Inflammation in HIV infection is predictive of non-AIDS morbidity and death1, higher set point plasma virus load2 and virus acquisition3; thus, therapeutic agents are in development to reduce its causes and consequences. However, inflammation may simultaneously confer both detrimental and beneficial effects. This dichotomy is particularly applicable to type I interferons (IFN-I) which, while contributing to innate control of infection4–10, also provide target cells for the virus during acute infection, impair CD4 T-cell recovery, and are associated with disease progression6,7,11–19. Here we manipulated IFN-I signalling in rhesus macaques (Macaca mulatta) during simian immunodeficiency virus (SIV) transmission and acute infection with two complementary in vivo interventions. We show that blockade of the IFN-I receptor caused reduced antiviral gene expression, increased SIV reservoir size and accelerated CD4 T-cell depletion with progression to AIDS despite decreased T-cell activation. In contrast, IFN-α2a administration initially upregulated expression of antiviral genes and prevented systemic infection. However, continued IFN-α2a treatment induced IFN-I desensitization and decreased antiviral gene expression, enabling infection with increased SIV reservoir size and accelerated CD4 T-cell loss. Thus, the timing of IFN-induced innate responses in acute SIV infection profoundly affects overall disease course and outweighs the detrimental consequences of increased immune activation. Yet, the clinical consequences of manipulation of IFN signalling are difficult to predict in vivo and therapeutic interventions in human studies should be approached with caution.

Summary Type I Interferons (IFNs) are important cytokines for innate immunity against viruses and cancer. Sixteen human IFN variants signal through the same cell surface receptors, IFNAR1 and IFNAR2, yet they can evoke markedly different physiological effects. The crystal structures of two human type I IFN ternary signaling complexes containing IFNα2 and IFNω reveal recognition modes and heterotrimeric architectures that are unique amongst the cytokine receptor superfamily, but conserved between different type I IFNs. Receptor-ligand cross-reactivity is enabled by conserved receptor-ligand "anchor-points" interspersed amongst ligand-specific interactions that ‘tune’ the relative IFN binding affinities, in an apparent extracellular ‘ligand proofreading’ mechanism that modulates biological activity. Functional differences between IFNs are linked to their respective receptor recognition chemistries, in concert with a ligand-induced conformational change in IFNAR1, that collectively control signal initiation and complex stability, ultimately regulating differential STAT phosphorylation profiles, receptor internalization rates, and downstream gene expression patterns.

Type I interferons (IFNs), including various IFN-α isoforms and IFN-β, are a family of homologous, multifunctional cytokines. IFNs activate different cellular responses by binding to a common receptor that consists of two subunits, IFNAR1 and IFNAR2. In addition to stimulating antiviral responses, they also inhibit cell proliferation and modulate other immune responses. We characterized various IFNs, including a mutant IFN-α2 (IFN-1ant) that bound tightly to IFNAR2 but had markedly reduced binding to IFNAR1. Whereas IFN-1ant stimulated antiviral activity in a range of cell lines, it failed to elicit immunomodulatory and antiproliferative activities. The antiviral activities of the various IFNs tested depended on a set of IFN-sensitive genes (the “robust” genes) that were controlled by canonical IFN response elements and responded at low concentrations of IFNs. Conversely, these elements were not found in the promoters of genes required for the antiproliferative responses of IFNs (the “tunable” genes). The extent of expression of tunable genes was cell type–specific and correlated with the magnitude of the antiproliferative effects of the various IFNs. Although IFN-1ant induced the expression of robust genes similarly in five different cell lines, its antiviral activity was virus- and cell type–specific. Our findings suggest that IFN-1ant may be a therapeutic candidate for the treatment of specific viral infections without inducing the immunomodulatory and antiproliferative functions of wild-type IFN.

Type I interferons trigger diverse biological effects by binding a common receptor, composed of IFNAR1 and IFNAR2. Intriguingly, while the activation of an antiviral state is common to all cells, antiproliferative activity and apoptosis affect only part of the population, even when cells are stimulated with saturating interferon concentrations. Manipulating receptor expression by different small interfering RNA (siRNA) concentrations reduced the fraction of responsive cells independent of the interferon used, including a newly generated, extremely tight-binding variant. Reduced receptor numbers increased 50% effective concentrations (EC 50 s) for alpha interferon 2 (IFN-␣2) but not for the tight-binding variant. A correlation between receptor numbers, STAT activation, and gene induction is observed. Our data suggest that for a given cell, the response is binary (؉/؊) and dependent on the stochastic expression levels of the receptors on an individual cell. A low number of receptors suffices for antiviral response and is thus a robust feature common to all cells. Conversely, a high number of receptors is required for antiproliferative activity, which allows for fine-tuning on a single-cell level.Type I interferons (IFNs) form a class of cytokines capable of mediating antiviral, growth inhibitory, and immunoregulatory activities (10,36,46). Consisting of 18 members in humans (32), all IFNs induce their biological activities through binding to the same receptor complex, composed of the two transmembrane proteins IFNAR1 and IFNAR2 (1). Upon formation of the ternary complex, the interferon signal is transduced through receptor-associated Janus kinases (JAK), which activate the signal transducers and activators of transcription (STAT) proteins. These, in turn, form homo-and heterodimers that translocate to the nucleus to promote the expression of interferon-stimulated genes (ISGs) (45).Despite their common biological activities and sequence homologies, type I IFNs are not redundant but rather induce their activities differentially (9, 41). These differences take effect in various ways, most notably in the antiviral (AV) and antiproliferative (AP) potencies of interferon subtypes (16,33) and in their abilities to induce different gene expression patterns (11,14,38,48). The AP activities of IFNs are a result of both apoptosis and cell cycle arrest (17,20,40). A profound example for differential activity is the substantially higher AP response induced by beta interferon (IFN-␤) than by 14,21,41). However, it should be noted that most of the differences between IFN-␣2 and IFN-␤ are quantitative and not qualitative; thus, higher IFN-␣2 concentrations mimic most IFN-␤ activities.IFNAR1 and IFNAR2 receptor subunits make distinct contributions to interferon binding, as IFNAR1 binds IFN-␣ with micromolar affinities, while the IFNAR2 subunit binds at nanomolar affinities (6). Nevertheless, the activation of both receptors is necessary to induce the interferon signal (3, 23).Mutagenesis studies have shown that the binding sites f...

Animals in the wild are able to subsist on pathogen-infected and poisonous food and show immunity to various diseases. These may be due to their microbiota, yet we have a poor understanding of animal microbial diversity and function. We used metagenomics to analyze the gut microbiota of over 180 species in the wild, covering diverse classes, feeding behaviors, geographies, and traits. Using de novo metagenome assembly, we constructed and functionally annotated a database of over 5,000 genomes, comprising 1,209 bacterial species of which 75% are unknown. The microbial composition, diversity, and functional content exhibit associations with animal taxonomy, diet, activity, social structure and lifespan. We identify the gut microbiota of wild animals as a largely untapped resource for the discovery of therapeutics and biotechnology applications.