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.
Highlights
Chronic immune activation during HIV infection is considered as the main driver of CD4+ T cell depletion and AIDS, and early T cell activation is a better predictor of the outcome of the infection than viral load [1]
We aimed to study if the lower levels of IFN-a described during SIVagm infection as compared to SIVmac infections matter in the resolution of the inflammation in African green monkeys (AGMs)
We tested here whether by artificially increasing IFN-a related inflammation during the acute phase of SIVagm infection, one can overcome the intrinsic control of immune activation in this natural host
Summary
Chronic immune activation during HIV infection is considered as the main driver of CD4+ T cell depletion and AIDS, and early T cell activation is a better predictor of the outcome of the infection than viral load [1]. Recent observations suggest that inflammation is even more important than T cell activation to predict disease progression and mortality [2,3]. Already in the acute primary phase of HIV-1 infection, the levels of soluble inflammatory mediators, such as IP-10 (CXCL10), were predictive of disease progression [4,5]. Type I IFN (IFN-I), such as IFN-a, is an important component of innate immunity providing a first-line defense to viral infections, as well as bridging the innate and adaptive immune systems. This cytokine is mainly produced by plasmacytoid dendritic cells (pDCs) in viral infections. IFN-a production is critical for the activation of NK cells, enhancing
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