In the decade following their initial discovery, the suppressor of cytokine signaling (SOCS) proteins have been studied for their potential use as immunomodulators in disease. SOCS proteins, especially SOCS1 and SOCS3, are expressed by immune cells and cells of the central nervous system (CNS) and have the potential to impact immune processes within the CNS, including inflammatory cytokine and chemokine production, activation of microglia, macrophages and astrocytes, immune cell infiltration and autoimmunity. We describe CNS-relevant in vitro and in vivo studies that have examined the function of SOCS1 or SOCS3 under various neuroinflammatory or neuropathological conditions, including exposure of CNS cells to inflammatory cytokines or bacterial infection, demyelinating insults, stroke, spinal cord injury, multiple sclerosis and glioblastoma multiforme. The SOCS familySuppressor of cytokine signaling (SOCS) proteins are intracellular, cytokine-inducible proteins that inhibit cytokine signaling in numerous cell types, including cells of the immune and central nervous systems (CNS). The SOCS family is composed of eight members: cytokine inducible SRC homology 2 (SH2)-domain-containing protein (CIS) and SOCS1 to SOCS7 [1,2]. To exert their function, SOCS proteins associate with phosphorylated tyrosine residues on Janus kinases (JAKs) and/or cytokine receptor subunits through a central SH2 domain. A C-terminal SOCS box then interacts with components of the ubiquitin ligase machinery and mediates proteosomal degradation of associated proteins [3]. In addition, the N-terminus of SOCS1 and SOCS3, specifically, contains a kinase-inhibitory region (KIR) (Figure 1), which acts as a pseudosubstrate for JAKs, conferring inhibition of JAK kinase activity [1]. Through these interactions, SOCS proteins attenuate responses to cytokines and growth factors. Because studies of SOCS family members have established SOCS1 and SOCS3 as the most important in regulating innate and adaptive immune responses, they are the focus of this review. There is limited information regarding the role of other SOCS family members in CNS immunity. Therefore, they are not discussed here. SOCS regulation of JAK/STAT signalingSignal transduction through the JAK/signal transducer and activator of transcription (STAT) signaling pathway is a crucial mediator of inflammatory and immune responses in the CNS [4]. Activation of the JAK/STAT pathway is achieved by cytokines binding to their associated cell-surface receptors, leading to a series of phosphorylation events, culminating in phosphorylation of the STAT transcription factors (Figure 2). Activated STATs promote Corresponding author: Benveniste, E.N. (tika@uab.edu). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Plea...

Over the past decade, a family of host proteins known as suppressors of cytokine signaling (SOCS) have emerged as frequent targets of viral exploitation. Under physiologic circumstances, SOCS proteins negatively regulate inflammatory signaling pathways by facilitating ubiquitination and proteosomal degradation of pathway machinery. Their expression is tightly regulated to prevent excessive inflammation while maintaining protective antipathogenic responses. Numerous viruses, however, have developed mechanisms to induce robust host SOCS protein expression following infection, essentially "hijacking" SOCS function to promote virus survival. To date, SOCS proteins have been shown to inhibit protective antiviral signaling pathways, allowing viruses to evade the host immune response, and to ubiquitinate viral proteins, facilitating intracellular viral trafficking and progeny virus assembly. Importantly, manipulation of SOCS proteins not only facilitates progression of the viral life cycle but also powerfully shapes the presentation of viral disease. SOCS proteins can define host susceptibility to infection, contribute to peripheral disease manifestations such as immune dysfunction and cancer, and even modify the efficacy of therapeutic interventions. Looking toward the future, it is clear that a better understanding of the role of SOCS proteins in viral diseases will be essential in our struggle to modulate and even eliminate the pathogenic effects of viruses on the host.

Viral DNA genomes replicating in cells encounter a myriad of host factors that facilitate or hinder viral replication. Viral proteins expressed early during infection modulate host factors interacting with viral genomes, recruiting proteins to promote viral replication, and limiting access to antiviral repressors. Although some host factors manipulated by viruses have been identified, we have limited knowledge of pathways exploited during infection and how these differ between viruses. To identify cellular processes manipulated during viral replication, we defined proteomes associated with viral genomes during infection with adenovirus, herpes simplex virus and vaccinia virus. We compared enrichment of host factors between virus proteomes and confirmed association with viral genomes and replication compartments. Using adenovirus as an illustrative example, we uncovered host factors deactivated by early viral proteins, and identified a subgroup of nucleolar proteins that aid virus replication. Our data sets provide valuable resources of virus-host interactions that affect proteins on viral genomes.

HIV-1 replication within macrophages of the CNS often results in cognitive and motor impairment, which is known as HIV-associated dementia (HAD) in its most severe form. IFN-β suppresses viral replication within these cells during early CNS infection, but the effect is transient. HIV-1 eventually overcomes this protective innate immune response to resume replication through an unknown mechanism, initiating the progression toward HAD. Here, we show that Suppressor Of Cytokine Signaling (SOCS) 3, a molecular inhibitor of IFN signaling, may allow HIV-1 to evade innate immunity within the CNS. We find that SOCS3 is elevated in an in vivo SIV/macaque model of HAD, and that the pattern of expression correlates with recurrence of viral replication and onset of CNS disease. In vitro, the HIV-1 regulatory protein transactivator of transcription (Tat) induces SOCS3 in both human and murine macrophages in a NF-κB-dependent manner. SOCS3 expression attenuates the response of macrophages to IFN-β at both proximal levels of pathway activation and downstream antiviral gene expression, and consequently overcomes the inhibitory effect of IFN-β on HIV-1 replication. These studies indicate that SOCS3 expression, induced by stimuli present in the HIV-1-infected brain such as Tat, inhibits antiviral IFN-β signaling to enhance HIV-1 replication in macrophages. This consequence of SOCS3 expression in vitro, supported by a correlation with increased viral load and onset of CNS disease in vivo, suggests that SOCS3 may allow HIV-1 to evade the protective innate immune response within the CNS, allowing the recurrence of viral replication, and ultimately promoting progression toward HAD.

Intrinsic antiviral host factors confer cellular defense by limiting virus replication and are often counteracted by viral countermeasures. We reasoned that host factors that inhibit viral gene expression could be identified by determining proteins bound to viral DNA (vDNA) in the absence of key viral antagonists. Herpes simplex virus 1 (HSV-1) expresses ICP0, which functions as an E3 ubiquitin ligase required to promote infection. Cellular substrates of ICP0 have been discovered as host barriers to infection, but mechanisms for inhibition of viral gene expression are not fully understood. To identify restriction factors antagonized by ICP0, we compared proteomes associated with vDNA during HSV-1 infection with wild-type (WT) virus and mutant lacking functional ICP0 (ΔICP0). We identified the cellular protein Schlafen 5 (SLFN5) as an ICP0 target that binds vDNA during HSV-1 ΔICP0 infection. We demonstrated that ICP0 mediates ubiquitination of SLFN5 which leads to its proteasomal degradation. In the absence of ICP0, SLFN5 binds vDNA to repress HSV-1 transcription by limiting accessibility of RNA polymerase II to viral promoters. These results highlight how comparative proteomics of proteins associated with viral genomes can identify host restriction factors, and reveal that viral countermeasure can overcome SLFN antiviral activity.