Poor HIV control in HLA-B*27 and B*57/58 noncontrollers is associated with limited number of polyfunctional Gag p24-specific CD8+ T cells

Techakriengkrai, Navapon; Tansiri, Yada; Hansasuta, Pokrath

doi:10.1097/qad.0b013e32835ac0e1

Cited by 7 publications

(15 citation statements)

References 45 publications

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“…Several studies have demonstrated strong associations between the presence of HLA-B*27 and certain alleles of the HLA-B*57/58 supertype with improved HIV clinical outcomes in different ethnic groups [ 26 ]. In addition, our previous study found a significant association between possession of HLA*B27 alleles and good HIV clinical outcome in Thai subjects, identified by low pVL and high CD4 counts [ 11 ]. In this study, however, these protective alleles were not over-represented in VC (36.84%) compared to NC (34.69%).…”

Section: Resultsmentioning

confidence: 99%

“…It has been previously suggested that the quantity of polyfunctional HIV-specific CD8 + T cells may provide a better indication of the robustness of HIV immune control. We previously found that the absolute numbers of polyfunctional HIVp24-specific CD8 + T cells were significantly higher in VC than NC, whereas the percentages of polyfunctional cells were not [ 11 ]. Taking advantage of the larger sample size and CD4 count matching in this cohort, we revisited the analysis of the functional quality in terms of percentage of cells and absolute cell numbers (calculating from CBC, CD4, and CD8 counts).…”

Section: Resultsmentioning

confidence: 99%

“…We therefore elected to focus on HIV p24-specific T-cell responses in our subjects in order to characterise protective immunity in HIV infection. In order to ensure the quality of our ELISpot assays, we always used fresh PBMC in our experiments; and to avoid antigen mismatch, we synthesized OLP based on recently-circulating Thai HIV strains [ 11 ]. However, our ELISpot experiments failed to show any difference in T-cell responses between VC and NC: in fact, NC showed a trend towards a greater breadth of response.…”

Section: Discussionmentioning

confidence: 99%

“…Twenty-three overlapping HIVp24 peptides (OLPs) (20 amino acids long, overlapping by 10 amino acids) and seven previously identified immunodominant epitopes within the HIVp24 protein (accession numbers: JN704002–JN704066) were designed according to a Thai consensus HIV sequence (Mimotope, Australia) [ 11 ]. HIV-specific responses were analysed by IFNγ ELISpot as previously described [ 22 ].…”

Section: Methodsmentioning

confidence: 99%

“…Polychromatic flow cytometry was performed in accordance with standard protocols, as previously described [ 11 , 23 ]. The functional qualities of CD8 + T cells were measured using a FACS ARIAII three-laser flow cytometer (Becton Dickinson, USA).…”

Section: Methodsmentioning

confidence: 99%

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Clinical Outcome of HIV Viraemic Controllers and Noncontrollers with Normal CD4 Counts Is Exclusively Determined by Antigen-Specific CD8+ T-Cell-Mediated HIV Suppression

et al. 2015

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In this cross-sectional study we evaluated T-cell responses using several assays to determine immune correlates of HIV control that distinguish untreated viraemic controllers (VC) from noncontrollers (NC) with similar CD4 counts. Samples were taken from 65 ART-naïve chronically HIV-infected VC and NC from Thailand with matching CD4 counts in the normal range (>450 cells/μl). We determined HIVp24-specific T-cell responses using standard Interferon-gamma (IFNγ) ELISpot assays, and compared the functional quality of HIVp24-specific CD8+ T-cell responses using polychromatic flow cytometry. Finally, in vitro HIV suppression assays were performed to evaluate directly the activity of CD8+ T cells in HIV control. Autologous CD4+ T cells were infected with primary patient-derived HIV isolates and the HIV suppressive activity of CD8+ T cells was determined after co-culture, measuring production of HIVp24 Ag by ELISA. The HIVp24-specific T-cell responses of VC and NC could not completely be differentiated through measurement of IFNγ-producing cells using ELISpot assays, nor by the absolute cell numbers of polyfunctional HIVp24-specific CD8+ T cells. However, in vitro HIV suppression assays showed clear differences between VC and NC. HIV suppressive activity, mediated by either ex vivo unstimulated CD8+ T cells or HIVp24-specific T-cell lines, was significantly greater using cells from VC than NC cells. Additionally, we were able to demonstrate a significant correlation between the level of HIV suppressive activity mediated by ex vivo unstimulated CD8+ T cells and plasma viral load (pVL) (Spearman r = -0.7345, p = 0.0003). This study provides evidence that in vitro HIV suppression assays are the most informative in the functional evaluation of CD8+ T-cell responses and can distinguish between VC and NC.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Clinical Outcome of HIV Viraemic Controllers and Noncontrollers with Normal CD4 Counts Is Exclusively Determined by Antigen-Specific CD8+ T-Cell-Mediated HIV Suppression

et al. 2015

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Interferon gamma (IFN-γ) negative CD4+ and CD8+ T-cells can produce immune mediators in response to viral antigens

Nakiboneka

Mugaba

Auma

et al. 2019

Vaccine

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Evaluation of antigen-specific T-cell responses to viral antigens is frequently performed on IFN-γ secreting cells. However, T-cells are capable of producing many more functions than just IFN-γ, some of which, like Perforin, are associated with immune protection in HIV-1 disease elite controllers. We evaluated the extent of missed T-cell functions when IFN-γ secretion is used as a surrogate marker for further evaluation of T-cell functions. Intracellular cytokine staining assay and flow cytometry were used to assess peripheral blood mononuclear cells (PBMCs) from 31 HIV-infected ART-naive individuals for the extent to which gated CD4+ and CD8+ IFN-γ producing and non-producing T-cells also secreted IL-2, Perforin, and TNF-α functions. Similarly, the extent of missed virus-specific responses in IFN-γ ELISpot assay negative T-cells from 5 HIV-1 uninfected individuals was evaluated. Cells from HIV-infected individuals were stimulated with pooled consensus group M (Con M) peptides; and those from healthy individuals were stimulated with pooled adenovirus (Ad) peptides. Overall, frequencies of virus-specific IFN-γ secreting CD4+ and CD8+ cells were low. Proportions of IFN-γ negative CD4+ expressing IL-2, Perforin, or TNF-α to Con M were significantly higher (5 of 7 functional profiles) than the corresponding IFN-γ positive CD4+ (0 of 7) T-cell phenotype, p = 0.02; Fisher’s Exact test. Likewise, proportions of CD8+ T-cells expressing other functions were significantly higher in 4 of the 7 IFN-γ negative CD8+ T-cells. Notably, newly stimulated Perforin, identified as Perforin co-expression with IL-2 or TNF-α, was significantly higher in IFN-γ negative CD8+ T-cell than in the positive CD8+ T-cells. Using SEB, lower responses in IFN-γ positive cells were most associated with CD4+ than CD8+ T-cells. These findings suggest that studies evaluating immunogenicity in response to HIV and Adenovirus viral antigens should not only evaluate T-cell responsiveness among IFN-γ producing cells but also among those T-cells that do not express IFN-γ.

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Role of HLA-B*58:01–Restricted CD8+ T Cells in HIV-1 Subtype AE Infection

Nguyen,

Chikata,

Zhang

et al. 2024

The Journal of Infectious Diseases

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HLA-B*58:01 and HLA-B*57 are protective alleles against human immunodeficiency virus type 1 (HIV-1) subtype B or C infection, whereas these HLA alleles have not been reported as protective in HIV-1 subtype AE infection. Although HLA-B*58:01–restricted and HLA-B*57–restricted HIV-1–specific CD8+ T cells have been thoroughly analyzed in subtype B or C infection, they have been only partially analyzed in subtype AE infection. We identified 6 HLA-B*58:01–restricted subtype AE epitopes in Vietnamese individuals infected with subtype AE. HLA-B*58:01–restricted T-cell responses to Gag epitopes, which may control disease progression in HLA-B*58:01+ and HLA-B*57+ individuals infected with subtype B or C, were not protective in subtype AE infection. These findings suggest that the loss of HLA-B*58:01–restricted T cells specific for some Gag epitopes and/or their reduced ability may account for the lack of protective effects conferred by HLA-B*58:01 in subtype AE infection.

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Poor HIV control in HLA-B27 and B57/58 noncontrollers is associated with limited number of polyfunctional Gag p24-specific CD8+ T cells

Abstract: We concluded that an adequate number of high functional quality Gag p24-specific CD8 T cells is strongly associated with a natural HIV controller status.

Cited by 7 publications

References 45 publications

Clinical Outcome of HIV Viraemic Controllers and Noncontrollers with Normal CD4 Counts Is Exclusively Determined by Antigen-Specific CD8+ T-Cell-Mediated HIV Suppression

Clinical Outcome of HIV Viraemic Controllers and Noncontrollers with Normal CD4 Counts Is Exclusively Determined by Antigen-Specific CD8+ T-Cell-Mediated HIV Suppression

Interferon gamma (IFN-γ) negative CD4+ and CD8+ T-cells can produce immune mediators in response to viral antigens

Role of HLA-B*58:01–Restricted CD8+ T Cells in HIV-1 Subtype AE Infection

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