Antiinflammatory profiles during primary SIV infection in African green monkeys are associated with protection against AIDS

Abstract

T cell activation levels in HIV infection are predictive of AIDS progression. We searched for the immunological correlates of protection against disease progression by studying the early stages of nonpathogenic SIV infection in African green monkeys (SIVagm). The African green monkeys (AGMs) displayed high peak viremias and a transient decline in levels of blood CD4(+) and CD8(+) T cells between days 5 and 17 after infection. A concomitant increase in levels of CD4(+)DR(+), CD8(+)DR(+), and CD8(+)CD28(-) cells was detected. After the third week, T cell activation returned to baseline levels, which suggested a protective downregulation of T cell activation. A very early (24 hours after infection) and strong induction of TGF-beta1 and FoxP3 expression was detected and correlated with increases in levels of CD4(+)CD25(+) and CD8(+)CD25(+) T cells. This was followed by a significant increase in levels of IL-10, whereas IFN-gamma gene upregulation was more transient, and levels of TNF-alpha and MIP-1alpha/beta transcripts did not increase in either blood or tissues. The profiles were significantly different during primary SIV infection in macaques (SIVmac); that is, there was a delayed increase in IL-10 levels accompanied by moderate and persistent increases in TGF-beta levels. Together, our data show that SIVagm infection is associated with an immediate antiinflammatory environment and suggest that TGF-beta may participate in the generation of Tregs, which may prevent an aberrant chronic T cell hyperactivation.

Figure 1

Plasma viral RNA copy numbers were measured by real-time PCR (cut off value, 10³ copies/ml of plasma). (A) Macaques infected with SIVmac251. (B) AGMs infected with SIVagm.sab92018.

Figure 2

CD4⁺/CD8⁺ T cell ratio during SIV infection. Data obtained with macaques (A and C) and AGMs (B and D). CD4⁺/CD8⁺ T cell ratios during SIV infection were determined in blood (A and B) and in LN (C and D) for 3 SIVagm-infected AGMs (SAB98007, SAB98008, and SAB98011), 2 SIVmac251-infected macaques (MACQ172 and MACQ205), and mock-infected controls (SAB98001, SAB98006, MACN894, and MAC141A). Similar profiles to these shown here were obtained in blood of the 6 other AGMs (SAB97008, SAB98013, SAB00020, SAB01013, SAB01015, and SAB02003) (data not shown). Open and filled symbols represent uninfected and SIV-infected monkeys, respectively.

Figure 3

Frequency of circulating activated T cells during SIV infection. Percentage of HLA-DR⁺ cells within blood CD4⁺ T (A and B) and CD8⁺ T cells (C and D). (A and C) SIVmac-infected macaques. Open and filled symbols represent uninfected and SIV-infected macaques, respectively. (B and D) Bold and thin lines represent the mean from 9 SIVagm-infected AGMs and 2 uninfected AGMs (SAB98001 and SAB98006), respectively.

Figure 4

Expression of β chemokine gene transcripts in blood and tissues of 3 SIVagm-infected AGMs (SAB98007, SAB98008, and SAB98011) (A) and 2 mock-infected AGMs (SAB98001 and SAB98006) (B). Values at time points after SIV inoculation (days 5–180) are expressed as n-fold increases relative to values found before infection (BI). Gene expressions levels are represented by box plots. Gray boxes indicate statistically significant increases (P < 0.05, Wilcoxon signed rank test) relative to baseline.

Figure 5

IL-10, TNF-α, and IFN-γ gene expressions in PBMCs, LNLC, and BALCs of 3 SIVagm-infected AGMs (SAB98007, SAB98008, and SAB98011) (A) and 2 mock-infected AGMs (SAB98001 and SAB98006) (B). Gray boxes indicate statistically significant increases (P < 0.05, Wilcoxon signed rank test) as compared with preinfection baseline values. See also legend to Figure 4.

Figure 6

Early pro- and antiinflammatory cytokine profiles in PBMCs and plasma. (A) TNF-α, IL-10, and IFN-γ gene expressions in PBMCs during primary SIVagm infection. Gene expressions were analyzed in 6 SIVagm-infected AGMs (SAB97008, SAB98013, SAB00020, SAB01013, SAB01015, and SAB02003) before and after infection, including very early time points (days 1 and 3 after infection). Values are expressed as n-fold increases relative to the calibrator. (B) Concentrations of IL-10 were measured in plasma collected from the same 6 SIVagm-infected AGMs and compared with 6 SIVmac251-infected rhesus macaques. Medium gray and dark gray boxes indicate statistically significant increases and decreases, respectively (P < 0.05, Wilcoxon signed rank test). The light gray box indicates a trend toward significant increase (IL-10 gene expression at day 10, P < 0.06, Wilcoxon signed rank test).

Figure 7

Assessment of CD25⁺ T cell percentages and of the expression levels of FoxP3 and TGF-β1. (A) CD4⁺CD25⁺ T cell percentages within lymphocytes of 6 SIVagm-infected AGMs (SAB97008, SAB98013, SAB00020, SAB01013, SAB01015, and SAB02003). (B) CD8⁺CD25⁺ T cell percentages within lymphocytes of these AGMs. (C) FoxP3 gene expression in PBMCs of these AGMs. (D) TGF-β1 gene expression in PBMCs of these AGMs. (E) Concentrations of TGF-β1 in plasma of these 6 AGMs. (F) Concentrations of TGF-β1 in plasma of 6 SIVmac251-infected rhesus macaques. See also legend to Figure 6 for medium gray and dark gray boxes.