunology

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HIV-1–specific CTL responses play a key role in limiting viral replication. CTL responses are sensitive to viral escape mutations, which influence recognition of the virus. Although CTLs have been shown to recognize epitope variants, the extent of this cross-reactivity has not been quantitatively investigated in a genetically diverse cohort of HIV-1–infected patients. Using a novel bioinformatic binding prediction method, we aimed to explain the pattern of epitope-specific CTL responses based on the patients’ HLA genotype and autologous virus sequence quantitatively. Sequences covering predicted and tested HLA class I-restricted epitopes (peptides) within the HIV-Gag, Pol, and Nef regions were obtained from 26 study subjects resulting in 1492 patient-specific peptide pairs. Epitopes that were recognized in ELISPOT assays were found to be significantly more similar to the autologous virus than those that did not elicit a response. A single substitution in the presented epitope decreased the chance of a CTL response by 40%. The impact of sequence similarity on cross-recognition was confirmed by testing immune responses against multiple variants of six selected epitopes. Substitutions at central positions in the epitope were particularly likely to result in abrogation of recognition. In summary, the presented data demonstrate a highly restricted promiscuity of HIV-1–specific CTL in the recognition of variant epitopes. In addition, our results illustrate that bioinformatic prediction methods are useful to study the complex pattern of CTL responses exhibited by an HIV-1–infected patient cohort and for identification of optimal targets for novel therapeutic or vaccine approaches.

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Section: Discussionsupporting

confidence: 91%

Interdisciplinary Analysis of HIV-Specific CD8+ T Cell Responses against Variant Epitopes Reveals Restricted TCR Promiscuity

Hoof

Pérez

Buggert

et al. 2010

The Journal of Immunology

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“…Given that the most common subtypes of HIV-1 are clade B in the United States and clade A in Mali, this remarkable overlap in terms of peptide recognition supports the hypothesis that immunogenicity of epitopes selected for this study would not be limited by location and would be important for inclusion in a globally relevant vaccine. That hypothesis is supported by the broad analysis shown in Figure 2 and by the validation of some of the peptides in other countries [74,78,80,88,89]. In examining the Providence and Mali cohorts, there are observable differences in the ELISpot responses.…”

Section: Discussionmentioning

confidence: 74%

“…Lower viral loads due to ART diminishes responses to viral epitopes and lack of response in these subjects does not detract from the value of these epitopes [78,79]. Providence subjects 0865 and 0912 had the most responses to the A2 epitopes, with eight and eleven responses, respectively.…”

Section: Discussionmentioning

confidence: 99%

Conservation of HIV-1 T cell epitopes across time and clades: Validation of immunogenic HLA-A2 epitopes selected for the GAIA HIV vaccine

Levitz

Koïta

Sangare

et al. 2012

Vaccine

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HIV genomic sequence variability has complicated efforts to generate an effective globally relevant vaccine. Regions of the viral genome conserved in sequence and across time may represent the “Achilles’ heel” of HIV. In this study, highly conserved T-cell epitopes were selected using immunoinformatics tools combining HLA-A2 supertype binding predictions with relative global conservation. Analysis performed in 2002 on 10,803 HIV-1 sequences, and again in 2009, on 43,822 sequences, yielded 38 HLA-A2 epitopes. These epitopes were experimentally validated for HLA binding and immunogenicity with PBMCs from HIV-infected patients in Providence, Rhode Island, and/or Bamako, Mali. Thirty-five (92%) stimulated an IFNγ response in PBMCs from at least one subject. Eleven of fourteen peptides (79%) were confirmed as HLA-A2 epitopes in both locations. Validation of these HLA-A2 epitopes conserved across time, clades, and geography supports the hypothesis that such epitopes could provide effective coverage of virus diversity and would be appropriate for inclusion in a globally relevant HIV vaccine.

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“…Lower viral loads in treatment failure individuals with overall strong CD8 T cell responses have been described previously [5,6] and might be partially attributable to speciWc CD8 responses targeting DRM. One of these reports shows stronger CD8 T cell responses toward Pol than toward the other HIV proteins in treatment-failure patients and a shift of immunodominance from Gag to Pol [6,28].…”

Section: Discussionmentioning

confidence: 99%

“…CD4 T cells of the individuals readily produced M184V mutated HIV in cell culture in the absence of CD8 T cells and antiretroviral drugs proving that T31 and T33 were not infected with a replication incompetent virus. Additionally, they did not carry the genetic factors which have been shown best to induce spontaneous control of HIV viremia, the HLA class I alleles B*27 and B*57 [28]. In contrast T31 carried two HLA class I alleles that are associated with more rapid disease progression, namely HLA-B*35 and HLA-C*07 [29].…”

Section: Discussionmentioning

confidence: 99%

Control of M184V HIV-1 mutants by CD8 T-cell responses

Vollbrecht

Eberle²,

Roider

et al. 2011

Med Microbiol Immunol

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Antiretroviral treatment directed against HIV is highly effective, yet limited by drug resistance mutations. We hypothesized that CD8 T cells targeting drug-resistant HIV mutants are able to inhibit viral replication in the setting of a failing therapeutic regimen. We evaluated CD8 T-cell responses and mapped epitopes in HIV-infected patients by interferon-gamma Elispot and intracellular cytokine staining. Autologous virus was sequenced by RT-PCR. Viral replication inhibition assays were performed using M184V mutant virus and CD8 T cell lines. CD8 T-cell responses toward the regions of viral drug resistance mutations in Pol are frequent. Focusing on the M184V mutation, A*02:01-YQYVDDLYV and A*02:01-VIYQYVDDLYV were identified as optimal epitopes for the majority of study subjects. Viral replication of M184V HIV mutants was inhibited by CD8 T cell lines in vitro. In case of a failing lamivudine/emtricitabine containing regimen, individuals with a CD8 T-cell response toward M184V had a significant lower viral load than those without a CD8 response (p = 0.005). Two study subjects even achieved an undetectable viral load. Our data suggest that control of M184V mutant virus by CD8 T-cell responses is possible in vitro and in vivo. This control has important implications for therapeutic vaccination strategies.

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Antiretroviral Drug Therapy Alters the Profile of Human Immunodeficiency Virus Type 1-Specific T-Cell Responses and Shifts the Immunodominant Cytotoxic T-Lymphocyte Response from Gag to Pol

Abstract: Antiretroviral drug therapy and cytotoxic T lymphocytes (CTL

Cited by 14 publications

References 46 publications

Interdisciplinary Analysis of HIV-Specific CD8+ T Cell Responses against Variant Epitopes Reveals Restricted TCR Promiscuity

Interdisciplinary Analysis of HIV-Specific CD8+ T Cell Responses against Variant Epitopes Reveals Restricted TCR Promiscuity

Conservation of HIV-1 T cell epitopes across time and clades: Validation of immunogenic HLA-A2 epitopes selected for the GAIA HIV vaccine

Control of M184V HIV-1 mutants by CD8 T-cell responses

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