PREFACE Many viruses infect humans and most are controlled satisfactorily by the immune system with limited damage to host tissues. Some viruses, however, do cause overt damage to the host, either in isolated cases or as a reaction that commonly occurs after infection. The outcome is influenced by properties of the infecting virus, the circumstances of infection and multiple factors controlled by the host. In this Review, we focus on host factors that influence the outcome of viral infection, including genetic susceptibility, the age of the host when infected, the dose and route of infection, the induction of anti-inflammatory cells and proteins as well as the presence of concurrent infections and past exposure to cross-reactive agents.

Summary The host response to viruses includes multiple cell types that have regulatory function. Most information focuses on CD4+ regulatory T cells that express the transcription factor Foxp3+ (Tregs), which are the topic of this review. We explain how viruses through specific and non-specific means can trigger the response of thymus-derived natural Tregs as well as induce Tregs. The latter derive under appropriate stimulation conditions either from uncommitted precursors or from differentiated cells that convert to become Tregs. We describe instances where Tregs appear to limit the efficacy of antiviral protective immunity and other perhaps more common immune-mediated inflammatory conditions, where the Tregs function to limit the extent of tissue damage that occurs during a virus infection. We discuss the controversial roles that Tregs may play in the pathogenesis of human immunodeficiency and hepatitis C virus infections. The issue of plasticity is discussed, since this may result in Tregs losing their protective function when present in inflammatory environments. Finally, we mention approaches used to manipulate Treg numbers and function and assess their current value and likely future success to manage the outcome of virus infection, especially those that are responsible for chronic tissue damage.

Herpes Simplex Virus-1 (HSV) infection of the cornea leads to a blinding immuno-inflammatory lesion of the eye termed stromal keratitis (SK). Recently, IL-17 producing CD4+ T cells (Th17) were shown to play a prominent role in many autoimmune conditions, but the role of IL-17 and/or of Th17 cells in virus immunopathology is unclear. Here we show that, after HSV infection of the cornea, IL-17 is upregulated in a biphasic manner with an initial peak production around day 2 pi and a second wave starting from day 7 pi with a steady increase until day 21 pi, a time point when clinical lesions are fully evident. Further studies demonstrated that innate cells particularly, γδ T cells, were major producers of IL-17 early after HSV infection. However, during the clinical phase of SK, the predominant source of IL-17 was Th17 cells which infiltrated the cornea only after the entry of Th1 cells. By ex-vivo stimulation, the half fraction of IFN-γ producing CD4+ T (Th1) cells were HSV specific, whereas very few Th17 cells responded to HSV stimulation. The delayed influx of Th17 cells in the cornea was attributed to the local chemokine and cytokine milieu. Finally, HSV infection of IL-17 receptor knockout mice, as well as IL-17 neutralization in WT mice showed diminished SK severity. In conclusion, our results show that IL-17 and Th17 cells contribute to the pathogenesis of SK, the most common cause of infectious blindness in the western world.

In this communication, we demonstrate that galectin (Gal)-9 acts to constrain CD8+ T cell immunity to Herpes Simplex Virus (HSV) infection. In support of this, we show that animals unable to produce Gal-9, because of gene knockout, develop acute and memory responses to HSV that are of greater magnitude and better quality than those that occur in normal infected animals. Interestingly, infusion of normal infected mice with α-lactose, the sugar that binds to the carbohydrate-binding domain of Gal-9 limiting its engagement of T cell immunoglobulin and mucin (TIM-3) receptors, also caused a more elevated and higher quality CD8+ T cell response to HSV particularly in the acute phase. Such sugar treated infected mice also had expanded populations of effector as well as memory CD8+ T cells. The increased effector T cell responses led to significantly more efficient virus control. The mechanisms responsible for the outcome of the Gal-9/TIM-3 interaction in normal infected mice involved direct inhibitory effects on TIM-3+ CD8+ T effector cells as well as the promotion of Foxp3+ regulatory T cell activity. Our results indicate that manipulating galectin signals, as can be achieved using appropriate sugars, may represent a convenient and inexpensive approach to enhance acute and memory responses to a virus infection.

Controlling chronic immunoinflammatory diseases such as lesions in eye caused by infection with herpes simplex virus (HSV) represents therapeutic challenge. Since CD4+ T cells are the primary orchestrators of lesions, targeting activated CD4+ T cell subsets and increasing the representation of cells that express regulatory function would be a logical therapeutic approach. We show that this outcome can be achieved by therapy, systemic or local, with the lectin-family member galectin-9. This molecule, which is a natural product of many cell types, acts as a ligand to the inhibitory molecule TIM-3 that is expressed by activated but not naïve T cells. We show that 50% or more of T cells in ocular lesions caused by HSV in mice express TIM-3 and that blocking signals from its natural ligand with a monoclonal antibody results in more severe lesions. More importantly the provision of additional galectin-9, either systemically or more effectively by local subconjuctival administration, diminished the severity of SK lesions as well as the extent of corneal neovascularization. Multiple mechanisms were involved in inhibitory effects. These included apoptosis of the orchestrating effector T cells with consequent reduction of proinflammatory cytokines, an increase in the representation of two separate subtypes of regulatory cells as well as inhibitory effects on the production of molecules involved in neovascularization, an essential component of SK pathogenesis. Our results indicate that galectin-9 therapy may represent a useful approach to control HSV induced lesions, the commonest cause of infectious blindness in the Western World.

The normal cornea is transparent which is essential for normal vision and although the angiogenic factor VEGF-A is present in the cornea, its angiogenic activity is impeded by being bound to a soluble form of the VEGF receptor-1 (sVR-1). This report investigates the effect on the balance between VEGF-A and sVR-1 that occurs following ocular infection with HSV, that causes prominent neovascularization, an essential step in the pathogenesis of the vision-impairing lesion, stromal keratitis (SK). We demonstrate that HSV-1 infection causes increased production of VEGF-A, but reduces sVR-1 levels resulting in an imbalance of VEGF-A and sVR-1 levels in ocular tissues. Moreover, the sVR-1 protein made was degraded by the metalloproteinase (MMP) enzymes MMP-2, MMP-7 and MMP-9 produced by infiltrating inflammatory cells that were principally neutrophils. Inhibition of neutrophils, or inhibition of sVR-1 breakdown with the MMP inhibitor (MMPi) marimostat, or the provision of exogenous recombinant sVR-1 protein all resulted in reduced angiogenesis. Our results make the novel observation that ocular neovascularization resulting from HSV infection involves a change in the balance between VEGF-A and its soluble inhibitory receptor. Future therapies aimed to increase the production and activity of sVR-1 protein could benefit the management of SK, an important cause of human blindness.

FTY720 has been used to control inflammatory lesions, but the mechanisms by which the drug acts in vivo are poorly understood. Such mechanisms may result primarily from effects on lymphocyte and dendritic cell homing to lymphoid and inflammatory sites. We demonstrate that FTY720 may also act by causing the conversion of TCR-stimulated nonregulatory CD4+ T cells to Foxp3+CD4+ regulatory T cells and by enhancing their suppressive activity. In a model in which mice were ocularly infected with HSV, daily treatment with FTY720 resulted in significantly diminished ocular lesions. The treated animals showed increased frequencies of Foxp3+ T cells in lymphoid organs and at two inflammatory sites, namely cornea and trigeminal ganglia. In a second series of experiments, immunized DO11.10RAG2−/− animals, normally lacking endogenous Foxp3+ T cells, that were given FTY720 treatment developed high frequencies of Foxp3+ regulatory T cells in lymph nodes. Some converted cells persisted in treated animals for several weeks after drug administration was discontinued. Finally, FTY720 could effectively induce Foxp3-expressing cells from Foxp3− cells in vitro, an effect inhibited by anti-TGF-β or the proinflammatory cytokine IL-6. Accordingly, the anti-inflammatory effects of FTY720 could be mediated at least in part by its ability to cause the conversion of Ag-stimulated conventional T cells to become Foxp3+ regulators. The use of FTY720 along with Ag administration could represent a useful therapeutic means to selectively expand Ag-specific regulators, which could be valuable in many clinical situations such as allotransplants, some autoimmunities, as well as with some chronic infections.

Most vertebrates are infected with one or more herpesviruses and remain so for the rest of their lives. The relationship of immunocompetent healthy host with herpesviruses may sometime be considered as harmonious. However, clinically severe diseases can occur when host immunity is compromised due to aging, during some stress response, co-infections or during neoplastic disease conditions. Discord can also occur during iatrogenic immunosuppression used for controlling graft rejection, in some primary genetic immunodeficiencies as well as when the virus infects a non-native host. In this review, we discuss such issues and their influence on host-herpesvirus interaction.