The Early Interferon Alpha Subtype Response in Infant Macaques Infected Orally With SIV

Abstract

Type I interferons play an important role in the early defense against viral and other pathogens. These innate responses are also critically important in shaping the subsequent adaptive response. Thus, a more thorough knowledge of innate response types and mechanisms will improve our understanding of pathogenesis and guide the development of new therapeutics. Interferon alpha is used clinically in the treatment of HIV and Hepatitis C infections. The majority of IFA-α therapies is based on a single IFN-α subtype, IFN-α2. However, IFN-α comprises a family of multiple subtypes. The biological functions of the distinct subtypes and how they relate to disease are poorly understood. The current study developed the tools to distinguish and measure multiple IFN-α subtypes on the mRNA level in rhesus macaques that are used widely as an important animal model for human diseases. We were able to identify and measure nine distinct rhesus IFN-α subtypes. Further, we could demonstrate that in response to oral pathogenic SIV infection, several IFN-α subtypes are rapidly induced in lymphoid but not at oral and gastrointestinal mucosal surfaces. While each IFN-α subtype was induced at distinct levels, their relative expression patterns were identical in all lymphoid tissues examined.

Interferons and viruses: an evolutionary arms race of molecular interactions

“…Some have shown that a broad range of IFN-α subtypes are produced following stimulation with various PAMPs, but that the relative levels of each subtype are similar [14,15,22], while others report that PAMPs differentially stimulate various IFN subtypes [13,17–21]. These discrepancies can potentially be explained by differences in experimental parameters.…”

“…Many studies to date have used preparations of peripheral blood mononuclear cells (PBMCs) – a mixed population of cells including B cells, T cells, dendritic cells, and natural killer (NK) cells, nearly all of which are capable of producing type I IFN and contributing to the overall IFN profile. While some studies have utilized cell populations that were enriched from PBMCs, such as plasmacytoid dendritic cells (pDCs), myeloid dendritic cells (mDCs), or monocytes [14,22], others did not enrich for any particular cell type [15,20,21]. It is possible that even in experiments performed without cell type enrichment, particular cell types such as pDCs may nevertheless dominate the response.…”

Interferon‐alpha, immune activation and immune dysfunction in treated HIV infection

“…Most IFN-α subtypes are inducible, acid stable and exhibit antiviral, antiproliferative and immunomodulatory activities. 4, 5 Differential expression profiles of type I IFN subtypes have been found in rhesus macaques infected with SIV, 6 but the effects of different IFN-α subtypes in the pathogenesis of SIV and HIV disease is unclear. Despite different biological effects, all type I IFNs share a surface receptor composed of two IFN-α receptor subunits (IFNAR1 and IFNAR2), which can be either anchored in the cell membrane or shed as a truncated soluble form.…”

Type I Interferons: Distinct Biological Activities and Current Applications for Viral Infection

“…This finding suggests that abundant IFNAR expression might compensate for the weak binding affinity of some IFN-α subtypes [60]. Moreover, the tissue-specific pattern of IFN-α subtypes and receptors may be involved in their biological activities [61]. In some studies, the type of IFN produced and the type of virus used may have influenced the expression and action of different IFN-α subtypes [62].…”