Effect of Low-Dose IL-2 Immunotherapy on Frequency and Phenotype of Regulatory T Cells and NK Cells in HIV/HCV-Coinfected Patients

Velilla, Paula A.; Shata, Mohamed T.; Lages, Celine S.; Ying, Jin; Fichtenbaum, Carl J.; Chougnet, Claire

doi:10.1089/aid.2007.0180

Cited by 13 publications

(6 citation statements)

References 49 publications

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“…Experimental evidence suggest several possibilities to account for this observation: (i) chronic expansion of Treg in vivo results in low levels of CD25 expression, retaining their suppressive activity, as previously reported in a murine model [35]; this constant expansion (high Treg frequency) is observed also in GALT from HIV infected patients [5, 30]; (ii) it might reflect internalization of the CD25 molecule after IL-2 binding [36]; in fact, the expansion of CD4 + CD25 lo CD127 lo Foxp3 + Treg is one of the long-term effects of IL-2 therapy in HIV patients [37, 38]; (iii) in vitro assays have shown that HIV induces down regulation of the CD25 molecule in CD4 + infected cells [39]. In addition, HIV viral proteins are involved in this process, inhibiting IL-2R expression; HIV p29 protein induces a two fold increase in the intracellular cyclic adenosine 3’,5’-monophosphate (cAMP) in PBMC which is associated with the decrease of CD25 [40].…”

Section: Discussionsupporting

confidence: 61%

Chronically HIV-1 Infected Patients Exhibit Low Frequencies of CD25+ Regulatory T Cells

Rios

Velilla²,

Rugeles³

2012

TOVJ

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The characterization of regulatory T cells (Treg) during HIV infection has become of particular interest considering their potential role in the pathogenesis of the acquired immunodeficiency syndrome. Different reports on Tregs in HIV-infected patients vary greatly, depending on the state of disease progression, anatomical compartment, and the phenotypic markers used to define this cell subpopulation. To determine the frequency of Tregs we included paired samples from peripheral blood and rectal biopsies from controls and chronic HIV patients with or without detectable viral load. Tregs were determined by flow cytometry using three different protocols: CD4+Foxp3+; CD4+Foxp3+CD127Low/-, and CD4+CD25+CD127Low/-. In addition, and with the purpose to compare the different protocols we also characterized Tregs in peripheral blood of HIV negative individuals with influenza like symptoms. Here, we report that Treg characterization in HIV-infected patients as CD4+Foxp3+ and CD4+Foxp3+CD127Low/- cells was similar, indicating that both protocols represent a suitable method to determine the frequency of Tregs in peripheral blood mononuclear cells (PBMC) and gut associated lymphoid tissue (GALT). In contrast, in HIV but not in flu-like patients, detection of Tregs as CD4+CD25+CD127Low/- cells resulted in a significantly lower percentage of these cells. In both, HIV patients and controls the frequency of Treg was significantly higher in GALT compared to PBMC. The frequency of Tregs in PBMC and GALT using CD4+Foxp3+ and CD4+Foxp3+CD127Low/- was higher in HIV patients than in controls. Similarly, the frequency of Treg using any protocol was higher in flu-like patients compared to controls. The results suggest that relying on the expression of CD25 could be unsuitable to characterize Tregs in PBMC and GALT samples from a chronic infection such as HIV.

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Section: Discussionsupporting

confidence: 61%

Chronically HIV-1 Infected Patients Exhibit Low Frequencies of CD25+ Regulatory T Cells

Rios

Velilla²,

Rugeles³

2012

TOVJ

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“…To date, there has only been one documented report looking at the proportion of circulating CD4 ϩ Tregs during HCV/HIV co-infection (42). This study examined the effect of IL-2 immunotherapy on the frequency and phenotype of Tregs in HCV/HIV co-infected patients.…”

Section: Fig 3 (A)mentioning

confidence: 99%

Phenotypic Characterization of Lymphocytes in HCV/HIV Co-infected Patients

et al. 2009

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While hepatitis C virus (HCV)-specific immune responses are attenuated in HCV/HIV co-infected patients compared to those infected with HCV alone, the reasons for this remain unclear. In this study, the proportions of regulatory, naïve, and memory T cells, along with chemokine receptor expression, were measured in co-infected and mono-infected patients to determine if there is an alteration in the phenotypic profile of lymphocytes in these patients. HCV/HIV co-infected patients had increased proportions of CD4(+) naïve cells and decreased proportions of CD4(+) effector cells when compared to HCV mono-infected patients. The proportions of CD4(+) Tregs and CD4(+) CXCR3(+) T cells were also significantly lower in co-infected patients. A decrease in CD4(+) Tregs and subsequent loss of immunosuppressive function may contribute to the accelerated progression to liver disease in co-infected individuals. Dysregulation of immune responses following reduction in the proportions of CD4(+) CXCR3(+) Th-1 cells may contribute to the reduced functional capacity of HCV-specific immune responses in co-infected patients. The findings of this study provide new information on the T-cell immunophenotype in HCV/HIV co-infected patients when compared to those infected with HCV alone, and may provide insight into why cell-mediated immune responses are diminished during HCV infection.

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“…Moreover, administration of a similar IL-2/Ig plasmid in macaques results in a dramatic increase in CD25 + T cells [50]. In addition, low-dose IL-2 therapy in HIV-1-infected patients results in expansion and activation of Treg [99]. Taken together, these data raise the possibility that the co-administration of the IL-2/IgG plasmid with the gag p15/p26 plasmid in the current study could have elicited Gag-specific Treg that suppressed potentially protective Gag-specific immune responses in the vaccinates.…”

Section: Discussionmentioning

confidence: 99%

Viral load and clinical disease enhancement associated with a lentivirus cytotoxic T lymphocyte vaccine regimen

Mealey

Leib

Littke

et al. 2009

Vaccine

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Effective DNA-based vaccines against lentiviruses will likely induce CTL against conserved viral proteins. Equine infectious anemia virus (EIAV) infects horses worldwide, and serves as a useful model for lentiviral immune control. Although attenuated live EIAV vaccines have induced protective immune responses, DNA-based vaccines have not. In particular, DNA-based vaccines have had limited success in inducing CTL responses against intracellular pathogens in the horse. We hypothesized that priming with a codon-optimized plasmid encoding EIAV Gag p15/p26 with co-administration of a plasmid encoding an equine IL-2/IgG fusion protein as a molecular adjuvant, followed by boosting with a vaccinia vector expressing Gag p15/p26, would induce protective Gag-specific CTL responses. Although the regimen induced Gag-specific CTL in four of seven vaccinated horses, CTL were not detected until after the vaccinia boost, and protective effects were not observed in EIAV challenged vaccinates. Unexpectedly, vaccinates had significantly higher viral loads and more severe clinical disease, associated with the presence of vaccine-induced CTL. It was concluded that 1.) further optimization of the timing and route of DNA immunization was needed for efficient CTL priming in vivo, 2.) co-administration of the IL-2/IgG plasmid did not enhance CTL priming by the Gag p15/p26 plasmid, 3.) vaccinia vectors are useful for lentivirus-specific CTL induction in the horse, 4.) Gag-specific CTL alone are either insufficient or a more robust Gag-specific CTL response is needed to limit EIAV viremia and clinical disease, and 5.) CTL-inducing vaccines lacking envelope immunogens can result in lentiviral disease enhancement. Although the mechanisms for enhancement associated with this vaccine regimen remain to be elucidated, these results have important implications for development of lentivirus T cell vaccines.

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Effect of Low-Dose IL-2 Immunotherapy on Frequency and Phenotype of Regulatory T Cells and NK Cells in HIV/HCV-Coinfected Patients

Cited by 13 publications

References 49 publications

Chronically HIV-1 Infected Patients Exhibit Low Frequencies of CD25+ Regulatory T Cells

Chronically HIV-1 Infected Patients Exhibit Low Frequencies of CD25+ Regulatory T Cells

Phenotypic Characterization of Lymphocytes in HCV/HIV Co-infected Patients

Viral load and clinical disease enhancement associated with a lentivirus cytotoxic T lymphocyte vaccine regimen

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