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1.
FIGURE 1

FIGURE 1. From: Immune Activation Driven by CTLA-4 Blockade Augments Viral Replication at Mucosal Sites in Simian Immunodeficiency Virus Infection.

SIV primary infection: study design and tissue collection. All macaques were infected with SIVmac251 by the intrarectal route, as previously described (31). Macaques were treated or not at the times indicated with MDX-010. The time of rectal or lymph node biopsy is indicated with symbols: *, Mamu-A*01+ macaques. The MDX-010 Ab was given i.v. at 10 mg/kg/dose; d, days.

Valentina Cecchinato, et al. J Immunol. ;180(8):5439-5447.
2.
FIGURE 7

FIGURE 7. From: Immune Activation Driven by CTLA-4 Blockade Augments Viral Replication at Mucosal Sites in Simian Immunodeficiency Virus Infection.

Virus-specific immune responses induced by vaccination. CD4+ and CD8+ T cell responses (A and B, respectively) measured as IL-2 or TNF-α and IFN-γ production following vaccination and ART suspension were evaluated in the same macaques used in Fig. 6D whose viremia remained suppressed during ART. These animals were selected to limit the confounding factor of overt viral replication on the vaccine immunogenicity. In these experiments, almost the entire SIV proteome was used as stimulus.

Valentina Cecchinato, et al. J Immunol. ;180(8):5439-5447.
3.
FIGURE 5

FIGURE 5. From: Immune Activation Driven by CTLA-4 Blockade Augments Viral Replication at Mucosal Sites in Simian Immunodeficiency Virus Infection.

Increased IDO expression and activity and decreased FoxP3+CD4+ T cells in MDX-010-treated macaques. A, IDO RNA levels were measured by RT-PCR in rectal mucosa. Horizontal bars in the smaller plot correspond to the median. B, The kynure-nine-to-tryptophan ratio was measured in plasma at the times indicated. *, Significant (p = 0.05) differences in the two groups. The data are expressed as mean value (±SE). Total number of CD4+FoxP3+ T cells/mm2 in lymph nodes (C) and rectal mucosa (D).

Valentina Cecchinato, et al. J Immunol. ;180(8):5439-5447.
4.
FIGURE 4

FIGURE 4. From: Immune Activation Driven by CTLA-4 Blockade Augments Viral Replication at Mucosal Sites in Simian Immunodeficiency Virus Infection.

Virus-specific immune responses in blood and tissues. A and B, Mean values (+SE) of the absolute number of CM9+ or SL8+tetramer+ T cells/mm3 of blood (A) and of the frequency of these responses in rectal mucosa (B) following exposure to SIVmac251 in treated and untreated macaques. C, Total number of CD4+ and CD8+ T cells producing IFN-γ, TNF-α, and IL-2 following in vitro stimulation with the entire SIV Gag peptide pool in the blood of macaques during primary infection. D, Titers of serum-binding Abs to gp120 measured by ELISA. Horizontal bars in the scatter dot plot correspond to the median.

Valentina Cecchinato, et al. J Immunol. ;180(8):5439-5447.
5.
FIGURE 6

FIGURE 6. From: Immune Activation Driven by CTLA-4 Blockade Augments Viral Replication at Mucosal Sites in Simian Immunodeficiency Virus Infection.

MDX-010 decreases ART responsiveness and abrogates the vaccine effect in chronically infected macaques. A, Schematic representation of the second study design and animal groups. MDX-010 was given at weeks 22, 27, 32, and 37 at a dose of 10 mg/kg. Vaccination was performed with two inoculations of modified vaccinia Ankara-expressing Gag, Pol, Env, and retanef (56) 4 days after the administration of the Ab in each case. *, Mamu-A*01+. Plasma virus levels during the study in all the MDX-010-treated macaques (groups 1 and 2) (B) and in macaques vaccinated only (C). *, Mamu-A*01+. D, Plasma virus levels in macaques M674, M601, M608 from group 1 and M677, M640, M647, and M649 from group 3. These animals were selected to evaluate the vaccine effect as they maintained adequate suppression of viral replication during ART treatment.

Valentina Cecchinato, et al. J Immunol. ;180(8):5439-5447.
6.
FIGURE 2

FIGURE 2. From: Immune Activation Driven by CTLA-4 Blockade Augments Viral Replication at Mucosal Sites in Simian Immunodeficiency Virus Infection.

MDX-010 treatment increases T cell activation and exacerbates CCR5+CD4+ T cell loss in tissues. Mean values (±SE) of the absolute CD3+CD4+ T cells/mm3 in blood (A). Total number of CD3+CD4+ T cells/mm2 in lymph nodes (B) and rectal mucosa (C). Total number of CD4+Ki67+ T cell numbers/mm2 in lymph nodes (D) and rectal mucosa (E). F, Frequency of CCR5+CD4+ T cells in rectal mucosa before and after challenge exposure to SIVmac251. For the after challenge analysis, the geometric mean of the frequency of CCR5+CD4+ T cells at weeks 7–14 is shown for each animal. The bars represent the mean value in each group. G, Mean value (+SE) of the frequency of effect or memory CD4+ T cells in lymph nodes of animals over time. Absolute number of CD3+CD8+ T cells/mm3 in blood (H) or CD3+CD8+ T cells/mm2 in lymph nodes (I) and rectal mucosa (J). Percentage (mean value + SE) of CD8+Ki67+ T cells in lymph nodes (K) and absolute number of CD8+Ki67+ T cells/mm2 in rectal mucosa (L). All the data in B–E and H–J and L were obtained by immunohistochemistry counting of the number of CD4+ or CD8+ T cells/mm2 of tissues. Lymph nodes were either axillary or inguinal. Horizontal bars in the scatter dot plots correspond to the median.

Valentina Cecchinato, et al. J Immunol. ;180(8):5439-5447.
7.
FIGURE 3

FIGURE 3. From: Immune Activation Driven by CTLA-4 Blockade Augments Viral Replication at Mucosal Sites in Simian Immunodeficiency Virus Infection.

Systemic and mucosal virus levels. A and B, Plasma SIV RNA level over time for each macaque in the control and MDX-010 groups, respectively. *, Mamu-A*01+. C, Geometric mean values of virus levels in the two groups. Statistical analysis by the Wei-Johnson test counting weeks 9, 10, 12, and 14 demonstrated significantly higher viremia in macaques treated with MDX-010 (p = 0.032). Similarly, from weeks 8 to 14, the difference between the two groups was significant (p= 0.040), as indicated in the figure. D and E, SIV Gag RNA levels normalized on GAPDH in RNA of lymph nodes (D) and rectal mucosa (E) of control animals (■) and MDX-010-treated macaques (□). Statistical analysis was performed using the repeated measures ANOVA. Horizontal bars in the scatter dot plots correspond to the median. F, Correlative analysis between the number of activated CD4+ T cells in blood and plasma virus levels at week 14 postinfection.

Valentina Cecchinato, et al. J Immunol. ;180(8):5439-5447.

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