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Immune-correlates analysis of an HIV-1 vaccine efficacy trial reveals an association of nonspecific interferon-γ secretion with increased HIV-1 infection risk: a cohort-based modeling study.

Huang Y, Duerr A, Frahm N, Zhang L, Moodie Z, De Rosa S, McElrath MJ, Gilbert PB - PLoS ONE (2014)

Bottom Line: This association remains after accounting for CD4(+) or CD8(+) T-cell activation.We observed a moderate correlation between ELISpot mock responses and CD4(+) T-cells secreting IFN-γ (ρ = 0.33, p = 0.007).In addition, the effect of the Step vaccine on infection risk appeared to vary with ELISpot mock response levels, especially among participants who had pre-existing anti-Ad5 antibodies (interaction p = 0.04).

View Article: PubMed Central - PubMed

Affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Public Health Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.

ABSTRACT

Background: Elevated risk of HIV-1 infection among recipients of an adenovirus serotype 5 (Ad5)-vectored HIV-1 vaccine was previously reported in the Step HIV-1 vaccine efficacy trial. We assessed pre-infection cellular immune responses measured at 4 weeks after the second vaccination to determine their roles in HIV-1 infection susceptibility among Step study male participants.

Methods: We examined ex vivo interferon-γ (IFN-γ) secretion from peripheral blood mononuclear cells (PBMC) using an ELISpot assay in 112 HIV-infected and 962 uninfected participants. In addition, we performed flow cytometric assays to examine T-cell activation, and ex vivo IFN-γ and interleukin-2 secretion from CD4(+) and CD8(+) T cells. We accounted for the sub-sampling design in Cox proportional hazards models to estimate hazard ratios (HRs) of HIV-1 infection per 1-log(e) increase of the immune responses.

Findings: We found that HIV-specific immune responses were not associated with risk of HIV-1 infection. However, each 1-log(e) increase of mock responses measured by the ELISpot assay (i.e., IFN-γ secretion in the absence of antigen-specific stimulation) was associated with a 62% increase of HIV-1 infection risk among vaccine recipients (HR = 1.62, 95% CI: (1.28, 2.04), p<0.001). This association remains after accounting for CD4(+) or CD8(+) T-cell activation. We observed a moderate correlation between ELISpot mock responses and CD4(+) T-cells secreting IFN-γ (ρ = 0.33, p = 0.007). In addition, the effect of the Step vaccine on infection risk appeared to vary with ELISpot mock response levels, especially among participants who had pre-existing anti-Ad5 antibodies (interaction p = 0.04).

Conclusions: The proportion of cells, likely CD4(+) T-cells, producing IFN-γ without stimulation by exogenous antigen appears to carry information beyond T-cell activation and baseline characteristics that predict risk of HIV-1 infection. These results motivate additional investigation to understand the potential link between IFN-γ secretion and underlying causes of elevated HIV-1 infection risk among vaccine recipients in the Step study.

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Correlations among IFN-γ-secreting Cellular Responses Measured by ELISpot, and T-cell Activation Responses among Vaccine Recipients.Values in the upper triangle indicate the Spearman's correlation coefficients for each pair of immune responses. Curves in the diagonal entries indicate the density distribution of each immune response. Plots in the lower triangle indicate the joint distribution of each pair of immune responses with a fitted simple linear regression line.
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pone-0108631-g003: Correlations among IFN-γ-secreting Cellular Responses Measured by ELISpot, and T-cell Activation Responses among Vaccine Recipients.Values in the upper triangle indicate the Spearman's correlation coefficients for each pair of immune responses. Curves in the diagonal entries indicate the density distribution of each immune response. Plots in the lower triangle indicate the joint distribution of each pair of immune responses with a fitted simple linear regression line.

Mentions: In examining the relationships between immune responses from vaccine recipients, we observed that ELISpot responses against different HIV-1 antigens were correlated with each other (Spearman correlation coefficients ρ>0.65), and T-cell activation was correlated between CD4+ and CD8+ T-cell subsets (ρ = 0.63). On the other hand, ELISpot mock responses showed no or low correlation with the HIV-specific ELISpot responses or T-cell activation (Figure 3). Among a subset of vaccine recipients in whom we measured other immune responses of interest, ELISpot mock responses also showed no correlation with Ad5-specific or CMV-specific CD4+ or CD8+ T-cells secreting IL-2 and/or IFN-γ (Figure S3 in Information S1), and no correlation with CD8+ T-cells, CD3+ CD4−CD8− (double negative) T cells or CD3− cells secreting IFN-γ (Figure S4 in Information S1). However, we observed a moderate correlation between ELISpot mock responses and ICS mock responses of CD4+ T-cells secreting IFN-γ (ρ = 0.33, p = 0.007), suggesting that CD4+ T-cells may have been the source of IFN-γ secretion in mock ELISpot (Figure S4 in Information S1).


Immune-correlates analysis of an HIV-1 vaccine efficacy trial reveals an association of nonspecific interferon-γ secretion with increased HIV-1 infection risk: a cohort-based modeling study.

Huang Y, Duerr A, Frahm N, Zhang L, Moodie Z, De Rosa S, McElrath MJ, Gilbert PB - PLoS ONE (2014)

Correlations among IFN-γ-secreting Cellular Responses Measured by ELISpot, and T-cell Activation Responses among Vaccine Recipients.Values in the upper triangle indicate the Spearman's correlation coefficients for each pair of immune responses. Curves in the diagonal entries indicate the density distribution of each immune response. Plots in the lower triangle indicate the joint distribution of each pair of immune responses with a fitted simple linear regression line.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4219669&req=5

pone-0108631-g003: Correlations among IFN-γ-secreting Cellular Responses Measured by ELISpot, and T-cell Activation Responses among Vaccine Recipients.Values in the upper triangle indicate the Spearman's correlation coefficients for each pair of immune responses. Curves in the diagonal entries indicate the density distribution of each immune response. Plots in the lower triangle indicate the joint distribution of each pair of immune responses with a fitted simple linear regression line.
Mentions: In examining the relationships between immune responses from vaccine recipients, we observed that ELISpot responses against different HIV-1 antigens were correlated with each other (Spearman correlation coefficients ρ>0.65), and T-cell activation was correlated between CD4+ and CD8+ T-cell subsets (ρ = 0.63). On the other hand, ELISpot mock responses showed no or low correlation with the HIV-specific ELISpot responses or T-cell activation (Figure 3). Among a subset of vaccine recipients in whom we measured other immune responses of interest, ELISpot mock responses also showed no correlation with Ad5-specific or CMV-specific CD4+ or CD8+ T-cells secreting IL-2 and/or IFN-γ (Figure S3 in Information S1), and no correlation with CD8+ T-cells, CD3+ CD4−CD8− (double negative) T cells or CD3− cells secreting IFN-γ (Figure S4 in Information S1). However, we observed a moderate correlation between ELISpot mock responses and ICS mock responses of CD4+ T-cells secreting IFN-γ (ρ = 0.33, p = 0.007), suggesting that CD4+ T-cells may have been the source of IFN-γ secretion in mock ELISpot (Figure S4 in Information S1).

Bottom Line: This association remains after accounting for CD4(+) or CD8(+) T-cell activation.We observed a moderate correlation between ELISpot mock responses and CD4(+) T-cells secreting IFN-γ (ρ = 0.33, p = 0.007).In addition, the effect of the Step vaccine on infection risk appeared to vary with ELISpot mock response levels, especially among participants who had pre-existing anti-Ad5 antibodies (interaction p = 0.04).

View Article: PubMed Central - PubMed

Affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Public Health Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.

ABSTRACT

Background: Elevated risk of HIV-1 infection among recipients of an adenovirus serotype 5 (Ad5)-vectored HIV-1 vaccine was previously reported in the Step HIV-1 vaccine efficacy trial. We assessed pre-infection cellular immune responses measured at 4 weeks after the second vaccination to determine their roles in HIV-1 infection susceptibility among Step study male participants.

Methods: We examined ex vivo interferon-γ (IFN-γ) secretion from peripheral blood mononuclear cells (PBMC) using an ELISpot assay in 112 HIV-infected and 962 uninfected participants. In addition, we performed flow cytometric assays to examine T-cell activation, and ex vivo IFN-γ and interleukin-2 secretion from CD4(+) and CD8(+) T cells. We accounted for the sub-sampling design in Cox proportional hazards models to estimate hazard ratios (HRs) of HIV-1 infection per 1-log(e) increase of the immune responses.

Findings: We found that HIV-specific immune responses were not associated with risk of HIV-1 infection. However, each 1-log(e) increase of mock responses measured by the ELISpot assay (i.e., IFN-γ secretion in the absence of antigen-specific stimulation) was associated with a 62% increase of HIV-1 infection risk among vaccine recipients (HR = 1.62, 95% CI: (1.28, 2.04), p<0.001). This association remains after accounting for CD4(+) or CD8(+) T-cell activation. We observed a moderate correlation between ELISpot mock responses and CD4(+) T-cells secreting IFN-γ (ρ = 0.33, p = 0.007). In addition, the effect of the Step vaccine on infection risk appeared to vary with ELISpot mock response levels, especially among participants who had pre-existing anti-Ad5 antibodies (interaction p = 0.04).

Conclusions: The proportion of cells, likely CD4(+) T-cells, producing IFN-γ without stimulation by exogenous antigen appears to carry information beyond T-cell activation and baseline characteristics that predict risk of HIV-1 infection. These results motivate additional investigation to understand the potential link between IFN-γ secretion and underlying causes of elevated HIV-1 infection risk among vaccine recipients in the Step study.

Show MeSH
Related in: MedlinePlus