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Clinical Trial
. 2009 Aug;15(8):876-8.
doi: 10.1038/nm.1989. Epub 2009 Jul 20.

Baseline Ad5 serostatus does not predict Ad5 HIV vaccine-induced expansion of adenovirus-specific CD4+ T cells

Natalie A Hutnick  1 , Diane G Carnathan, Sheri A Dubey, George Makedonas, Kara S Cox, Lisa Kierstead, Sarah J Ratcliffe, Michael N Robertson, Danilo R Casimiro, Hildegund C J Ertl, Michael R Betts
Affiliations
Clinical Trial

Baseline Ad5 serostatus does not predict Ad5 HIV vaccine-induced expansion of adenovirus-specific CD4+ T cells

Natalie A Hutnick et al. Nat Med. 2009 Aug.

Erratum in

  • Nat Med. 2009 Nov;15(11):1333. Makedonas, George [added]

Abstract

The mechanisms underlying possible increased HIV-1 acquisition in adenovirus 5 (Ad5)-seropositive subjects vaccinated with Ad5-HIV-1 vectors in the Merck STEP trial remain unclear. We find that Ad5 serostatus does not predict Ad5-specific CD4(+) T cell frequency, and we did not observe durable significant differences in Ad5-specific CD4(+) T cells between Ad5-seropositive and Ad5-seronegative subjects after vaccination. These findings indicate no causative role for Ad5-specific CD4(+) T cells in increasing HIV-1 susceptibility in the STEP trial.

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Figures

Figure 1
Figure 1. Ad5-specific CD4+ T-cell frequency does not correlate with Ad5 neutralizing antibody titer
Forty total subjects with a range of Ad5 nAb titers were analyzed. Ten seronegative (five assessed weeks 0–4, five assessed weeks 0–78, gray symbols) and five seropositive subjects (black symbols) received Merck Ad5 gag/pol/nef as described in Supplementary Methods. a) Similar Ad5-specific CD4+ T-cell magnitude regardless of baseline Ad5 serostatus. IFN-γ IL-2, MIP-1α, TNF- α, and/or perforin production in response to Ad5 virus particles was measured by polychromatic flow cytometry. Frequencies reflect the total percent of cells responding by any of these functions. b) No correlation between total Ad5-specific CD4+ T-cell magnitude and Ad5 nAb titer. c) Ad5 nAbs titers increase in Ad5 seronegatives after one vaccination (P < 0.05). d) Ad5 nAb titers remain elevated in baseline seronegatives throughout the vaccine course (gray asterisk, P < 0.05). e) Ad5-specific CD4+ T-cell frequency increases after vaccination in Ad5 seropositives (open boxes, black asterisk) at weeks 4 (P < 0.002) and 8 (P < 0.03) and Ad5 seronegatives (grey boxes, gray asterisk) at week 4 (P < 0.02). Plots depict the median, 25th and 75th percentile (box plots) and the minimum and maximum values (whiskers). Triangles indicate vaccination time points.
Figure 2
Figure 2. CD4+ effector functions do not differ with baseline serostatus
IL-2 (2, downward triangle), IFN-γ (G, circle), MIP-1α (M, diamond), perforin (P, square) and TNF-α (T, upward triangle) production in response to Ad5 virus were measured by intracellular cytokine staining. Subjects for all studies are as described previously. For all panels, gray symbols, lines, or box plots depict baseline Ad5 seronegative subjects, and open black symbols, lines, or box plots depict baseline Ad5 seropositive subjects. a) Percentage of baseline Ad5-specific CD4+ T-cells producing various responses separated by Ad5 seropositivity. Bars represent the mean ± SEM. b) Percent contribution of Ad5- specific CD4+ T-cells making each respective function to the total Ad5-specific CD4+ T-cell response at baseline. c) Fold change in each Ad-specific CD4+ T-cell function after a single vaccination. IL-2 fold change was significantly higher in Ad5 seropositives at week 4 (P < 0.02). d) Transient changes in Ad-specific CD4+ T-cell function after vaccination. In seropositive subjects IFN-γ increased from baseline (black asterisk) in the seropositive group at week 4 (P < 0.005), 8 (P < 0.05) and 30 (P < 0.5), IL-2 at week 4 (P < 0.03), MIP-1α at week 4 (P < 0.03), and TNF- α at weeks 4 (P < 0.0001) and 8 (P < 0.005); in seronegative subjects, IFN-γ increased (gray asterisk) above baseline at week 4 (P < 0.03), MIP-1α at weeks 4 (P < 0.005) and 42 (P < 0.001), and perforin at weeks 4 (P < 0.001), 42 (P < 0.0001), 52 (P < 0.05) and 78 (P < 0.05). Plots depict the median, 25th and 75th percentile (boxes) and the minimum and maximum values (whiskers). Triangles indicate vaccination time points. e) Ki67 expression on Ad-specific CD4+ T-cells does not change after vaccination. Plots depict the median, 25th and 75th percentile (boxes) and the minimum and maximum values (whiskers). Triangles indicate vaccination time points. f) Percentage of A5-specific CD4+ T memory (dashed lines) or effector memory (solid lines) that express both α4 and β7.g) α4 and β7 co-expression on memory (dashed line) or effector memory (solid lines) CD4+ T-cells. P value shown denotes a significant difference between the groups at week 8. h) Percentage of α4+ β7+ memory (dashed lines) or effector memory (solid lines) CD4+ T-cells that are Ad5-specific.
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