Innate Immune Responses and Rapid Control of Inflammation in African Green Monkeys Treated or Not with Interferon-Alpha during Primary SIVagm Infection

Abstract

Chronic immune activation (IA) is considered as the driving force of CD4 ⁺ T cell depletion and AIDS. Fundamental clues in the mechanisms that regulate IA could lie in natural hosts of SIV, such as African green monkeys (AGMs). Here we investigated the role of innate immune cells and IFN-α in the control of IA in AGMs. AGMs displayed significant NK cell activation upon SIVagm infection, which was correlated with the levels of IFN-α. Moreover, we detected cytotoxic NK cells in lymph nodes during the early acute phase of SIVagm infection. Both plasmacytoid and myeloid dendritic cell (pDC and mDC) homing receptors were increased, but the maturation of mDCs, in particular of CD16 ⁺ mDCs, was more important than that of pDCs. Monitoring of 15 cytokines showed that those, which are known to be increased early in HIV-1/SIVmac pathogenic infections, such as IL-15, IFN-α, MCP-1 and CXCL10/IP-10, were significantly increased in AGMs as well. In contrast, cytokines generally induced in the later stage of acute pathogenic infection, such as IL-6, IL-18 and TNF-α, were less or not increased, suggesting an early control of IA. We then treated AGMs daily with high doses of IFN-α from day 9 to 24 post-infection. No impact was observed on the activation or maturation profiles of mDCs, pDCs and NK cells. There was also no major difference in T cell activation or interferon-stimulated gene (ISG) expression profiles and no sign of disease progression. Thus, even after administration of high levels of IFN-α during acute infection, AGMs were still able to control IA, showing that IA control is independent of IFN-α levels. This suggests that the sustained ISG expression and IA in HIV/SIVmac infections involves non-IFN-α products.

Author Summary

Chronic inflammation is considered as directly involved in AIDS pathogenesis. The role of IFN-α as a driving force of chronic inflammation is under debate. Natural hosts of SIV, such as African green monkeys (AGMs), avoid chronic inflammation. We show for the first time that NK cells are strongly activated during acute SIVagm infection. This further demonstrates that AGMs mount a strong early innate immune response. Myeloid and plasmacytoid dendritic cells (mDCs and pDCs) homed to lymph nodes; however mDCs showed a stronger maturation profile than pDCs. Monitoring of cytokine profiles in plasma suggests that the control of inflammation in AGMs is starting earlier than previously considered, weeks before the end of the acute infection. We tested whether the capacity to control inflammation depends on the levels of IFN-α produced. When treated with high doses of IFN-α during acute SIVagm infection, AGMs did not show increase of immune activation or signs of disease progression. Our study provides evidence that the control of inflammation in SIVagm infection is not the consequence of weaker IFN-α levels. These data indicate that the sustained interferon-stimulated gene induction and chronic inflammation in HIV/SIVmac infections is driven by factors other than IFN-α.