The AIDS resistance of naturally SIV-infected sooty mangabeys is independent of cellular immunity to the virus - PubMed (original) (raw)

. 2006 Jul 1;108(1):209-17.

doi: 10.1182/blood-2005-12-4897. Epub 2006 Mar 7.

Paola Pagliardini, Shari Gordon, Beth Sumpter, Jessica Engram, Abeer Moanna, Mirko Paiardini, Judith N Mandl, Benton Lawson, Seema Garg, Harold M McClure, Yong-Xian Xu, Chris Ibegbu, Kirk Easley, Nathalia Katz, Ivona Pandrea, Cristian Apetrei, Donald L Sodora, Silvija I Staprans, Mark B Feinberg, Guido Silvestri

Affiliations

The AIDS resistance of naturally SIV-infected sooty mangabeys is independent of cellular immunity to the virus

Richard Dunham et al. Blood. 2006.

Abstract

In contrast to human immunodeficiency virus (HIV)-infected humans, natural hosts for simian immunodeficiency virus (SIV) very rarely progress to acquired immunodeficiency syndrome (AIDS). While the mechanisms underlying this disease resistance are still poorly understood, a consistent feature of natural SIV infection is the absence of the generalized immune activation associated with HIV infection. To investigate the immunologic mechanisms underlying the absence of AIDS in SIV-infected sooty mangabeys (SMs), a natural host species, we performed a detailed analysis of the SIV-specific cellular immune responses in 110 SIV-infected SMs. We found that while SIV-specific T-cell responses are detectable in the majority of animals, their magnitude and breadth are, in fact, lower than what has been described in HIV-infected humans, both in terms of cytokine production (ie, IFN-gamma, TNF-alpha, and IL-2) and degranulation (ie, CD107a expression). Of importance, SIV-specific T-cell responses were similarly low when either SIVmac239-derived peptides or autologous SIVsmm peptides were used as stimuli. No correlation was found between SIV-specific T-cell responses and either viral load or CD4+ T-cell count, or between these responses and markers of T-cell activation and proliferation. These findings indicate that the absence of AIDS in naturally SIV-infected sooty mangabeys is independent of a strong cellular immune response to the virus.

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Figures

Figure 1.

Figure 1.

Viral load and CD4+ T-cell count in naturally SIV-infected SMs. (A) Viral load (SIV RNA copies/mL plasma) in 110 SIV-infected SMs included in this study. (B) CD4+ T-cell counts (cells/mm3) in the same 110 SIV-infected SMs. (C) Lack of correlation between CD4+ T-cell counts (cells/mm3) and viral load (SIV RNA copies/mL plasma) in the same cohort of 110 SIV-infected SMs. For panel C, P = ns indicates that the P value of the correlation coefficient was more than .05 (Spearman rank correlation test).

Figure 2.

Figure 2.

SIV-specific T-cell responses in naturally SIV-infected SMs. The responses were measured by intracellular cytokine staining for IFN-γ, TNF-α, and IL-2 in response to peptide pools encompassing the entire sequence of gag, pol, env, and nef genes of SIVmac239. A positive T-cell response was defined as cytokine production greater than unstimulated negative control by at least 0.01%. (A) Representative plot of an IFN-γ response to Gag pool no. 3 and Env pool no. 3 (right) along with the unstimulated negative control (left) and positive control (PMA and ionomycin: middle). (B) Distribution of naturally SIV-infected SMs based on the presence of above-background responses to SIV by CD3+CD8+ (right) and CD3+CD8- (left) T cells. Animals were divided as producing no cytokine, IFN-γ only, TNF-α only, or both cytokines in response to any pool of SIVmac239 peptides. (C) Magnitude of SIV-specific T-cell responses defined as percent of CD3+CD8+ (left) or CD3+CD8- (right) T cells producing either IFN-γ or TNF-α in response to SIVmac239 peptide stimulation. Each bar represents an individual animal. The contribution of each of the tested antigens to the total SIV-specific T-cell response is shown. (D) Average magnitude of the responses to the 4 tested SIV antigens by CD3+CD8+ (left) and CD3+CD8- (right) T cells. (E) Percentage of CD3+CD8+ (left) or CD3+CD8- (right) T cells producing IL-2 in response to SIVmac239 peptide stimulation in 39 SIV-infected SMs. The contribution of each of the tested antigens to the total SIV-specific T-cell response is shown. (F) Magnitude of SIV-specific T-cell responses in 8 experimentally SIVsm-infected rhesus macaques (RMs) defined as percent of CD3+CD8+ (left) or CD3+CD8- (right) T cells producing IFN-γ or TNF in response to SIV stimulation. The total SIV-specific 6T-cell response is broken down as response to any of the 4 tested SIV antigens.

Figure 3.

Figure 3.

CD8+ T-cell degranulation in response to SIV peptides in naturally SIV-infected SMs. In all experiments, degranulation was measured as the percentage of CD3+CD8+ T cells coexpressing CD69 and CD107a. (A) Representative plot of a positive response to SIV-Pol pool no. 2 (right) along with the unstimulated negative control (left) and 2 positive controls (SEB and PMA + ionomycin: middle). (B) Percentage of CD8+ T cells that degranulate in response to SIV peptide stimulation in 18 naturally SIV-infected SMs. Each bar represents an individual animal. The contribution of each of the tested antigens to the total SIV-specific T-cell response is shown.

Figure 4.

Figure 4.

Lack of correlation between magnitude or breadth of SIV-specific T-cell responses and viral load in naturally SIV-infected SMs. (A-B) The percent of SIV-specific CD3+CD8+ T cells (A) or CD3+CD8- T cells (B) was plotted along with SIV viremia (copies/mL plasma). Magnitude of the SIV-specific response is represented by the percent of CD3+CD8+ or CD3+CD8- T cells producing either IFN-γ or TNF-α in response to SIVmac239 peptide pools. P = ns indicates that the P value of the correlation coefficient is more than .05 (Spearman rank correlation test). (C-D) Comparison of viral load (copies/mL plasma) in naturally SIV-infected SMs grouped by the presence of detectable CD3+CD8+ (C) or CD3+CD8- (D) T-cell-mediated responses to 4, 3, 2, 1, or no SIVmac239 antigens. One-way nonparametric ANOVA (Kruskal-Wallis) followed by Dunn multiple comparison test found no significant differences between the groups. Horizontal lines indicate mean values.

Figure 5.

Figure 5.

Lack of correlation between magnitude or breadth of SIV-specific T-cell responses and CD4+ T-cell counts in naturally SIV-infected SMs. (A-B) The percent of SIV-specific CD3+CD8+ T cells (A) or CD3+CD8- T cells (B) was plotted along with CD4+ T-cell counts (cells/mm3). Magnitude of the SIV-specific response is represented by the percent of CD3+CD8+ or CD3+CD8- T cells producing either IFN-γ or TNF-α in response to SIVmac239 peptide pools. P = ns indicates that the P value of the correlation coefficient is more than .05 (Spearman rank correlation test).

Figure 6.

Figure 6.

Similar magnitude or breadth of SIV-specific T-cell responses in naturally SIV-infected SMs grouped by infecting SIVsmm viral subtypes. A total of 84 animals were included in this study. (A-B) Magnitude of CD3+CD8+ (A) and CD3+CD8- (B) T-cell responses in SIV-infected SMs grouped by infecting viral subtype. One-way nonparametric ANOVA (Kruskal-Wallis) of all groups followed by Dunn multiple comparison test found no significant differences between the groups. Horizontal lines indicate mean values. (C) Percentage of CD3+CD8+ T cells producing IFN-γ in response to pools of SIVsmm-Gag subtype-1 or -2 “consensus” peptides in 9 SIVsmm subtype-1-infected and 10 SIVsmm subtype-2-infected SMs. Each bar represents an individual animal. No significant differences were observed between groups using a 2-way ANOVA. Error bars indicate standard deviation.

Figure 7.

Figure 7.

Lack of correlation between magnitude of SIV-specific T-cell responses and the level of T-cell proliferation measured as fraction of Ki67+ T cells. (A-B) Comparison of the percent of Ki67+ cells in the CD3+CD8+ (A) or CD3+CD4+ (B) T-cell subsets in SIV-infected and uninfected animals (**P < .01, ***P < .001 as determined by the Mann-Whitney U test.) (C-D) Lack of correlation between the percent of CD3+CD8+ (C) and CD3+CD4+ (D) T cells expressing the Ki67 proliferation marker and the magnitude of SIV-specific responses mediated by CD3+CD8+ (C) and CD3+CD8- (D) T cells. P = ns indicates that the P value of the correlation coefficient is more than .05 (Spearman rank). Error bars in panels A and B indicate standard deviation.

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