Induction of novel CD8+ T-cell responses during chronic untreated HIV-1 infection by immunization with subdominant cytotoxic T-lymphocyte epitopes

Kløverpris, Henrik N.; Karlsson, Ingrid; Bonde, Jesper; Thorn, Mette; Vinner, Lasse; Pedersen, Anders Elm; Hentze, Julie L.; Andresen, Betina S; Svane, Inge Marie; Gerstoft, Jan; Kronborg, Gitte; Fomsgaard, Anders

doi:10.1097/qad.0b013e32832d9b00

Cited by 57 publications

(58 citation statements)

References 43 publications

(49 reference statements)

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“…Our results indicate that mutational constraints in general, and structural entropy in particular, constitute a feature that is useful in identifying potentially subdominant protective epitopes for further study. Indeed, an important recent result indicates that vaccination against specific epitopes can substantially alter immunodominance hierarchies (90), even if administered after the onset of infection (91), validating the approach of designing a prophylactic or therapeutic vaccine to elicit such (hypothetical) protective subdominant targeting.…”

Section: Discussionmentioning

confidence: 97%

HIV Control Is Mediated in Part by CD8 ⁺ T-Cell Targeting of Specific Epitopes

Pereyra

Heckerman

Carlson

et al. 2014

J Virol

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We investigated the hypothesis that the correlation between the class I HLA types of an individual and whether that individual spontaneously controls HIV-1 is mediated by the targeting of specific epitopes by CD8 ؉ T cells. By measuring gamma interferon enzyme-linked immunosorbent spot (ELISPOT) assay responses to a panel of 257 optimally defined epitopes in 341 untreated HIV-infected persons, including persons who spontaneously control viremia, we found that the correlation between HLA types and control is mediated by the targeting of specific epitopes. Moreover, we performed a graphical model-based analysis that suggested that the targeting of specific epitopes is a cause of such control-that is, some epitopes are protective rather than merely associated with control-and identified eight epitopes that are significantly protective. In addition, we use an in silico analysis to identify protein regions where mutations are likely to affect the stability of a protein, and we found that the protective epitopes identified by the ELISPOT analysis correspond almost perfectly to such regions. This in silico analysis thus suggests a possible mechanism for control and could be used to identify protective epitopes that are not often targeted in natural infection but that may be potentially useful in a vaccine. Our analyses thus argue for the inclusion (and exclusion) of specific epitopes in an HIV vaccine. IMPORTANCESome individuals naturally control HIV replication in the absence of antiretroviral therapy, and this ability to control is strongly correlated with the HLA class I alleles that they express. Here, in a large-scale experimental study, we provide evidence that this correlation is mediated largely by the targeting of specific CD8 ؉ T-cell epitopes, and we identify eight epitopes that are likely to cause control. In addition, we provide an in silico analysis indicating that control occurs because mutations within these epitopes change the stability of the protein structures. This in silico analysis also identified additional epitopes that are not typically targeted in natural infection but may lead to control when included in a vaccine, provided that other epitopes that would otherwise distract the immune system from targeting them are excluded from the vaccine.

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Section: Discussionmentioning

confidence: 97%

HIV Control Is Mediated in Part by CD8 ⁺ T-Cell Targeting of Specific Epitopes

Pereyra

Heckerman

Carlson

et al. 2014

J Virol

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“…11,37,38 Some studies in animal models suggest that animals immunized with DCs loaded with HIV-1 viral lysate, envelope glycoproteins or inactivated virus mount a potent immune response against HIV-1. [39][40][41]42 Although it has been performed at least 13 published clinical trials of DC-based immunotherapy for HIV infection in humans [43][44][45][46][47][48][49][50]55 (reviewed in ref. 9), most of them were non-controlled, nonrandomized studies.…”

Section: Clinical Trials With Md-dcbased Therapeutic Vaccinesmentioning

confidence: 99%

“…However, only five of these studies reported virological responses to immunization, 44,45,51,52,55 three have not assessed virological responses 47,50,53 and five failed to show any response. 43,46,48,49,54 Recently, our group reported the results of a blinded placebo controlled trial of a therapeutic vaccine using autologous MD-DC pulsed with autologous heatinactivated whole HIV. We immunized 36 patients on cART with high CD4 T-cell counts with 3 doses of MD-DC cells (n = 24) or with non-pulsed MD-DC (n = 12).…”

Section: Clinical Trials With Md-dcbased Therapeutic Vaccinesmentioning

confidence: 99%

Dendritic cell based vaccines for HIV infection

García

Plana

Climent

et al. 2013

Human Vaccines & Immunotherapeutics

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“…Such vaccines would elicit or boost HIV specific cytotoxic T cells (CTLs) to eliminate infected cells and CD4 + T cells, which can help to induce and maintain B cell and CD8 + T cells responses [92]. Several strategies are currently under investigation to establish effective T cell responses in either a preventive or therapeutic setting either based on protein [93,94] or peptide [95] vaccinations, virus like particles (VPLs) [96], DNA vaccination using viral vectors [97,98], prime-boost vaccinations [99,100] or DC-based vaccines [101][102][103][104][105][106][107][108][109].…”

Section: Prophylactic Vaccinesmentioning

confidence: 99%