Proliferation Capacity and Cytotoxic Activity Are Mediated by Functionally and Phenotypically Distinct Virus-Specific CD8 T Cells Defined by Interleukin-7Rα (CD127) and Perforin Expression

Cellerai, Cristina; Perreau, Matthieu; Rozot, Virginie; Enders, Felicitas Bellutti; Pantaleo, Giuseppe; Harari, Alexandre

doi:10.1128/jvi.02565-09

Cited by 43 publications

(53 citation statements)

References 71 publications

(129 reference statements)

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“…This notion is strengthened by a significant positive correlation between the fraction of IL-2-producing CD8 ϩ T cells and CD4 ϩ T cell count, which in turn could be associated with a lower viral evolutionary rate and risk of disease progression. Several studies have underlined the important role of IL-2-producing CD8 ϩ T cell functional subsets to mediate protective immunity at different stages of infection (12,41,43). In a recent review, Makedonas and Betts (42) suggest that IL-2 production enhancement of a central memory-type profile is necessary to maintain a healthy antiviral CD8 ϩ T cell population.…”

Section: Fig 4 Median Nucleotide Substitution Rate and 95% Hpd Intervmentioning

confidence: 99%

“…It has been shown that polyfunctional HIV-1-specific CD8 ϩ T cells in LTNPs/ECs maintain a high proliferative capacity that is coupled to increased interleukin-2 (IL-2) production (5,12,80) and preserved in HIV subjects with nonprogressive infections (50). Furthermore, IL-2 secretion by CD8 ϩ T cells has been linked to enhanced viral suppression in chronic HIV-1 controllers (1).…”

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confidence: 99%

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Combination of Immune and Viral Factors Distinguishes Low-Risk versus High-Risk HIV-1 Disease Progression in HLA-B*5701 Subjects

Norström

Buggert

Tauriainen

et al. 2012

J Virol

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HLA-B*5701 is the host factor most strongly associated with slow HIV-1 disease progression, although rates can vary within this group. Underlying mechanisms are not fully understood but likely involve both immunological and virological dynamics. The present study investigated HIV-1in vivoevolution and epitope-specific CD8+T cell responses in six HLA-B*5701 patients who had not received antiretroviral treatment, monitored from early infection for up to 7 years. The subjects were classified as high-risk progressors (HRPs) or low-risk progressors (LRPs) based on baseline CD4+T cell counts. Dynamics of HIV-1 Gag p24 evolution and multifunctional CD8+T cell responses were evaluated by high-resolution phylogenetic analysis and polychromatic flow cytometry, respectively. In all subjects, substitutions occurred more frequently in flanking regions than in HLA-B*5701-restricted epitopes. In LRPs, p24 sequence diversity was significantly lower; sequences exhibited a higher degree of homoplasy and more constrained mutational patterns than HRPs. The HIV-1 intrahost evolutionary rate was also lower in LRPs and followed a strict molecular clock, suggesting neutral genetic drift rather than positive selection. Additionally, polyfunctional CD8+T cell responses, particularly to TW10 and QW9 epitopes, were more robust in LRPs, who also showed significantly higher interleukin-2 (IL-2) production in early infection. Overall, the findings indicate that HLA-B*5701 patients with higher CD4 counts at baseline have a lower risk of HIV-1 disease progression because of the interplay between specific HLA-linked immune responses and the rate and mode of viral evolution. The study highlights the power of a multidisciplinary approach, integrating high-resolution evolutionary and immunological data, to understand mechanisms underlying HIV-1 pathogenesis.

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Section: Fig 4 Median Nucleotide Substitution Rate and 95% Hpd Intervmentioning

confidence: 99%

mentioning

confidence: 99%

Combination of Immune and Viral Factors Distinguishes Low-Risk versus High-Risk HIV-1 Disease Progression in HLA-B*5701 Subjects

Norström

Buggert

Tauriainen

et al. 2012

J Virol

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“…Cryo-preserved blood mononuclear cells (1-2 × 10 6 ) were rested overnight and then stimulated, permeabilized, and stained as described [48]]. For functional analyses (i.e., ICS), the following antibodies were used: CD3-allophycocyanin-H7, CD8-PB, IFN-γ-allophycocyanin, IL-2-PE, and TNF-α-PECY-7.…”

Section: Flow Cytometry Analysismentioning

confidence: 99%

“…Following an overnight rest, cryo-preserved blood mononuclear cells were labeled with 0.25 μM 5,6-carboxyfluorescein succinimidyl ester (CFSE, Molecular Probes, USA) as described [48] and stimulated with HIV peptide or peptide pools (1 μg/mL of each peptide). Staphylococcal enterotoxin B (SEB) stimulation (100 ng/mL) served as positive control.…”

Section: Ex Vivo Proliferation Assaymentioning

confidence: 99%

NYVAC immunization induces polyfunctional HIV‐specific T‐cell responses in chronically‐infected, ART‐treated HIV patients

et al. 2012

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We report the results of the Theravac-01 phase I trial, which was conducted to evaluate the safety and immunogenicity of a poxvirus-based vector, NYVAC, expressing Gag, Pol, Nef, and Env from an HIV clade B isolate. NYVAC-B vaccine was injected intramuscularly into ten HIV-infected patients successfully treated with antiretroviral therapy, twice on day 0 and again at week 4. Safety and immunogenicity were monitored for 48 weeks. HIV-specific T-cell responses following immunization were quantitatively analyzed using an IFN-γ ELISPOT assay and qualitatively characterized for their functional profile (including multiple cytokines secretion plus cytotoxic and proliferation capacity) by polychromatic flow cytometry. Our results indicate that the NYVAC-B vaccine is safe and highly immunogenic, as indicated by increased HIV-specific T-cell responses in virtually all vaccinees. Interestingly, both an expansion of preexisting T-cell responses, and the appearance of newly detected HIV-specific CD4 + and CD8 + T-cell responses were observed. Furthermore, immunization mostly induced an increase in Gag-specific T-cell responses. In conclusion, NYVAC-B immunization induces broad, vigorous, and polyfunctional HIV-specific T-cell responses, suggesting that poxvirus-based vaccine regimens may be instrumental in the therapeutic HIV vaccine field. Eur. J. Immunol. 2012. 42: 3038-3048 Clinical immunology 3039 IntroductionThe development of antiviral therapy has dramatically changed the course and the prognosis of HIV infection. More than 30 antiviral drugs available offer many therapeutic options for the patients and some of these drugs used in combination are able to induce long-term suppression of virus replication as indicated by the persistence of levels of viremia below the limit of detection of highly sensitive PCR assays [1]. The antiviral therapy-mediated suppression of virus replication has resulted in dramatic reduction of morbidity and mortality, and HIV infection has shifted from being a life threatening to a chronic viral disease [2]. In this regard, recent studies have estimated a life expectancy of 25-30 years for subjects with HIV infection [3,4]. Despite the long-term suppression of virus replication and the normalization of a series of immunological parameters, which are not limited to the CD4 + T-cell counts but also to the recovery of a series of antigen-specific (including HIV) immunological functions, the interruption of antiviral therapy is almost invariably associated to virus rebound [1,5]. These observations indicated that the long-term suppression of virus replication does not result in the generation of an effective HIV-specific immune response [6].For these reasons, a number of immunological interventions have been investigated in the past and are currently being investigated to stimulate HIV-specific immune responses that may efficiently control HIV replication also in the absence of antiviral therapy. Among these interventions, particular attention has been given to the development of therapeutic v...

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“…It has been debated that effective antiretroviral treatment instituted during acute infection period, which occurs during the immunologic window period, may contribute to a better restructuration of the host immune system, thus allowing to a better long term virologic control or to slower pace of disease progression. [2] Detection of infections during the immunologic window period is also a necessity in order to increase the safety of the blood supply. Furthermore, detection of HIV-1 infection is not specific enough in the cases where the passive transfer of antibodies occurs, such as among infants born from HIV infected mothers.…”

Section: Introductionmentioning

confidence: 99%

Nucleic Acid Testing for HIV-1 Diagnosis and Monitoring

Diaz¹

2012

HIV Testing

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Proliferation Capacity and Cytotoxic Activity Are Mediated by Functionally and Phenotypically Distinct Virus-Specific CD8 T Cells Defined by Interleukin-7Rα (CD127) and Perforin Expression

Cited by 43 publications

References 71 publications

Combination of Immune and Viral Factors Distinguishes Low-Risk versus High-Risk HIV-1 Disease Progression in HLA-B*5701 Subjects

Combination of Immune and Viral Factors Distinguishes Low-Risk versus High-Risk HIV-1 Disease Progression in HLA-B*5701 Subjects

NYVAC immunization induces polyfunctional HIV‐specific T‐cell responses in chronically‐infected, ART‐treated HIV patients

Nucleic Acid Testing for HIV-1 Diagnosis and Monitoring

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