• Persistent viral infection;
  • T-cell dysfunction;
  • T-cell immunity


  1. Top of page
  2. Abstract
  3. Introduction
  4. Concluding remarks
  5. Acknowledgements
  6. References

Persistent viral infections are, by definition, associated with ineffective antiviral immunity, in particular those infections caused by viruses that are highly productive and replicative (including HIV, HBV and HCV). The reasons for ineffective antiviral immunity in these types of infections are complex and manifold, and only recently a more comprehensive picture of the parameters responsible for attenuation of immune function is emerging. One reason for poor viral control in these types of infections is the functional deterioration of antiviral T-cell responses and understanding the underlying mechanisms is of key importance. This review summarizes our current knowledge of cell-intrinsic and cell-extrinsic parameters that contribute to T-cell exhaustion during chronic viral infections and discusses related implications for host survival, immunopathology, and control of infection.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Concluding remarks
  5. Acknowledgements
  6. References

Persistent viral infections, by definition, are not entirely controlled by the host's immune system and are often associated with relevant clinical disease outcomes. Persistent viral infections can be roughly divided into (i) highly productive and replicative infections (associated with continued high abundance of viral antigens) and (ii) latent/reactivating infections (associated with low and perhaps sporadic levels of viral antigens). Well-known examples of the former are HIV, HBV and HCV, which together infect more than 2 billion people worldwide (;;, and lymphocytic choriomeningitis virus (LCMV) infection in the mouse. Examples of the latter are herpes virus infections, including EBV, CMV, and HSV, which affect together almost 100% of the population. Viruses falling into these two categories have evolved very diverse strategies for co-existence in an immunocompetent host. Highly productive and replicative viruses tend to induce impaired virus-specific adaptive immune responses, which are characterized by limited and dysfunctional T-cell responses, and mutational escape from immune (or drug) pressure are common features of these viruses. Viruses causing latent/reactivating infections have, as a result of their large coding capacity, evolved strategies to interfere with host immunity (immune evasion mechanisms) and have acquired genetic programs that permit a latent, non-replicative existence of the viral genetic information with the option of resuming viral replication in response to certain stimuli. These viral reactivation events, however, are generally well controlled by host immunity and only become clinically apparent in circumstances of immunosuppression.

This review focuses on highly productive and replicative persistent viral infections (hereafter referred to as persistent viral infection) with specific emphasis on cell-intrinsic and -extrinsic mechanisms responsible for constraining the size of the antiviral T-cell response and for T-cell dysfunction (summarized in Fig. 1). This review also evaluates and discusses novel intervention strategies as a result of this knowledge.

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Figure 1. Summary of factors positively or negatively influencing T-cell function and maintenance during chronic viral infections. Parameters that positively affect function or maintenance of virus-specific T-cell responses are shown on the left side of the figure (shaded in blue) whereas those impacting on T-cell dysfunction or deletion of virus-specific T-cell responses are shown on the right side of the figure (shaded in red).

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Characterization of T-cell exhaustion

In the face of persistent viral infections, T cells are continuously confronted with moderate to high levels of viral antigens expressed on a variety of cells, depending on the tropism of the respective virus. Such continued triggering of T cells, in combination with other parameters as discussed in the Insights into deregulation of effector functions section, eventually leads to constrained size of the antiviral T-cell response and results in continuous deterioration with respect to the T cells' functional capacities. This process, collectively termed “T-cell exhaustion”, was first and best described for murine chronic LCMV infection 1, but seems to also apply to other persistent infections such as HCV 2 and HIV 3–7 infection in humans; simian immunodeficiency virus (SIV) in rhesus macaques 8; and polyomavirus 9, adenovirus 10, Friend retrovirus 11, and mouse hepatitis virus 12 infection in mice. Loss of functional properties of antiviral T cells comprises a continuum of severity ranging from mild deficiencies such as the failure to produce certain cytokines − often observed in a hierarchical manner (IL-2>TNF-α>IFN-γ) 13–15 − to more severe symptoms including complete deficiency in cytokine production, proliferative potential, and antigen-independent survival 16, up to the most severe form of exhaustion, i.e. physical deletion of specific antiviral T-cell populations 1, 17.

A molecular definition of T-cell exhaustion on a cell-intrinsic level (summarized in Table 1) is starting to emerge and involves (i) altered regulation of TCR and cytokine signaling pathways 18, 19; (ii) specific gene expression patterns (including the expression of multiple inhibitory receptors and specific transcription factors 19–21); (iii) exhibition of metabolic and bioenergetic insufficiencies 19; and (iv) skewed T-cell maturation/differentiation in the context of HIV-1 infection 22–24. On a cell-extrinsic level (also summarized in Table 1), various regulatory mechanisms are recognized to shape T-cell exhaustion, including (i) the expression of inhibitory receptors; (ii) susceptibility to regulatory cytokines such as IL-10 25, 26 and TGF-β 27; (iii) dependence on non-homeostatic growth factors such as IL-2 and IL-21 28–31; (iv) suppression by Treg 32, 33; and (v) the level of antigen exposure 34–36.

Table 1. Factors involved in T-cell exhaustion
Cell-intrinsic factors  
Receptors and ligandsIL-2R, IL-7R, IL-15R, IL-21R, Fas/FasL, TNFR1/2, CD40/CD40L28, 38–40, 29–31
Intracellular regulationCbl-b, Bim, Blimp-1, Spi-6, NFAT-218, 21, 41–43
Co-stimulatory/co-inhibitory receptorsPD-1, CD27/CD70, DAF-1, TGF-βR, LAG-3, Tim-3, CTLA-420, 27, 44–48
Effector moleculesIFN-α/β, IFN-γ, Perforin38, 49–52
Cell-extrinsic factors  
ImmunosuppressorsIL-10, TGF-β25–27
Other extrinsic factorsTreg, level of antigen load, presence/absence of T help17, 28, 32–35, 37, 44

The continued exposure to viral antigen and thus the level of antigen load is a crucial primary factor in driving T-cell exhaustion 34–37 and experimental or interventional reduction of antigen load allows at least partial recovery of T-cell functions. This opens the relevant question of causality: is T-cell exhaustion a consequence of continued exposure to high levels of antigen or is T-cell exhaustion the cause for the uncontrolled viral replication and hence high antigen loads? Presumably there is no definitive answer to this question, as these two parameters are intricately linked with each other and manipulation of one will inevitably affect the other. This question is particularly relevant in the context of developing new interventional strategies aimed at restoring T-cell function in the context of chronic viral infections.

Insights into deregulation of effector functions

Cytokine production and degranulation

The effector functions by which CD8+ T cells interfere with intracellular viral replication include the secretion of soluble mediators such as TNF-α and IFN-γ and contact dependent cytolytic activity (via perforin/granzyme exocytosis or via Fas-FasL interactions). Contact-dependent cytotoxicity plays a crucial role in the containment of non- or poorly cytopathic viral infections such as LCMV or HIV 53. While the cytokine production capacity of virus-specific CD8+ T cells may be severely impaired in the setting of a chronic infection 13–15, 17, 35, 37, degranulation and immediate in vitro and in vivo cytotoxicity seem to be less affected during chronic infection 18, 21, implying that TCR signaling pathways are differentially affected in CD8+ T cells of chronically infected hosts. Indeed, in the context of chronic LCMV infection, CD8+ T cells retain their ability to flux Ca2+ upon TCR engagement (which is required for degranulation and cytokine production) and to shuttle NF-κB (p50 and p65, which are downstream of the PKC pathway; PKC-α, β and PKC-δ, θ being required for degranulation and cytokine production (our unpublished data)) into the nucleus. In contrast, despite intact Ca2+ flux, there was a complete block of nuclear import of NFAT-2 upon TCR triggering (which is required for transcription of many cytokine genes but not for degranulation), suggesting a defect in either NFAT-2 dephosphorylation by the phosphatase calcineurin and/or nuclear import of dephosphorylated NFAT-2 18. Furthermore, the silencing of cytokine production capacity in CD8+ T cells from chronically LCMV-infected mice is not attributable to defects in proximal TCR signaling, as it is also apparent upon T-cell stimulation with PMA/ionomycin, which directly lead to Ca2+ flux and PKC activation (our unpublished data).

Inhibitory receptors

Recently, much attention has been devoted to the relevance of inhibitory receptor expression on T cells during chronic infections, including PD-1, LAG-3, Tim-3, CTLA-4, 2B4, and CD160 19, 20. Although many of these markers are also expressed on activated effector T cells early on during acute infections, sustained expression of PD-1 on virus-specific CD8+ T cells is associated with chronic viral infections and was initially described in chronic LCMV infection 19, 44 and shortly afterwards confirmed in human HIV 54–56 and HCV infection 57, 58, as well as in monkey SIV infection 59, 60. Importantly, interference with PD-1 signaling in vivo (LCMV, SIV) 44, 61 and in vitro (LCMV, HIV, HCV) 44, 54–57, 62 led to (partial) restoration of T-cell function − in particular to an alleviation of the proliferative blockade of T cells. These results suggest that there is a component of reversibility of T-cell dysfunction by interfering with inhibitory receptor signals 44, 63; however, this functional salvage seems to be restricted to a less terminally differentiated subset of virus-specific CD8+ T cells (characterized by lower PD-1 expression levels) 63.

In addition to PD-1, a variety of other inhibitory receptors (including LAG-3, CTLA-4, CD160, CD244, GP49, Tim-3) were found to be expressed on T cells, which are continuously exposed to their cognate antigen during persistent infections 20, 47; co-expression of multiple inhibitory receptors correlated with increased functional deficits and decreased control of viral loads. Simultaneous blocking of more than one inhibitory receptor permitted enhanced functional restoration compared with blocking of single inhibitory receptors 20, 48, 64. The next obvious question was how the expression of inhibitory receptors is regulated in CD8+ T cells during chronic LCMV infection and a very recent report showed that transcriptional regulation of inhibitory receptor expression was to a certain extent dependent on the transcription factor Blimp-1 21. In contrast, Blimp-1 did not seem to greatly influence the cytokine production capacity of T cells, indicating that other regulatory mechanisms might be responsible for silencing cytokine production. Furthermore, a certain level of Blimp-1 expression was required for the effective differentiation of the cytolytic capacity of CD8+ T cells in the context of chronic LCMV infection 21, demonstrating that complete abrogation of Blimp-1 expression would, overall, not be beneficial for enhancing control of persistent viral infections − at least not of those viruses, the control of which depends on direct cytolytic activity of CD8+ T cells.

Regulation of cell numbers/proliferation/apoptosis

Besides downregulation of effector functions such as cytokine production, another critical layer of T-cell immune regulation during chronic viral infection comprises the number and frequency of virus-specific T cells. Several parameters have been shown to critically shape the expansion/contraction pattern of virus-specific CD8+ T cells during chronic infections. These may be divided into external parameters including growth factors and inflammatory cytokines and into internal parameters comprising regulators of TCR signaling and apoptosis. In the former category two growth factors seem to be critically involved in sustaining antiviral T-cell populations in the context of chronic viral infections − a process that is antigen-dependent and involves significant cell cycling 65. These two growth factors are IL-2 and IL-21, which were shown to promote CD8+ T-cell cycling during chronic LCMV infection 28–31. Importantly, both cytokines act directly on LCMV-specific CD8+ T cells as shown in mixed bone marrow chimeric mice exhibiting WT and receptor-deficient CD8+ T-cell populations. It is very likely that the essential IL-2 and IL-21 are provided by CD4+ T cells (IL-2 during earlier phases of the chronic infection and IL-21 during later phases), which would account for the often reported but still ill-defined role of T-helper cells in sustaining CD8+ T-cell responses during chronic viral infections 66, 67. Another way of CD4+ T cells contributing to sustained CD8+ T-cell responses in case of persistent infection is via the continued induction and maintenance of (neutralizing) antibody responses 68, 69. Enhanced induction of neutralizing antibody responses via blocking CD27 signaling led to reduced CD4+ T-cell-mediated destruction of secondary lymphoid architecture, which allowed the control of otherwise chronic LCMV infection with concomitant improvement of CD8+ T-cell functionality 46.

Other external parameters shaping the number and function of virus-specific CD8+ T cells are IFN – as shown in chronic LCMV infection. Specifically, lack of type I and/or type II IFN may lead to fatal immunopathology in case of viruses that are not replicating/disseminating fast enough to induce early downregulation of T-cell numbers and function of CD8+ T cells 51, 52. This regulation, however, seems to be primarily indirect, as type I and type II IFN critically affect the dynamics of viral load at early phases of the infection, which is decisive in determining the balance between viral replication and immune control 70.

Further regulation of T-cell numbers and function during persistent viral infections is ascribed to Treg. In the murine Friend retrovirus (FV) infection model, Treg regulate CD8+ T-cell numbers and function in an organ-specific manner and experimental abrogation of Treg led to increased peak expansion of fully functional FV-specific CD8+ T cells, which were able to significantly reduce FV loads in lymphatic organs 32, 33. Treg are also associated with ineffective immune responses in chronic HIV, HCV, and HBV infection, albeit the causal relationship and the mechanisms of how Treg impact on numbers and function of antiviral T-cell responses remain poorly defined in these human infections (reviewed in 71, 72).

T-cell-internal parameters that are involved in regulating the number of antiviral T cells during chronic viral infections include the pro-apoptotic molecule Bim, the serine protease inhibitor Spi-6, the TCR signaling inhibitor Cbl-b, and the cytotoxic effector molecule perforin. In the absence of the pro-apoptotic molecule Bim, downregulation of certain LCMV-specific CD8+ T-cell populations was attenuated, leading to slightly improved control of chronic infection 41. The serine protease inhibitor Spi-6 is involved in cytoplasmic inhibition of granzyme B, thereby representing a safe-guard for effector CD8+ T cells protecting them from self-inflicted death. In the absence of Spi-6, LCMV-specific effector CD8+ T cells exhibit increased apoptosis leading to impaired control of infection 43. The TCR signaling inhibitor Cbl-b is involved in downregulating CD8+ T-cell responses as demonstrated by delayed contraction and functional impairment of LCMV-specific CD8+ T-cells in Cbl-b-deficient mice, which was associated with increased immunopathology 42. Finally, the CD8+ T-cell effector molecules perforin, Fas, and TNF are also involved in downregulating virus-specific CD8+ T-cell numbers during advanced stages of chronic LCMV infection as demonstrated by increased numbers of certain LCMV-specific CD8+ T-cell populations due to decreased apoptotic death in perforin-, FasL-, or TNFR1-deficient mice 38.

Negative regulatory cytokine networks

Regulation of CD8+ T-cell function or numbers during chronic infections can also be a result of immunosuppressive cytokines including IL-10 and TGF-β. In the context of chronic infection with LCMV clone 13, lack of IL-10 or IL-10 signaling was associated with ameliorated CD8+ T-cell responses and drastically enhanced control of the infection 25, 26; however, the mechanisms of how IL-10 leads to enhanced control of infection and/or to enhanced LCMV-specific CD8+ T-cell responses are still ill-defined. Increased levels of IL-10 were also shown in human HIV infection 73, and IL-10 was found to influence CD4+ T-cell function in HIV patients 74. Furthermore, polymorphisms in the IL-10 promoter are associated with diverse disease progression rates in chronic HBV infection 75, HCV infection 76, and HIV infection 77. TGF-β, another immuno-modulatory cytokine, was recently found to influence CD8+ T-cell responses in the setting of chronic LCMV infection: LCMV-specific CD8+ T cells exhibited sustained expression of TGF-β and phosphorylation of its downstream signaling mediator Smad-2 27. Selective reduction of TGF-β signaling in CD8+ T cells led to increased numbers and enhanced function of virus-specific CD8+ T cells in chronic LCMV infection 27.

Antigen load

Exhaustion of virus-specific CD8+ T cells (i.e. constrained size of the antiviral T-cell pool combined with (partial) dysfunction) is mostly documented for infections with high level replicating viruses such as LCMV in the mouse or HIV, HCV, and HBV in humans. These types of infections often lead to high levels of virus-derived peptide antigens presented by MHC class I molecules on a variety of infected cell types, depending on the tropism of the virus. Exhaustion of antiviral CD8+ T cells occurs rapidly and extensively in chronic LCMV infection, which is likely attributable to the fact that LCMV infects in vivo a large variety of hematopoietic as well as non-hematopoietic cells and therefore leads to high antigen burden perceived by LCMV-specific CD8+ T cells 70, 78. Exhaustion of HIV-specific CD8+ T cells is much less pronounced and is a much slower process compared with murine LCMV infection and this is probably to be explained by the much smaller pool of actively infected cells presenting HIV-derived peptides. It is still debated, however, whether high levels of antigen presentation are the cause of T-cell exhaustion or whether T-cell exhaustion is the cause for the high antigen levels. Several reports support the notion that the level of antigen exposure is indeed directly affecting the function of CD8+ T cells: (i) reduction of antigen load (either naturally in later stages of LCMV infection, or via Nef-mediated downregulation of HLA-A and B molecules or drug-induced in human HIV infection or due to the selection of T-cell epitope escape variants) leads to a slow reversal of CD8+ T-cell dysfunction 4, 35, 37, 79, 80; (ii) impairment of cytokine production by virus-specific CD8+ T cells is delayed in chronically LCMV-infected mice, which can only present viral antigens on hematopoietic cells 34; iii) repeated infection of mice with influenza A virus and therefore repeated stimulation with antigen leads to a slight impairment of T-cell function 36; and (iv) viral infections with much lower antigen loads such as reactivating herpes virus infections are generally associated with functional T-cell responses and mildly dysfunctional cells might only be apparent during very late stages of infection 66, 81, 82.

Virus-specific CD4+ T-cell responses in chronic viral infections

Although much more data are available for CD8+ T-cell regulation during chronic viral infections, virus-specific CD4+ T cells seem to be also severely affected in their function and/or maintenance. Furthermore, the molecular mechanisms affecting CD4+ T-cell regulation during chronic viral infections have so far been poorly studied. Nevertheless, there are many overlaps between CD4+ and CD8+ T cells (summarized in Table 2): both CD4+ and CD8+ T-cell responses are compromised in their functional capacities such as cytokine secretion and proliferative potential and both express various inhibitory receptors and show (partial) restoration of their function (e.g. proliferation and cytokine secretion) after blockade of particular receptors in combination with an antigenic stimulus. As the physical quantification of virus-specific CD4+ T-cell responses is rather difficult due to lower numbers compared with CD8+ T-cell responses and a relatively limited availability of peptide/MHC multimers, it is not clear whether substantial downregulation of CD4+ T-cell responses during chronic viral infections is due to impaired function (which is normally the read-out) or due to downregulation of virus-specific CD4+ T-cell numbers. The limited number of studies physically measuring virus-specific CD4+ T-cell numbers (using adoptive transfer of TCR transgenic CD4+ T cells or using peptide/MHC multimers) suggests that cytokine production is compromised followed by reduction/deletion of virus-specific CD4+ T-cell numbers 83–88.

Table 2. Comparison of CD4+ and CD8+ T-cell dysfunction in chronic viral infections
Chronic infectionCD8+ T cellsCD4+ T cellsReferences
LCMV•Functionally impaired (loss of cytokine production and proliferative capacity)•Loss of effector function (IL-2, TNF-α and IFN-γ production)1, 13–15, 17, 18, 83, 84, 89
 •Deletion of specific CD8+ T-cell populations•Physical reduction/deletion17, 83, 84
 •Expression of multiple inhibitory receptors 19, 20, 44
 •(Partial) functional restoration by blocking inhibitory receptors (e.g. PD-1, LAG-3) 20, 44
  •Maintenance of IL-21 production29–31
HCV•Functional impairment (cytokine production, proliferative capacity)•Functional impairment (cytokine production, proliferative capacity)2, 58, 90–92
 •Expression of inhibitory receptors (Tim-3, PD-1)•Expression of inhibitory receptors (Tim-3, PD-1)57, 93, 94
 •(Partial) functional restoration by blocking inhibitory receptors (e.g. Tim-3, PD-1 and CTLA-4)•(Partial) functional restoration by blocking inhibitory receptors (e.g. Tim-3, PD-1)58, 64, 93, 95
  •Physical deletion86, 88
HIV/SIV•Functional impairment (cytokine production, proliferative capacity)•Functional impairment (cytokine production, proliferative capacity)6–8, 37, 54, 96–99
 •Physical deletion•Physical deletion5, 87
 •Expression of inhibitory receptors (PD-1, Tim-3)•Expression of inhibitory receptors (PD-1, CTLA-4)47, 100, 101
 •(Partial) functional restoration by blocking inhibitory receptors (e.g. PD-1, Tim-3)•(Partial) functional restoration by blocking inhibitory receptors (e.g. CTLA-4, PD-1)47, 54–56, 59, 61

Based on the novel concept that various mechanisms are involved in simultaneously downregulating CD8+ T-cell responses during chronic viral infections, new possibilities for immuno-modulatory interventions have emerged and are currently actively pursued. These involve the blockade of inhibitory receptors constitutively expressed on virus-specific T cells during chronic infections or the attenuation of immunosuppressive cytokines such as IL-10, TGF-β, or of immunosuppressive networks such as that imposed by Treg. To date, these new modes of interventions are still at an experimental level and are tested in mouse and monkey infection models with the hope of eventually using these strategies in the human setting.

Several reports have documented the in vitro reversal of CD8+ T-cell function isolated from chronically LCMV-infected mice, from SIV-infected macaques, or from HIV- or HCV-infected humans by blocking a single or multiple inhibitory receptor/s 44, 47, 54–56, 64, 102. Such functional restoration was dependent on prolonged in vitro culture in the presence of the respective blocking antibodies and was preceded by proliferation of the CD8+ T cells. Induction of proliferation in the presence of blocking antibodies against PD-1 has been shown to result in reduced apoptosis 56 and an increase in both telomere length and telomerase activity 103, both likely contributing to the increased proliferative potential and the associated recovery of effector functions.

In mice, in vivo blockade of PD-1 signaling as well as neutralization of IL-10 or blocking of IL-10R enhance CD8+ T-cell function during persistent LCMV infection and as a result, increase virus control 25, 26, 44. More recently it was shown that blocking of multiple inhibitory receptors (PD-1, LAG-3, CTLA-4) 20 or the combined blocking of inhibitory receptors and immunosuppressive cytokines 59, 104 is superior to blocking a single inhibitory receptor. In SIV-infected monkeys, in vivo blocking of PD-1 enhanced both cellular and humoral immune responses 61. The underlying mechanisms, however, of how these interventions restore the function of CD8+ T cells, which cell types are involved in the recovery of CD8+ T-cell function, potential side effects of treatment (such as immunopathology) and the general applicability of these interventions remain to be thoroughly studied. As many of these novel interventions do not specifically target the population of virus-specific CD8+ T cells, precaution has to be taken, as many of the targeted regulatory pathways are important for maintenance of peripheral tolerance or are critical for the balance between pathogen-specific immunity and immune-mediated tissue damage 105. As it is likely that such interventions may require prolonged application in order to effectively enhance virus-specific CD8+ T-cell immunity, prolonged suppression of Treg or IL-10 signaling for instance might eventually lead to autoimmune phenotypes or dysregulated T-cell homeostasis in the gastrointestinal tract 106–108. To date, none of the studies involving inhibitory receptor blockade, IL-10/IL-10R blockade, or a combination thereof, have reported any overt immunopathology 25, 26, 44, 104. It has to be noted, however, that the increase in T-cell function and the concomitant decrease in viral load as a result of immune-intervention during established infection was transient. Sustainment of enhanced T-cell function would likely require prolonged treatment, which will demand careful analysis of potential immune homeostasis perturbation and protocols set in place for the control of unrelated infections. Furthermore, it is conceivable that downmodulation of immunity and, in particular, of T-cell responses during chronic persistent viral infections may in fact have evolved for the benefit of the host, in order to avoid uncontrolled and overwhelming immunopathology 49, 51, 83, 109. In support of this notion, it was shown that chronic LCMV infection in PD-L1-deficient mice led to fatal immunopathology 44, and mouse hepatitis virus infection in the absence of IL-10 triggered demyelinating encephalomyelitis 110. Thus, while immune-interventions are likely to lead to enhanced virus-specific T-cell function and increased viral control, this beneficial effect has to be balanced against potentially harmful immunopathology, which is a likely side effect of regained immune effector functions.

Concluding remarks

  1. Top of page
  2. Abstract
  3. Introduction
  4. Concluding remarks
  5. Acknowledgements
  6. References

Chronic high level viral infections are often associated with a limited population size and impaired function of virus-specific T cells, which may be critically responsible for the impaired viral control. We are starting to unravel the cellular and molecular pathways involved in these processes, opening new exciting possibilities for immune-based interventions with the aim of restoring functional antiviral T-cell responses combined with improved virus control, and first promising results have been demonstrated in animal models of chronic viral infections. However, as most of these novel interventions are targeting general immuno-modulatory pathways, caution has to be taken as there is a risk of disturbing immune homeostasis leading either to immunopathology (due to restored function of antiviral T-cell immunity), autoimmunity (due to suppression of regulatory networks involved in peripheral tolerance), or poor immune responsiveness in the context of novel infections.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Concluding remarks
  5. Acknowledgements
  6. References

This work was supported by the ETH Zurich, the Swiss National Science Foundation (Grant No. 310030-113947) and the Horten Foundation.

Conflict of interest: The authors declare no financial or commercial conflict of interest.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Concluding remarks
  5. Acknowledgements
  6. References
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