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. 2008 Mar;24(3):505-19.
doi: 10.1089/aid.2007.0191.

DNA-MVA vaccine protection after X4 SHIV challenge in macaques correlates with day-of-challenge antiviral CD4+ cell-mediated immunity levels and postchallenge preservation of CD4+ T cell memory

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DNA-MVA vaccine protection after X4 SHIV challenge in macaques correlates with day-of-challenge antiviral CD4+ cell-mediated immunity levels and postchallenge preservation of CD4+ T cell memory

Mariana Manrique et al. AIDS Res Hum Retroviruses. 2008 Mar.

Abstract

The ability of vaccines to induce immunity both in mucosal and systemic compartments may be required for prevention of HIV infection and AIDS. We compared DNA-MVA vaccination regimens adjuvanted by IL-12 DNA, administered intramuscularly and nasally or only nasally. Most of the vaccinated Rhesus macaques developed mucosal and systemic humoral and cell-mediated SHIV-specific immune responses. Stimulation of mucosal anti-Env IgA responses was limited. After rectal challenge with SHIV 89.6P, all vaccinated and naive animals became infected. However, most of the vaccinated animals showed significant control of viremia and protection from CD4(+) T cell loss and AIDS progression compared to the control animals. The levels of CD4(+) and CD8(+) T cell virus-specific responses measured on the day of challenge correlated with the level of viremia control observed later during the chronic infection. Postchallenge viremia levels inversely correlated with the preservation of SHIV-specific CD4(+)/IL-2(+) and CD8(+)/TNF-alpha(+) T cells but not with CD4(+)/IFN-gamma(+) T cells measured over time after challenge. We also found that during the early chronic infection SHIV vaccination permitted a more significant preservation of both naive and memory CD4(+) T cells compared to controls. In addition, we observed a more significant and prolonged preservation of memory CD4(+) T cells after SHIV vaccination and challenge than that observed after SIV vaccination and challenge. As the antiviral immunity stimulated by vaccination is present in the memory CD4(+) T cell subpopulations, its more limited targeting by SHIV compared to SIV may explain the better control of X4 tropic SHIV than R5 tropic SIVs by vaccination.

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Figures

FIG. 1
FIG. 1
Vaccination protocol. Schematic representation of the proviral DNAs used in the vaccine regimens (a) and regimens administered to the four groups (b). N, nasal immunization; i.m., intramuscular immunization.
FIG. 2
FIG. 2
Plasma anti-SHIV IgG titers. Geometric mean of reciprocal endpoint titers of (a) anti-SIV Gag/Pol, (b) anti-HIV gp120, (c) anti-HIV gp41-specific IgG, and (d) neutralizing antibodies measured in plasma collected during vaccination, on the day of challenge (week 47) and postchallenge at 4 week intervals up to week 64. Error bars represent SEM. Arrows indicate day of challenge.
FIG. 3
FIG. 3
SHIV-specific systemic cell-mediated immune responses. Percentage of SHIV-specific T cells detected in PBMCs by intracellular staining after stimulation with an SIV Gag or an HIV-1 89.6 Env peptide pool. (a) Values for the individual animals are reported as the sum of percentages of Gag-specific and Env-specific cells. (b) Group means of the values reported in (a). (c) Percentage of CD3+/CD8+/p11c tetramer-positive T cells in PBMCs of Mamu-A*01-positive animals in each group during the entire experiment (left) and in rectal MC 2 and 4 weeks after the third DNA vaccination and 2 weeks after rMVA boosting in Mamu-A*01+ animals (right). The two graph bars for each Mamu-A*01 animal represent the percentage of rectal mononuclear cells. CD3+/CD8+ (open bar) and CD3+/CD8+/β7+ (striped bar) T cells colabeled with Gag p11C tetramer. (d) Number of IFN-γ-secreting PBMCs per million cells detected by ELISPOT after stimulation with SIV Gag or Env peptide pools. 50 SFU corresponds to the level of 2-fold the average background and is the threshold for significant responses. Graph bars represent the mean number of spots per million cells of Gag-specific plus Env-specific cells, detected in triplicate cultures of PBMCs cultured with peptides, after subtracting of the mean number of spots found in triplicate control cultures of PBMCs in medium alone. The arrows indicate the days of the second and third vaccinations. The asterisks indicate the day of challenge.
FIG. 4
FIG. 4
RNA viral loads in macaques challenged rectally with SHIV89.6P (expressed as log10). (a) Values of viral RNA copies detected in the plasma of each animal are reported for individual time points. (b) The geometric mean of viral RNA copy numbers detected in the animals of each group at each time point is reported. Postchallenge absolute CD4+ T cell counts per μl (c) and percentage (e) in PBMCs of animals in the four groups. CD4+ T cells were evaluated in PBMCs on the day of challenge (week 47) and up to 28 weeks postchallenge (week 75). (d) The mean of the absolute CD4 T cell counts (d) and percentage (f) detected in the PBMC of the animals of each regimen group is reported. Error bars represent SEM. (g,h) Kaplan-Meier survival curves following challenge for the different groups (g) or after dividing vaccinated and control animals into two groups based on their viral load at set point (week 8 postchallenge) (h). Significance, evaluated by the log rank test, was observed when Group 2 was compared to Group 4 (p < 0.01), when Group 3 was compared to Group 4 (p < 0.03), and when Group A (good controllers) was compared to Group B (poor controllers) (p < 0.01). Animals included in Group B are 182 (Group 1), 190, 192, 320 (Group 3), and 161, 223, 212, 537 (control Group 4). All the remaining animals were included in Group A.
FIG. 5
FIG. 5
SHIV-specific IgA fold increase in rectal secretions after challenge. The fold increase is expressed as a ratio between postimmune sample-specific activity and background-specific activity measured before immunization. The first panel shows the IgA fold increase detected using an SIV viral lysate, the second panel shows the anti-gp120 IgA fold increase, and the third panel shows the anti-gp41 IgA fold increase.
FIG. 6
FIG. 6
SHIV-specific cell-mediated responses in good (dashed line) and poor (solid line) virus controllers (a-d). Group averages and SEM are represented at each time point. p values for the comparison of the values measured on the day of challenge (week 47) and for the areas under the curve of the two groups from week 24 to 27 (immunization) and from 49 to 67 (postchallenge) are reported. NS, nonsignificant.
FIG. 7
FIG. 7
Naive, CM, and EM CD4+ T cell populations after challenge. Percentage of naive (CD95-/CD28+), CM (CD95+/CD28+), and EM (CD95+/CD28-) CD4+ T cells in vaccinated and control animals (a) and in individual vaccine and control groups (b). The average of values measured 8 and 12 weeks after challenge is represented for each animal. p values for each pair comparison were calculated using the Wilcoxon rank-sum test.

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