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Nat Rev Immunol. Author manuscript; available in PMC 2014 January 23.

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Published in final edited form as:
Nat Rev Immunol. 2010 July ; 10(7): 514–526. doi:10.1038/nri2802.

IMMUNITY AND IMMUNOPATHOLOGY TO VIRUSES: what
decides the outcome?
Barry T. Rouse1 and Sharvan Sehrawat2
1Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville,
Tennessee 37996-0845, USA
2Whitehead

Institute of Biomedical Research, 9 Cambridge center, Cambridge, Massachusetts

02142, USA

PREFACE
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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.

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Humans may be infected by and suffer clinical consequences from numerous different
viruses, and in most instances the infection is resolved with or without tissue damage. Reinfection is usually subclinical and for many viruses we have effective vaccines. Classic
examples include measles, mumps, rubella, rotavirus and chickenpox viruses. Other viruses,
such as HIV, hepatitis C virus (HCV), hepatitis B virus (HBV) and some herpesviruses, can
cause significant tissue damage in some or all individuals they infect and lesions may
become chronic. These viruses usually have one or more properties that allow them to
diminish the efficacy of adaptive or innate immunity and we lack effective vaccines against
most of these agents. Viruses such as influenza virus and respiratory syncytial virus (RSV)
have a variable outcome. Most individuals may suffer mild or subclinical infection but
others experience severe disease that can be lethal. Of particular interest are agents such as
West Nile virus, dengue virus and formerly poliovirus that can cause severe disease, but
only in a small minority of infected persons. Finally some viruses, such as Coxsackie B
virus, human T lymphotropic virus, Epstein-Barr virus (EBV) and possibly rubella virus, are
considered to act as triggering agents for autoimmune diseases and cancer in genetically
susceptible individuals. This latter topic has been reviewed by others and will not be
discussed here1, 2.
In this Review, we discuss our current understanding of the circumstances of infection and
host controlled factors that could explain why an infection can be resolved with minimal
impact or cause significant tissue damage. Understanding such issues could prove useful in
the future for the control and perhaps prevention of tissue-damaging virus infection.

Correspondence to B.T.R. btr@utk.edu.

Rouse and Sehrawat

Page 2

TISSUE DAMAGE CAUSED BY THE IMMUNE SYSTEM (see Fig 1)
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Almost all virus infections cause the recruitment and activation of inflammatory cells types,
particularly macrophages, and in some infections neutrophils, that in turn release a range of
molecules that induce tissue damage or malfunction. These include cytotoxic cytokines,
cationic proteins, lipid mediators, metalloproteinases and components of the oxygen burst.
The reactive oxygen species that accumulate in the mitochondria may further contributes to
tissue damage3. Both innate and adaptive immune signaling events are involved in
mediating tissue damage.
Contribution by innate immune response

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Invading viruses and their replicative intermediates can be recognized by several innate
immune receptors expressed either at the surface or within cells. Many types of innate
immune receptor can participate in the immune response, but in virus infections, the most
studied are the Toll-like receptors (TLRs), retinoic acid inducible gene-I (RIG-I) and NODlike receptors (NLRs). Virus infections usually activate the endosomal TLRs; TLR3, TLR7,
TLR8 and TLR9, that recognize viral nucleic acids and double-stranded RNA
intermediates4. The cytoplasmic RIG-I-like receptors recognize viral genomic RNA or RNA
encoded by genomic DNA, whereas the NLRs recognize the virus DNA genome (reviewed
in5). In general, activation of many of these receptors causes the production of proinflammatory cytokines and interferons (IFNs), as well as signals that recruit and activate
cells involved in inflammation and the induction of adaptive immunity. The pattern of innate
immune events induced after the entry of virus may dictate the outcome of infection. Many
viruses that persist signal innate cells such as dendritic cells NK cells and macrophages to
produce anti-inflammatory molecules such as IL-10 and TGFβ. For example, dendritic cells
from LCMV infected mice produce abundant IL-106 and IL-10 is produced by monocytes
from HIV, HCV and HBV infected individuals7–9. Upon RSV infection the interaction made
with lung plasmacytoid dendritic cells (pDC) is critical since pDC removal before infection
favors an immunopathological reaction in the lungs10. A damaging response to a virus
infection is more likely to occur with viruses that can interfere with one or more innate
defences. Some examples and the innate defence mechanism that is blunted are listed in
table 1.
Contribution by adaptive immune response

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Once adaptive immune effectors are produced, these can contribute to tissue damage. T cells
for example, can directly destroy virus-infected cells or release cytokines such as tumour
necrosis factor (TNF) that damages cells. With some non-cytopathic virus infections, such
as HCV and HBV, destruction of infected cells by CD8+ T effectors is the main cause of
damage to the liver11, 12 (Box 1 and Fig 1). Responses to infected cells by different types of
CD4+ T cells orchestrate a tissue-damaging inflammatory reaction and these become chronic
against persistent viruses. Most often the cell subsets involved are T helper 1 (Th1) cells, but
Th17 cells may contribute to inflammatory reactions with HIV, HCV and influenza virus
infections13–15. In such reactions neutrophils are recruited and become a major source of
tissue-damaging molecules. With viruses Th2 cells are rarely associated with inflammatory
reactions but this like happens with severe lung reactions to RSV16
Box 1
Viruses that persist and cause chronic disease
Several human viral infections, for example HIV, hepatitis B virus and hepatitis C virus
(HCV), become persistent and some can cause severe chronic disease that is usually the
consequence of an immune reaction to the infections. Many herpes viruses persist but

Nat Rev Immunol. Author manuscript; available in PMC 2014 January 23.

Lesions include nephritis. accounting for the different pattern of response observed among individuals. it is not clear what accounts for the different outcome of HCV infection. Author manuscript. In spite of all the above-mentioned events that can elicit tissue damage. antibody mediated inflammatory reactions involve toxicity mediated by IgG engaging Fc receptors on inflammatory cells causing mediator release17. These include antigenic variability. It has been suggested that dose of exposure. polymorphism of genes affecting NK cell activation and concurrent disease or infections (for example. tissue damage is modest in most cases but can be quite variable between individuals infected with the same virus. co-infection with HIV and HCV results in more severe hepatitis). These are now mentioned. Individuals that develop chronic disease instead mount a response comprising interleukin-10 (IL-10)-producing CD8+ and CD4+ T cells and sometimes FOXP3+ regulatory T cells. raising the activation threshold of natural killer (NK) cell activation and having negative effects on dendritic cell maturation and function. Viruses such as RSV express antigens that may induce an IgE response and type I hypersensitivity might partially account for lung lesions in some children infected with RSV22. replication in and destruction of CD4+ T cells. but the remaining ~15% control the infection and clear virus from the liver. activates complement and causes an inflammatory reaction. The role of innate and adaptive events that affect HCV pathogenesis recently received an excellent review12. the virus is never removed from the body. polyarteritis and arthritis. There are several responses the host can make to minimize tissue damage. HOST FACTORS THAT LIMIT TISSUE DAMAGE The host can use many counter-measures to limit tissue damage after virus infection. NIH-PA Author Manuscript Antibody responses to viruses may also contribute to tissue damage. Alternatively. HCV is a non-cytolytic infection that replicates for several weeks before an adaptive immune response occurs.Rouse and Sehrawat Page 3 NIH-PA Author Manuscript rarely cause chronic disease in normal hosts. Immune complex lesions were first reported for lymphocytic choriomeningitis virus (LCMV) but have also been reported in chronic HCV and HBV as well as in idiotypic IgA nephropathy associated with HIV infection18–21. In HIV infection. However. . These tissue protective events are more effective against some viruses and some circumstances of infection than others. which makes it refractory to neutralizing effect of antibodies. The innate immune attenuators encoded by the virus include inhibiting type I interferon (IFN) responses at several levels. This occurs when antibody reacts with an infected cell. Viral clearance is mediated by T cells and this causes hepatocyte destruction and mild hepatitis. Immune complex lesions can occur when viruses persist and poorly neutralizing IgG is produced. available in PMC 2014 January 23. as it integrates into the genome of infected host cells and as multiple immune evasive properties. the structure of its envelope. The countermeasures include the production of cytokines such as interleukin-10 (IL-10) and transforming growth factor-β (TGFβ) that have anti-inflammatory activity. or are the consequence of viral antigen antibody complexes being trapped in capillary beds and activating the complement cascade. NIH-PA Author Manuscript HCV infection causes chronic lesions in ~85% of infected individuals. other host derived anti-inflammatory mediators such as resolvins and galectins. The virus has several means of inhibiting innate immune mechanisms and the impact of these may relate to whether viral control or chronicity ultimately occurs. the activity of cell Nat Rev Immunol. induction of immune imbalance and induced expression of negative regulatory receptors on CD8+ T cells which makes them functionally ineffective. Protective immunity is associated with the induction of IFNγ-producing CD8+ T cells and high numbers of T helper 1 cells.

which impairs their inflammatory activity. activated regulatory T (TReg) cells. Moreover. The TGFβ superfamily of cytokines has a similar counter-inflammatory role to IL-10. 9. Although. B cells and some subsets of natural killer (NK) cells following stimulation with TLR ligands23. These include subsets of activated DCs. although the effects of TGFβ are more complex. Accordingly. These cytokines have a wide range of activities that include both anti-inflammatory and pro-inflammatory effects with the outcome depending on the concentration of TGFβ available and some other factors 33. TGFβ inhibits several functions of T cells that include proliferation. or is artificially suppressed by antibodies to IL-10 or its receptor.Rouse and Sehrawat Page 4 NIH-PA Author Manuscript subsets that inhibit other cells from mediating inflammatory events. IL-10 production by effector CD8+ T cells and its suppression of IL-2 production by these cells was also demonstrated in HIV-infected patients31. available in PMC 2014 January 23. Suppression of the effector T cell IL-10 response by lethal strains of influenza virus. . nuclear factor-kB (NF-kB) signalling is inhibited by IL-10 mediated induction of p50 and p105 units one of which (p50) binds to the stimulatory subunit p65. 25. For example mice lacking an IL-10 response develop more severe inflammatory reactions to ocular infection with herpes simplex virus (HSV) than do normal controls27. 28. These counterinflammatory factors are discussed and are depicted in Figure 2. as well as the induction of molecules on effector cells that result in the loss of effector functions. such as the 1918 H1N1 strain and the H5N1 strains. IFNγ. In some instances excessive IL-10 production during a virus infection may inhibit protective effector T cells response and favour viral persistence6. macrophages when infected with some viruses. IL-10 production by virus-specific effector T cells during the acute response to influenza virus was shown responsible for minimizing the severity of pulmonary lesions in mice30. differentiation into effector T cells and inhibition of some effector Nat Rev Immunol. Thus. 29. This can happen in some circumstances with LCMV infection and may also be happening during HIV infection6. TGFβ superfamily members exist in a latent inactive form and must be cleaved before they can bind to receptors and mediate their effects on cells. MHC class II expression and can also interfere with signaling of many pathways that result in pro-inflammatory cytokine production. Inhibiting the response to IL-10 with antibody specific for the IL-10 receptor resulted in more severe and sometimes fatal virusinduced lung damage. IL-10 may be of particular importance to constrain the severity of inflammatory reactions caused by chronic infections and its anti-inflammatory value has been advocated with viruses such as HCV and HIV 9. IL-10 also suppresses type I interferon-induced tyrosine phosphorylation of signal transducer and activator of transcription 1 (STAT1) and also induces the expression of suppressor of cytokine signalling 3 (SOCS3) by macrophages and neutrophils. Host derived IL-10 can act to block pro-inflammatory cytokine and chemokine production. some viruses such as EBV and cytomegalovirus (CMV) produce an IL-10-like molecule that functions in vitro like host IL-10 it is still not clear if this viral IL-10 plays any role during viral infections in vivo24. NIH-PA Author Manuscript Recently. Many cell types can produce IL-10. the extent of TGFβ production during virus infection could influence whether or not the response becomes overtly tissue damaging. sequestering it in the cytoplasm and making it unavailable for binding to the IL-6 and macrophage inflammatory protein 1 (MIP1 ) promoters for their transcription (reviewed in26). The extent of IL-10 induction during an infection could influence the amount of tissue damage that occurs. is thought to contribute to their virulence32. The responding CD8+ cells showed plasticity and gained the ability to produce IL-10 in addition to their main effector product. inflammatory reactions to infectious agents may be exaggerated. Nevertheless. Anti-inflammatory cytokines NIH-PA Author Manuscript The two best-known cytokines that inhibit inflammatory reactions are IL-10 and TGFβ. Author manuscript. if the IL-10 response is lacking. For example. owing to genetic mutation.

Moreover. NIH-PA Author Manuscript IL-10 and TGFβ are not the only cytokines that can limit damage caused by inflammatory reactions. Furthermore. 36. Most of our knowledge on the role of TGFβ in microbial pathogenesis concerns non-viral pathogens35. Author manuscript. 48. In the HSV ocular immunopathology model. These molecules contribute to the resolution of inflammatory lesions in several noninfection related lesions43. Such TReg cells could influence the outcome of infection particularly those that are chronic in nature 50. The inflammatory activities of CD8+ T cells. resolvins and protectins. This was observed with the blinding corneal response to HSV in mice51. Of note. In model systems where the activity of TReg cells can be inhibited. available in PMC 2014 January 23. influenza virus neuraminidase can activate TGFβ and the extent to which this happens could influence virulence 37. The best studied TReg cells are CD4+ T cells that express the transcription factor forkhead box P3 (FOXP3)49. Similar useful effects of TReg cells were noted in a Friend retrovirus model as well as with mouse models of RSV and West Nile virus52. but at the same time expands the TReg response44–46. 53. Acute infection with reovirus may also activate TGFβ signalling to an extent that correlates with damage to the central nervous system38. Currently there is no support for this ideas. IL-17. some viruses do cause an increase in TGFβ levels and other viruses express proteins that can cleave and activate TGFβ. For example. The suppressive effect of IL-17 was noted initially with autoimmune lesions but was recently also observed in Theilers virus encephalitis in mice42. a cytokine that is normally associated with the promotion of tissue damage was shown to have an anti-inflammatory role by suppressing Th1-mediated inflammatory effects41. as well the production of inflammatory products by recruited cells. Among the viruses that cause increased TGFβ production are chronic infections by HBV and HCV. along with IL-10 production. A nonstructural protein of HCV (NS4) was shown responsible for TGFβ induction and it seems that the magnitude of the TGFβ response. could determine if HCV infection is effectively cleared or becomes chronic14. Other counter-inflammatory molecules NIH-PA Author Manuscript Several other natural host products can also participate in the control and resolution of inflammatory reactions (Figure 3). activation or expansion of several types of TReg cell whose main activity is to inhibit the function of other cell types. a recent report attributed an intrinsic role of TGFβ signaling in effector T cells to explain their diminished survival and effector functions during chronic LCMV infection40. but galectin levels are different between HIV and HCV infected person and controls and with HCV galectin levels may correlate with viral loads47. blockade of TGFβ enhanced the in vitro activity of T cells39. Both effects minimize tissue damage. Galectin-9. for example. However. recent observations showed the therapeutic Nat Rev Immunol. variations in galectin concentrations between individuals could explain why the outcome in some is rapid and protective but in others prolonged and tissue damaging. These include the galectins. Th1 cells and Th17 cells.Rouse and Sehrawat Page 5 NIH-PA Author Manuscript functions such as cytotoxicity34. Recently for example. Members of the galectin family might also help to constrain inflammatory reactions43. Regulatory T cells Another mechanism of counteracting excessive tissue damage following virus infection is the induction. tissue-damaging immunopathological reactions to some viruses are increased. are all inhibited by TGFβ34. . Conceivably. virus-specific CD8 T cells isolated from HCV infected individuals produce TGFβ that suppresses virus specific T cell responses39. binds to the T cell immunoglobulin domain and mucin domain protein 3 (TIM-3) on activated effector cells and causes apoptosis.

Many of these act by terminating NF-kB signalling which curtails pro-inflammatory cytokine and chemokine production58. Examples include the deubiquitinase A20 that terminates NF-kB signalling and IRAK-M that interferes with TLR and IL-1 signaling 58. Additionally however. The protective function of effector T cells may also be compromised if they express inhibitory receptors and engage their ligands. . Author manuscript. which promote tissue damage. Role of inhibitory receptors An additional mechanism that could affect the pattern of events that follow virus infection is the signalling of inhibitory receptors on effector cells of both innate and adaptive immune systems. such as galectin-9 and the fungal metabolite FTY720. Some of the well characterized receptors that can be induced in chronic infection include programmed cell death 1 (PD-1) and IL-10R. Some of these molecules recruit other inflammatory cells such as neutrophils. This was achieved by administering reagents. The circumstances that result in upregulation of inhibitory receptors by effector T cells is not fully understood at a mechanistic level. SOCS proteins are also induced as a result of TAM signalling140. Such events may favour tissue damage over infection control. SOCS proteins and myeloid cell-associated immunoglobulin-like receptors (MAIRs) also known as CD300 and TAM receptors. the subsequent signalling events induced might also moderate immune-mediated tissue damage. SOCS proteins interfere with cytokine signalling and are induced as a result of IL-10 receptor and TAM receptor signalling in macrophages and granulocytes. Some of the noted molecules and pathways include A20 deubiquitinase. but the effect usually becomes evident during chronic infections. Box 2 NIH-PA Author Manuscript Regulators of innate immune cells NIH-PA Author Manuscript Innate immune cells after recognizing PAMPs via their innate receptors such as TLRs. TNF and IL-6. type IFNs. the host has evolved mechanisms to counter-regulate some or all of these pathways. IL-1β and some chemokines. this scenario needs to be formally investigated in virus-induced pathogenesis.Rouse and Sehrawat Page 6 NIH-PA Author Manuscript value of increasing the proportion of FOXP3+ TReg cells to manage viral immunopathological reactions54.6. Some of these negative signalling systems affect innate immune responses to virus infections. 55. it could be that while the use of these receptors by some viruses promotes infection and cause damage to the host. Several negative signalling systems that affect innate immune responses to virus infections have been noted. but this view remains debatable and is difficult to evaluate in natural disease situations 56. A more detailed description is included in box 2. especially those that involve high levels of persistent antigen59. Some of the best evidence that TReg cells are beneficial in a human chronic viral infection came from observations on the disease outcome in patients accidentally infected with HCV. that could cause some conventional CD4+ T cells to convert in vivo to become FOXP3+ and regulatory in function45. These molecules are expressed at higher levels on CD8+ T cells during chronic infection with LCMV infection in mice60. RLRs and NLRs become activated and produce abundant of inflammatory cytokines that include. TReg cells are advocated to influence the extent of tissue damage. However some viruses use such pathways for their entry and enhanced tissue tropism. After infection with filoviruses. available in PMC 2014 January 23. innate cells secrete abundant of proinflammatory cytokines such as type I IFNs. Tollips. For example viruses such as Filoviruses (Ebola and Marburgvirus) exploit TAM receptors. Here it was shown that a favourable outcome was more likely to occur in those individuals that made the highest IL-10-producing TReg cell responses57. However. Their engagement with the respective ligands impair effector T Nat Rev Immunol. Therefore. However. IRAK-M. 55. In several chronic human virus infections.

Reasons for susceptibility to the disease remain unexplained but one favoured idea was that CNS involvement reflected a defect in type I IFN induction. Furthermore. although primary infection can occasionally result in encephalitis and is a common outcome in seronegative neonates infected with HSV type 2. blocking either PD-1/PD-L1 and IL-10R or PD-1/PDL-1 and LAG-3 receptors provided the best approach to achieve immune recovery and viral control after chronic LCMV infection in mice. One anticipates similar strategies might prove useful to control human chronic infections.Rouse and Sehrawat Page 7 NIH-PA Author Manuscript cell function giving a so-called exhaustion phenotype. Thus. Author manuscript. This challenge is particularly difficult to meet with sporadic diseases that cause overt disease in only a very small minority of infected persons. available in PMC 2014 January 23. The section that follows deals with situations that favour a tissue-damaging response over immune control. 65 or TLR ligands expressed by viruses are thought to have a role66. 74. often lethal. NIH-PA Author Manuscript An important outcome of recognizing the exhaustion phenomenon is that an opportunity arises for a novel effective means of improving immunity and controlling the severity of chronic viral infections. . although recently a minority of cases of herpes encephalitis in children were associated with polymorphism of TLR3 or the UNC93B genes involved in TLR signaling 73. triggering the PD-1 receptor by its ligand (PDL-1) induced high levels of IL-10 production in monocytes that in turn inhibited the function of CD4 T cells64. the HCV core protein) and in others viralinduced interferons63. The disease usually occurs following reactivation of the host’s resident latent virus. debilitating disease caused by HSV type 172. TIM3 and perhaps others. The classic example is paralytic polio that affected <1% of those infected with poliovirus 71. For example. This exhaustion phenotype has since been observed in other chronic infections that include HIV. HCV and HBV61–63. 70. allowing viruses to persist and cause more tissue damage. combining exhaustion blockade with therapeutic vaccination was a superior means of controlling chronic LCMV infection than either approach alone69. the TNF-producing ability of exhausted T cells that contributes to tissue damage is one of the last functions to wane59. intrauterine infections may result in severe tissue damage as happens Nat Rev Immunol. Age of infection Whether a virus causes severe tissue damage often depends on the age at which infection occurs. Lesions of herpes encephalitis in adults are in part immunopathological. Specific examples are listed in table 1. Another example is herpes encephalitis that occurs in adults. The IL-10 mediated inhibition of CD4 T cells effector function was also demonstrated in chronic LCMV infection in mice6. Thus. Primary genetic susceptibility factors have not been implicated nor has the emergence of a neurotropic mutant.6. 68. Some recent studies have suggested the existence of cross talk between the PD-1/PDL-1 pathway and the production of IL-10. FACTORS THAT FAVOUR TISSUE DAMAGE NIH-PA Author Manuscript The aim of this review is to explain the variable outcome of a virus infection between different individuals infected with the same virus. This is a rare. Binding of inhibitory receptors on exhausted T cells diminishes their protective function. In fact. allowing robust poliovirus replication in the periphery and spread to the CNS71. It is not clear how infection causes inhibitory receptor upregulation but in some instances a viral component has been implicated (for example. Accordingly. Initial observations focused on blockade of PD1 or PDL-1 as well as IL-10R using monoclonal antibodies but blocking multiple inhibitory signals was even more efficacious than only single blockade 67. but why they only occur in an unfortunate few is not known. Exhausted T cells may express additional inhibitory receptors that include lymphycyte activation gene (LAG) 3. blocking the signals responsible for the exhaustion state can result in partial recovery of immune function and more effective infection control60. with distribution varying in different locations59.

as illustrated by increased morbidity and mortality among these age groups following infection with seasonal influenza virus76. RSV is the first pathogen a human infant usually encounters and clinical signs of RSV infection are common by 2–3 months of age 77. Dose and route of infection As can readily be shown in experimental systems. In addition. In general. understanding at a mechanistic level why some individuals develop severe lesions to RSV becomes a critical issue. aged individuals may develop lesions following reactivation of latent infections that had been successfully controlled by their immune system for decades. Presumably this T cell activity can fail at some sites but not others. 78. Premature infants are particularly prone to develop severe lesions in the respiratory tract following RSV infection and these account for many of the 3–5% of childhood RSV infections that require hospitalization77. the DCs that are stimulated tend to produce IL-10 and TGFβ and to act as inducers of FOXP3+ Treg cells80. which is characterized by painful inflammatory skin lesions that occur at sites innervated by a sensory ganglion in which varicella zoster virus has been reactivated from latency82. aged individuals often have increased numbers of CD8+ T cells that recognize latent viral infections. Indeed.and Th1 cellmediated protective responses79. mainly done in mice. NIH-PA Author Manuscript Understanding senescence of the immune system is an active area of research and the topic has been covered in excellent reviews84. have revealed that ageing has a greater effect on primary than on memory immune responses 84. re-exposure of aged individuals to RSV can cause lesions similar to those that occur in infants81. these CMV-specific CD8+ T cells can account for 50% or more of the total CD8+ memory T cell population. it is the young and the elderly who suffer the most severe consequences of infection. Why this happens in only a few of the many ganglia that contain latent virus is unknown. compared with young individuals. especially neonates. has been attributed to immature responsiveness of the immune system. It is possible that reactivation of latent virus occurs often but is successfully controlled by T cell immunity83. . Instead. Since childhood infection with RSV is a significant health problem against which there is no effective vaccine. Author manuscript. For example. the dose and route of virus transmitted can markedly influence the outcome of a virus infection. NIH-PA Author Manuscript Aged individuals may also suffer more problems than younger individuals following primary or secondary infection with some viruses. available in PMC 2014 January 23.Rouse and Sehrawat Page 8 NIH-PA Author Manuscript with rubella and CMV infections in humans75. Increased susceptibility of the young. Some indicate a pathological role for TNF producing CD8+ T cells and others advocate that lesions are associated with Th2 cell-dominated responses16. Studies of RSV infection using animal model systems indicate that the main mediators of the lung pathology are T cells but there is still debate as to which subsets are mainly involved. The space such cells occupy could diminish the number of lymphocytes available to react to pathogens perhaps explaining why infections such as influenza virus are more severe in the elderly. For example. further study is required to understand how this happens. The debate has been recently reviewed 78. This high susceptibility of infants is mainly explained by an inadequate type I IFN response together with a failure to activate subsets of DCs that induce CD8+ T cell. Minimal doses may be controlled subclinically by innate defences and may be insufficient to induce adaptive immune Nat Rev Immunol. particularly components of innate immunity. An additional effect observed during senescence is that the breath of the T cell repertoire is reduced perhaps because the thymus has involuted84. The best example of this is shingles. Moreover. naive T cells from aged compared with young animals undergo less homeostatic proliferation probably because of competition with memory T cells for growth factors and anatomical space84. Studies. particularly cytomegalovirus (CMV) infections — an effect known as memory inflation86. 85. The T and B cells from aged individuals respond less well to antigens and are compromised in their ability to perform effector functions as compared to responses in young individuals.

Thus. Reasons for this are still uncertain but it is possible that at low doses. Moreover. However. the outcome of infection was similar. Author manuscript. for cytopathic viruses. However occasional individuals suffer a life threatening meningoencephalitis. it is clear from studies with protein antigens that the magnitude and quality of immune responses induced is influenced by the type of DCs that engage antigen87. animals infected with a very low dose (100 or less) had a comparable immunopathological outcome to those infected with a large dose. after administering a large dose (>108) of virus. DC infection does not occur and the protective CD8+ T cell response is not compromised. Massive doses can overwhelm immune defences and cause severe disease and rapid death. the dose of infection of mice also affects the range of cells that become infected. an interesting and unexpected effect of infection dose was noted in chimpanzees infected with HBV92. dose effects might depend on the type of virus. the dose seems to have little effect perhaps because potent infection is usually established by a single (founder) virion from the large numbers of virions (up to 106) that are transmitted to the host88. West Nile virus is becoming a common infection in the western hemisphere but most infected persons suffer no clinical consequences. but it is a common practice for those who study viral pathogenesis to choose optimal doses of infection to evaluate their concepts. . By contrast. At high doses. Thus. the virus can go undetected by the immune system and fail to induce priming of CD4+ T cells. some flaviviruses. How these observations relate to HBV infection of humans needs evaluation. Curiously. which are needed to provide ‘help’ to mount a protective CD8+ T cell response. the infected DCs deliver apoptotic signals to the CD8+ T cells that normally have the principal role in resolving infection. the dose of infection can influence the response pattern90. This scenario is more likely to occur in those exposed to many mosquito bites (providing a high dose infection). NIH-PA Author Manuscript Dose of infection could be the explanation for the variable outcome of infection by insect transmitted flaviviruses. stimulate TLR3 (which recognizes double-stranded DNA) and induces TNF Nat Rev Immunol. as well as the balance of the immune response that results91. for example. This issue has received surprisingly little formal study with virus infections.Rouse and Sehrawat Page 9 NIH-PA Author Manuscript NIH-PA Author Manuscript responses. Dose and route of infection is expected to influence how successful the virus will be to gain access to susceptible target cell as well as to be transported by different types of DCs to lymphoid tissues. For lentiviruses. At lower doses. In such individuals virus crosses the blood–brain barrier and lesions are then the consequence of a viral antigenspecific T cell-mediated immunopathological reaction to infected cells93. Experimental studies of simian immunodeficiency virus (SIV) infection of macaques also show little or no effect of dose on the outcome of infection89. Recently. for example West Nile virus. Furthermore. Over a wide dose range (104–108 virions). HBV is a non-cytopathic virus and both control of the virus and the development of immunopathological hepatic lesions are mediated by CD8+ T cells. DCs and alveolar epithelial cells become infected. With replicating agents such as viruses. in some instances by direct cytotoxic effects of viral components. One idea to explain the pathological outcome is that it occurs in circumstances in which the virus replicates rapidly and exceeds the host’s ability to constrain it despite the induction of an neutralizing antibody response and numbers of functional T cells that would otherwise be protective93. if animals were depleted of CD4+ T cells and given the medium dose of virus they developed chronic active hepatitis. Curiously for influenza virus. Doses in between these extremes can have a variable outcome from inapparent infection to tissuedamaging lesions. aged or has some degree of immunodeficiency. being controlled successfully 6–8 weeks after infection with minimal hepatitis. rates of replication and intrinsic properties such as expression of ligands for innate immune receptors. 100% of hepatocytes became infected. especially if the infected person is young. available in PMC 2014 January 23. virus reached high levels for at least 16 weeks and animals developed chronic active hepatitis. Unexpectedly.

there is a 5–20 fold increase in circulating T cells. The disease is serious and can last for weeks but it only occurs in a minority of usually young adults who receive a primary infection with EBV. In patients that develop infectious mononucleosis. but may still be able to mediate tissue damage. Nat Rev Immunol. An initial explanation for the DHF syndrome was that it occurred because cross-reactive yet non-neutralizing antibodies opsonized virus for uptake by macrophages99. available in PMC 2014 January 23. However the cross-reactive cells that dominate the response have low affinity for the virus antigen-expressing cells and are unable to adequately control the infection. Following infection with the second pathogen. the cross-reactive memory cells expand more rapidly and may dominate the overall response. circulatory shock and some bleeding manifestations. This was proposed to result in immune activation. hypotension. However. The expanded T cells are non-protective yet they can mediate a severe inflammatory reaction that includes VEGF-A production. vascular leakage. with infectious mononucleosis only occurring in individuals with EBV cross-reactive T cells at the time of infection101. Similarly. abundant production of cytokines and vascular leakage. NIH-PA Author Manuscript The route of infection can also impact on the extent of tissue damage that ensues. the main mediator of vascular leakage. It usually occurs in individuals who are already immune to one dengue virus strain and become infected with a heterologous strain. Influence of heterologous immunity NIH-PA Author Manuscript Heterologous immunity is the term used to describe the observation that exposure to one pathogen will generate an immune response against numerous antigenic epitopes derived from that pathogen some of which might cross react with epitopes derived from other pathogens. Other examples of cross-reactivity between different pathogens that influence disease patterns are reviewed in REF104. thereby setting the stage for chronic immunopathology. The pathogenesis of infectious mononucleosis is poorly understood but one provocative idea is that the disease is the consequence of heterologous immunity. this cross-reactive response may be of low avidity and poorly protective. Experimental evidence that heterologous immunity can account for immunopathological responses in some but not all animals was provided by Kim and colleagues103. Dengue haemorrhagic fever does not occur as often as might be expected on the basis of this mechanism. These include viral virulence. cross-reactivity between the influenza virus matrix protein and the EBV BMLF1 protein has been noted102. These circumstances could explain the occurrence of severe disease (dengue haemorrhagic fever-DHF) that affects only a small minority of the 50 million people who are infected with dengue DHF is characterized by high fever. However. For example. NIH-PA Author Manuscript Another tissue-damaging human disease that could be explained by the existence of heterologous immunity is infectious mononucleosis. oral or genital infection usually results in lesions that resolve without long-term damage. The meningitis that adult mice develop after LCMV infection only occurs if virus is administered directly into the CSF and is not evident if infected by other routes98. Author manuscript. the ability to replicate efficiently and host genetic factors. which suggests that additional factors are also involved. Such cross-reactive T cells are proposed to expand more rapidly than EBVspecific naive T cells induced following infection. mice infected with corona virus or Theilers virus can develop immunopathological lesions in the CNS. Clinical and experimental evidence for the proposed pathogenesis of DHF is reviewed in REF100. Others now suggest that T cells are the main orchestrators of the disease and that they cross-react with epitopes primed by exposure to a different viral strain99. infection of the eye can result in blinding chronic immunoinflammatory lesions95. 97. . but this response only occurs if virus is given intracerebrally or intranasally and fails to occur after systemic infection96. Supporting this concept. with HSV infection of humans.Rouse and Sehrawat Page 10 production. most of which are viral antigen-specific CD8+ T cells. and this may increase the permeability of the blood–brain barrier and allow entry of the virus to the CNS94.

Mutations in genes that encode proteins involved in innate defence such as the TLRs can affect the clinical expression of infections74 but little so far has been reported for viruses. These effects will impact on the balance of response by individuals to exogenous agents. some of which are transcriptionally active. for example Nat Rev Immunol. Investigations on this topic of have focused on HIV but most changes detected so far have been minor probably because multiple genes affect resistance. which encodes a transmembrane protein involved in TLR signalling111. the entry co-receptor for X5 HIV) have increased resistance to HIV compared with heterozygous individuals109. This topic has been reviewed recently106. 113. One example is a mutation in UNC93B. Some viruses. CONCLUSIONS Whether a virus infection results in severe. This knowledge might provide clues to customize successful preventative and therapeutic approaches for viral infection and associated immunopathology. Thus. including viruses. With technological advances in detecting both host polymorphisms and the virome. individuals with a homozygous 32 base pair deletion in CCchemokine receptor 5 (CCR5. 112. especially IFNα and IFNβ. Another example is that non-secretors of ABO blood groups are refractory to diarrhea caused by Norwalk virus110. For example. we anticipate that the influence of these factors on the outcome of virus infection will soon be better understood. Author manuscript. is directed by multiple genes that act at different stages of the virus–host interaction. Exceptions to this generalization include the primary immunodeficiencies that arise from rare monogenic defects and lead to increased susceptibility to various virus infections108. every individual may harbour several (8–12) different chronic viral infections that lie undetected and unsymptomatic59. As a result. .Rouse and Sehrawat Page 11 Host genetics and the ‘virome’ NIH-PA Author Manuscript NIH-PA Author Manuscript Variation in clinical responses of individuals to virus infections is influenced by the host genotype. Virulent infectious agents are assumed to have helped to shape our genome and are responsible for the extreme polymorphisms of many loci involved in MHC antigen processing and presentation105. There is evidence that the outcome of the virus infection is affected by the HLA alleles expressed106. although this needs to be formally shown. the absence or malfunction of a single gene would probably have a negative or minimal effect on the outcome of a virus infection. but curiously not other problems with HSV infection or other viruses. According to a recent review. lesions or is resolved with minimal bystander tissue damage depends on numerous factors. but the influence is usually modest. Both defects result in defective cytokine production. The others are exogenous viruses that establish persistent infections and are mainly not retroviruses. Affected children develop herpes encephalitis 74. Together these endogenous and exogenous viruses have been referred to as the ‘virome’59. The more common scenario that accounts for more severe disease following virus infection is polymorphisms in a few or many genes. available in PMC 2014 January 23. sometimes prolonged. resistance to pathogens. at least 250 genes are estimated to affect the outcome of infection by HIV107. Resident exogenous viruses might also influence the T cell repertoire and could also influence the activity status of the innate immune system causing. Genetic factors have not yet been implicated to explain that around 1% of HIV -infected patients control their infection long term without treatment114. Mutations of genes encoding viral receptors and co-receptors can also influence disease susceptibility. deleting some specificities and expanding others116. Already it is known that endogenous retroviruses could help to shape the T cell repertoire. the production of cytokines and altered antigen presentation efficiency of DCs. that are estimated to contribute to 8–9% of total human DNA115. for example. NIH-PA Author Manuscript In addition to host genetics affecting the pattern of disease other sources of genetic material in the host could also influence the outcome. For example. These are the endogenous retrovirus elements. Another is a loss of function mutation of TLR374.

[PubMed: 19365081] 10. [PubMed: 19196953] 4. for example many herpes viruses. Rehermann B. 135:462–6. but tissue damage occurs in those individuals that have predisposing genetic or acquired problems with one or more components of innate or adaptive defence. Other agents. age at infection. host genetics. Science. 5:987–95. J Immunol. Crit Rev Oncol Hematol. Miller SD. PLoS Pathog. 203:1153–9. 2009. 12:1301–9. [PubMed: 18802051] 15. et al. This paper showed that the Th17 cells are induced after SIV infection and that the balance of Th17 and Tregs is critically involved in the progression of disease in pigtailed macaques but not in African green monkeys in which Th17 cells are progressively depleted. Hyodo N. Guidotti LG. Rudd BD. Toll-like receptor control of the adaptive immune responses. Immunity. 5:e1000295. Viral clearance without destruction of infected cells during acute HBV infection. Nat Med. Eur J Immunol. Brooks DG. [PubMed: 14635055] 8. Rowan AG. Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling. [PubMed: 16682497] 11. 2006. [PubMed: 19319143] 2. [PubMed: 17041596] 7. Medzhitov R. 80:4521–7. available in PMC 2014 January 23. 33:3448–57. 27:370–83. 114:346–56. 70:183–94. Imawari M. Tregoning JS. J Exp Med. some infections that are normally well controlled can cause major tissue damage under unusual circumstances. Interleukin-10 determines viral clearance or persistence in vivo. [PubMed: 20003352] 16. 2007. Hepatitis C virus-specific Th17 cells are suppressed by virus-induced TGF-beta. [PubMed: 10221919] 12. 1999. Mills KH. Munz C. Innate recognition of viruses. 119:1745–54. References NIH-PA Author Manuscript NIH-PA Author Manuscript 1. [PubMed: 18805702] 3. Differential chemokine expression following respiratory virus infection reflects Th1. Lunemann JD. Nakamura I. 106:2770–5. Culley FJ.or Th2-biased immunopathology. 2009. Pennycook AM. Proc Natl Acad Sci U S A. Finally. 2004. [PubMed: 15454922] 6. 2003. Bermejo-Martin JF. Brockman MA. 2008. Hepatitis C virus non-structural protein 4 suppresses Th1 responses by stimulating IL-10 production from monocytes. 2009. Franceschi S. 181:4485–94. are successfully controlled in most individuals. Author manuscript. This paper implicated the role of IL-10 in persistence of LCMV infection of mice and showed the therapeutic value of its neutralization in achieving viral control. Hepatitis B core antigen stimulates interleukin-10 secretion by both T cells and monocytes from peripheral blood of patients with chronic hepatitis B virus infection. et al. Getts MT. 2009. Lukacs NW. Brady MT. Iwasaki A. J Clin Invest. Nat Immunol. [PubMed: 17892846] 5. et al. 2006. and priming with cross-reacting viruses or co-infection with other agents. Tal MC. Hussell T. de Martel C. This is the first study to demonstrate that viral antigen-specific Th17 cells are induced in HCV infected individuals and that viral protein. MacDonald AJ. Favre D. [PubMed: 15008979] 9.Rouse and Sehrawat Page 12 NIH-PA Author Manuscript HIV and HCV. 2004. Plasmacytoid dendritic cells inhibit pulmonary immunopathology and promote clearance of respiratory syncytial virus. Pichlmair A. [PubMed: 16611912] Nat Rev Immunol. . Crit Care. Reis e Sousa C. Smit JJ. Antiviral immune responses: triggers of or triggered by autoimmunity? Nat Rev Immunol. 2009. 9:246–58. 2006. J Virol. Clin Exp Immunol. Critical loss of the balance between Th17 and T regulatory cell populations in pathogenic SIV infection. Rowan AG. Blood. Th1 and Th17 hypercytokinemia as early host response signature in severe pandemic influenza. et al. et al. Infections and cancer: established associations and new hypotheses. IL-10 is up-regulated in multiple cell types during viremic HIV infection and reversibly inhibits virus-specific T cells. Openshaw PJ. 284:825–9. Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence. [PubMed: 19214220] 14. et al. NS4 induced TGF-beta can inhibit the activity of Th17 cells. These might relate to dose or route of exposure. 2009. 13:R201. 2009. [PubMed: 19587449] 13. et al. have intrinsic properties that make immune control difficult and attempts to achieve control results in notable tissue damage.

1978. . Isolation and expression of human cytokine synthesis inhibitory factor cDNA clones: homology to Epstein-Barr virus open reading frame BCRFI. This is the first report in which immune complex deposits were measured using sensitive immunofluorscence and radioimmuneoprecipitation in the tissue sites after a viral infection. Suvas S. et al. [PubMed: 17312176] 32. 328:465–70. [PubMed: 18400189] 34. Sun J. Oldstone MB. 200:448–52. Nat Immunol. [PubMed: 14698136] 29. 270:229–39. Rouse BT. Proc Natl Acad Sci U S A. 1975. Moore KW. 2000. Hirsch CS. In vivo veritas: the surprising roles of Fc receptors in immunity. Interleukin-10 promoter polymorphisms influence HIV-1 susceptibility and primary HIV-1 pathogenesis. IL-10 haplotypes as possible predictors of spontaneous clearance of HCV infection. 2008. 178:3265–71. Corran PH. Author manuscript. Brief report: idiotypic IgA nephropathy in patients with human immunodeficiency virus infection. [PubMed: 19534595] 30. Sultan AA. Schultz-Cherry S. [PubMed: 15454] 20. 2007. [PubMed: 8970987] Nat Rev Immunol. Immunity. 2008. 120:1297–304. 1993. 2005. 1992. Kotenko SV. 2008. 2007. et al. Human cytomegalovirus harbors its own unique IL-10 homolog (cmvIL-10). Contextual regulation of inflammation: a duet by transforming growth factorbeta and interleukin-10. J Infect Dis. Vieira P. Pestka S. 61:558–65. [PubMed: 7678440] 21. 15:277–84. Saccani S. Toossi Z. Dakhama A. [PubMed: 15963051] 36. Flavell RA. Omer FM.Rouse and Sehrawat Page 13 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript 17. de Souza JB. Li MO. 97:1695– 700. Madan R. 327:702–6. J Virol. 445:319–23. Proc Natl Acad Sci U S A. J Allergy Clin Immunol. Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10. Elrefaei M. 2004. [PubMed: 76662] 19. [PubMed: 11244051] 27. [PubMed: 14676296] 37. et al. Nature. Ravetch J. Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. TGF-beta: a master of all T cell trades. 2001. J Immunol. [PubMed: 10677520] 26. Kimmel PL. Slusarczyk J. Wu M. Flavell RA. [PubMed: 18424693] 24. [PubMed: 19234462] 31. [PubMed: 1847510] 25. et al. [PubMed: 17230189] 33. Riley EM. [PubMed: 18692464] 35. et al. Sehrawat S. Couper KN. 25:103–9. HIV-specific IL-10-positive CD8+ T cells suppress cytolysis and IL-2 production by CD8+ T cells. IL-10 and natural regulatory T cells: two independent anti-inflammatory mechanisms in herpes simplex virus-induced ocular immunopathology. Johnson RJ. 123:138–145. Influenza virus neuraminidase activates latent transforming growth factor beta. de Waal Malefyt R. Virus-specific IgE enhances airway responsiveness on reinfection with respiratory syncytial virus in newborn mice. Nowoslawski A. Mirochnitchenko OV. 1991. Kobasa D. J Exp Med. Naicker DD. Li MO. Johnson JL. 2009. Immunopathological aspects of hepatitis type B. N Engl J Med. 134:392–404. Aung H. Karp CL. Blount DG. Krawczynski K. Sarangi PP. 180:5771–7. e5. Am J Med Sci. Cell. Riley EM. 2009. IL-10: the master regulator of immunity to infection. 180:6297–306. 19:683–765. [PubMed: 18424753] 28. Buchmeier MJ. et al. Coffman RL. This study demonstrated that effector CD8 T cells by making IL-10 limit the extent of pulmonary tissue damage. [PubMed: 20157296] 18. Bioactivation of latent transforming growth factor beta1 by Mycobacterium tuberculosis in human mononuclear phagocytes. 2009. 1996. Interleukin-10 and the interleukin-10 receptor. 2003. [PubMed: 1495523] 22. Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. O’Garra A. J Immunol. 88:1172–6. Nazarewicz T. [PubMed: 19056111] 23. Virus-induced immune complex disease: identification of specific viral antigens and antibodies deposited in complexes during chronic lymphocytic choriomeningitis virus infection. J Immunol. 70:8624–9. et al. Activation of transforming growth factor beta by malaria parasite-derived metalloproteinases and a thrombospondin-like molecule. 28:468–76. Izotova LS. available in PMC 2014 January 23. Annu Rev Immunol. Mangia A. Hinshaw VS. Braciale TJ. Scand J Immunol. N Engl J Med. 2008. 11:183– 5. Cytokine. 198:1817–27. et al. J Immunol. Nat Med.

2004. J Virol. This paper showed that galectin-9 could promote Foxp3+ Treg responses and that ligation of TIM-3 with galectin-9 induces apoptosis of effector T cells but not Tregs. 182:3191–201. 2009. 2009. Yang Y. [PubMed: 19234217] 46. Nat Rev Immunol. Rabinovich GA. [PubMed: 19638732] 48. [PubMed: 20209097] 49. Reddy PBJ. 101:455–8. 206:313–28. Azkur AK. 82:6838–51. 2009. J Exp Med. 6:e1000882. In vitro-generated antigen-specific CD4+ CD25+ Foxp3+ regulatory T cells control the severity of herpes simplex virus-induced ocular immunoinflammatory lesions. Alcalde V. Graham BS. Hirashima M. [PubMed: 16286920] 45. et al. Tuttle K. Rouse BT. et al. Hirashima M. [PubMed: 17376924] 40. J Immunol. J Immunol. Th17 cells enhance viral persistence and inhibit T cell cytotoxicity in a model of chronic virus infection. [PubMed: 19604493] 41. 6:1245–52. Lanteri MC. 2009. A crucial role for kupffer cell-derived galectin-9 in regulation of T cell immunity in hepatitis C infection. Rouse BT. et al. 2009. PLoS One. Sehrawat S. This report showed that induction of Tr1 cells in HCV patients negatively corelated with the extent of liver dmage. Regulatory T cells promote early influx of CD8+ T cells in the lungs of respiratory syncytial virus-infected mice and diminish immunodominance disparities. Suvas S. Rajasagi N. J Immunol. J Virol. 2005. Zhu C. 83:5035–45. [PubMed: 15034024] 52. 119:3266–77. [PubMed: 19448631] 42. 2009. Sehrawat S. 218:285–92. Kim BS. Kim BS.Rouse and Sehrawat Page 14 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript 38. Nat Immunol. J Virol. CD4 T helper type 1 and regulatory T cells induced against the same epitopes on the core protein in hepatitis C virus-infected persons. 2009. Regulatory T cells in virus infections. Role of Tim-3/galectin-9 inhibitory interaction in viral-induced immunopathology: shifting the balance toward regulators. Reovirus activates transforming growth factor beta and bone morphogenetic protein signaling pathways in the central nervous system that contribute to neuronal survival following infection. Alatrakchi N. 2009. J Infect Dis. 2008. [PubMed: 19279118] 39. 2007. Author manuscript. 2002. CD4+CD25+ regulatory T cells control the severity of viral immunoinflammatory lesions. 31:145–57. [PubMed: 19204109] 43. Suryawanshi. O’Connor W Jr. Rouse BT. [PubMed: 19302048] 51. [PubMed: 19855131] 54. Kumaraguru U. Suryawanshi A. et al. Cell-intrinsic transforming growth factor-beta signaling mediates virus-specific CD8+ T cell deletion and viral persistence in vivo. 83:3019–28. Suvas S. Tinoco R. 2010. 180:7636–47. et al. Cell. 10:603–9. Sarangi PP. Hou W. Chagan-Yasutan H. Sarangi PP. J Clin Invest. Tregs control the development of symptomatic West Nile virus infection in humans and mice. Tohoku J Exp Med. Rouse BT. 2008. 2006. Beckham JD. Tyler KL. Immunity. 172:4123–32. 9:338–52. [PubMed: 18490766] 56. Sehrawat S. [PubMed: 16903920] 57. 185:720–7. Ruckwardt TJ. J Virol. Immunol Rev. Zuniga EI. 2009. Persistent elevation of plasma osteopontin levels in HIV patients despite highly active antiretroviral therapy. 81:5882–92. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. 27:551–89. Nat Immunol. This report showed that TGF beta acts intrinsically to limit CD8 T cell responses to viral infection. Suvas S. Regulatory T cells: key controllers of immunologic self-tolerance. Galectin-9/TIM-3 interaction regulates virus specific primary and memory CD8T cell response. Kang HS. et al. Toscano MA. Regulatory T cells in the control of host-microorganism interactions (*). Mengshol JA. A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Sakaguchi S. Annu Rev Immunol. Suryawanshi A. [PubMed: 19365409] 44. [PubMed: 20463811] 47. Rouse BT. PLOS Pathog. Hepatitis C virus (HCV)-specific CD8+ cells produce transforming growth factor beta that can suppress HCV-specific T-cell responses. Sauer K. Belkaid Y. 2000. Bonaparte KL. 2009. et al. [PubMed: 19153229] 53. Nason MC. Rouse BT. Anti-inflammatory effects of FTY720 against viral-induced immunopathology: role of drug-induced conversion of T cells to become Foxp3+ regulators. [PubMed: 11920289] Nat Rev Immunol. Sehrawat S. [PubMed: 10850488] 50. . [PubMed: 18480441] 55. 212:272–86. MacDonald AJ. available in PMC 2014 January 23. Turning ‘sweet’ on immunity: galectin-glycan interactions in immune tolerance and inflammation. 5:e9504. Tarbell K.

82:2040–55. J Virol. T cell dysfunction by hepatitis C virus core protein involves PD-1/PDL-1 signaling. [PubMed: 17182670] 63. Nature. Nature. 317:1522–7. et al. O’Neill LA. [PubMed: 16382236] 61. . et al. 2006. 2007. Schwarze J. New York: 2001. Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3. Xu D. 2008. Day CL. [PubMed: 16921384] 62. 16:452–9. Ha SJ. et al. Collins PL. 10:29–37. et al. 439:682–7. Lee AM. J Exp Med. PMh. beta. Cell. 2006. Prayther D. et al. Nat Immunol. et al. Ahmed R. 2008. 129:132–44. McGavern DB. [PubMed: 18374680] 77. One hundred years of poliovirus pathogenesis. Redefining chronic viral infection. [PubMed: 18332180] 70.. 7:156–64. 2009. Brint EK. Science. [PubMed: 19075244] 68. virology. 2007. 205:533–41. 2006. 2009. [PubMed: 19596234] 60. [PubMed: 17603844] 66. [PubMed: 15928677] 59. Nat Med. J Exp Med. 344:9–16. 23:2087–9. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Zhang SY. Brown RB. Viral and host factors in human respiratory syncytial virus pathogenesis. 2007. 5:446–58. [PubMed: 16364730] 72. TLR3 deficiency in patients with herpes simplex encephalitis. Yin D. Yao ZQ. Whitley. Nat Rev Immunol. [PubMed: 20065326] 78. and immunology. Clin Microbiol Rev. McIntosh ED. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Isogawa M. [PubMed: 18650129] 67. Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic infection. Haessler SD. 2005. [PubMed: 17928346] 79. 7 and 9. Spann KM. 2008. Elsaesser H. editors. 2005. Brooks DG. Maier H. Lippincott Williams and wilkins. 81:2545–53. Virgin HW. J Immunol. [PubMed: 19043418] 69. 105:20428–33. 2008. [PubMed: 15755576] 76. Freeman GJ. Barber DL. Liew FY. Chisari FV. 2008. Am J Med. Viral Immunol. Brooks DG. Nat Immunol. Proc Natl Acad Sci U S A. Rothberg MB.Rouse and Sehrawat Page 15 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript 58. Tran KC. et al. 2007. Paediatric infections: prevention of transmission and disease--implications for adults. 121:258–64. Suppression of the induction of alpha. available in PMC 2014 January 23. J Virol. Moorman J. IL-10 and PD-L1 operate through distinct pathways to suppress T-cell activity during persistent viral infection. [PubMed: 16415873] 74. Blackburn SD. and lambda interferons by the NS1 and NS2 proteins of human respiratory syncytial virus in Nat Rev Immunol. Boasso A. This seminal paper showed that the functional exhaustion caused by a chronic viral infection could be reversed using antibody to the inhibitory molecule PD1. et al. 178:2714–20. Racaniello VR. Tregoning JS. Chi B. Oldstone MB. Wherry EJ. Knipe. Restoring function in exhausted CD8 T cells during chronic viral infection. Negative regulation of toll-like receptor-mediated immune responses. clinical symptoms. Said EA. Rabin RL. [PubMed: 20208540] 65. Complications of viral influenza. Respiratory viral infections in infants: causes. 20:276–87. Vaccine. et al. 138:30–50. King E. Radziewicz H. 205:543–55. 2008. Clin Immunol. 73. [PubMed: 18332181] 71. 2006. [PubMed: 17312113] 64. PDL-1 upregulation on monocytes and T cells by HIV via type I interferon: restricted expression of type I interferon receptor by CCR5-expressing leukocytes. PD-1:PD-L1 interactions contribute to the functional suppression of virus-specific CD8+ T lymphocytes in the liver. Graham BS. [PubMed: 17872438] 75. Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression. Tabeta K. Herpes Simplex Viruses. RJ. et al. A report showed that antigen-specific CD8 T cells isolated from HIV infected individuals expressed higher levels of the inhibitory molecule PD1 and that the exhaustion could be reversed at least ex vivo using blocking antibody. David. 443:350–4. Collins PL. Virology. 23:74–98. IL-10 blockade facilitates DNA vaccine-induced T cell responses and enhances clearance of persistent virus infection. M. Author manuscript.

[PubMed: 10823850] 91. McDermott AB. 1973. J Virol. JAMA. 30:301–5. Nat Rev Immunol. 2009 This study investigated the influence of dose of infecting HBV on the pathogenesis of liver disease and clearly demonstrated that very high or very low doses of infection led to severe liver damage. Repeated low-dose mucosal simian immunodeficiency virus SIVmac239 challenge results in the same viral and immunological kinetics as high-dose challenge: a model for the evaluation of vaccine efficacy in nonhuman primates. Requirement for theta-bearing cells in lymphocytic choriomeningitis virus-induced central nervous system disease. 196:1381–6. Clin Infect Dis. Eichelberger MC. 2008. Dose-dependent changes in influenza virus-infected dendritic cells result in increased allogeneic T-cell proliferation at low. Lancet. et al. Immunity. et al. Rouse BT. Pathogenesis of demyelination induced by a mouse hepatitis. 2000. Wang T. Exp Dermatol. Nature. [PubMed: 15558055] 95. [PubMed: 17993365] 100. The balance between plasmacytoid DC versus conventional DC determines pulmonary immunity to virus infections. T-cell immunosenescence: lessons learned from mouse models of aging. 3:e1720. 85:33–42. functional T cells. 18:264–73. [PubMed: 16477558] 84. McCaffery JM. Smit JJ. Schakel K. Immunopathology of flavivirus infections. 2009. Koelle DM. 2002. 93. [PubMed: 14990733] 90. [PubMed: 19541537] 86. et al. [PubMed: 15047850] 80. [PubMed: 19491172] 83. A tale of 2 alpha-herpesviruses: lessons for vaccinologists. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Lymph node dendritic cells control CD8+ T cell responses through regulated FasL expression. Corey L. Dendritic cells--why can they help and hurt us. Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Fazakerley JK. Halstead SB. 10:1366–73. 302:73– 80. J Virol. 2009. Oh S. 2004. 1972. Whitley RJ. J Virol. 78:3140–4. available in PMC 2014 January 23. Braciale TJ. 9:148–64. Arch Neurol. 238:335–7. J Exp Med. doses of virus. 5:e1000274. 225:300–13. Annu Rev Med. 78:4363–9. Trends Immunol. 8:512–22. [PubMed: 12707846] 98. Legge KL. [PubMed: 18837790] Nat Rev Immunol. [PubMed: 16356862] 92. Nikolich-Zugich J. [PubMed: 12438429] 82. 29:650–9. 28:298–303. et al. Maue AC. Cole GA. Pollott J. et al. et al. 2007. Immunol Rev. Understanding the contribution of cellular immunity to dengue disease pathogenesis. 2009. The Size of the Viral Inoculum Contributes to the Outcome of Hepatitis B Virus Infection. 2004. J Neurovirol. Virus demyelination. [PubMed: 19183400] 88. Nathanson N. 370:1644–52. J Virol. Inflammatory genital infections mitigate a severe genetic bottleneck in heterosexual transmission of subtype A and C HIV-1. et al. [PubMed: 4561841] 99. [PubMed: 18186706] 96. 2009. 2008. Memory inflation during chronic viral infection is maintained by continuous production of short-lived. 59:381–95. Immunity. [PubMed: 17146465] 94. 2008. [PubMed: 18320041] 81. Dengue. The influence of age at first exposure to a vial infection on the susceptibility of the same infection later in the life was demonstrated in mouse model of RSV infection. 2003. 23:649–59.Rouse and Sehrawat Page 16 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript human epithelial cells and macrophages [corrected]. Rothman AL. King NJ. Openshaw PJ. Author manuscript. [PubMed: 19165325] 89. A 70-year-old woman with shingles: review of herpes zoster. . Walker R. Culley FJ. Herpes simplex: insights on pathogenesis and possible vaccines. 2007. Weiner LP. 74:5460–9. Mathew A. PLoS Pathog. [PubMed: 18957267] 87. but not high. 2008. 2005. Asabe S. [PubMed: 18469829] 85. 2006. et al. [PubMed: 4348723] 97. Nat Med. Age at first viral infection determines the pattern of T cellmediated disease during reinfection in adulthood. Kaistha SD. Prendergast RA. PLoS One. 42:810–7. Immunol Cell Biol. Haaland RE. 2008. Snyder CM. 2004.

[PubMed: 8643549] 117. 77:525–35. 111:1420–7. Hansen MA. Masucci MG. Seifarth W.Rouse and Sehrawat Page 17 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript 101. 22:41–7. Levitskaya J. 11:445–8. J Virol. 94:12616–21. et al. This study showed demonstrated that some of the HIV infected individuals could control virus for long time without the need of anti-retroviral therapy. 1996. Good RA. J Exp Med. Brass AL. available in PMC 2014 January 23. Hadinoto V. [PubMed: 15710651] 104. Immunity. . Adv Exp Med Biol. et al. 93:5177–84. Nature. Hill AV. Inborn errors of interferon (IFN)-mediated immunity in humans: insights into the respective roles of IFN-alpha/beta. A cytosolic herpes simplex virus protein inhibits antigen presentation to CD8+ T lymphocytes. Kaur G. 2009. Gale M Jr. 2008. 1996. [PubMed: 9356498] 122. Segal S. AIDS. Genetic susceptibility to infectious disease. These study showed that major contributors to infectious mononucleosis are cross-reactive T cells specific to a previously encountered virus. Cell. Primary immunodeficiency diseases. Author manuscript. Kurth R. 8:619–30. [PubMed: 17558423] 105. Liu R. On the dynamics of acute EBV infection and the pathogenesis of infectious mononucleosis. 2005. Lower R. Leonchiks A. [PubMed: 19161414] 113. Proc Natl Acad Sci U S A. 383:720–2. Zhang SY. 2005. 1994. Ahn K. Welsh RM. 2008. 1996. Natural history of serum HIV-1 RNA levels in 330 patients with a known date of infection. Mehra N. Proc Natl Acad Sci U S A. Nat Rev Immunol. York IA. [PubMed: 18187620] 108. Science. and IFN-lambda in host defense. Recognition of viruses by cytoplasmic sensors. et al. 73:289–301. [PubMed: 8878482] 121. de Waal Malefyt R. [PubMed: 793332] 109. [PubMed: 17094741] 111. Science. 2008. [PubMed: 13678861] 106. 2008. 201:523–33. [PubMed: 10708282] 115. IFN-gamma. Impact of MHC class I diversity on immune control of immunodeficiency virus replication. Ciechanover A. Trends Microbiol. J Clin Invest. 1976. Lower J. The viruses in all of us: characteristics and biological significance of human endogenous retrovirus sequences. heterologous immunity and vaccine design. Watkins DI. 1997. 2000. Cross-reactive influenza virus-specific CD8+ T cells contribute to lymphoproliferation in Epstein-Barr virus-associated infectious mononucleosis. 1997. Neefjes JJ. Cell. Inhibition of ubiquitin/ proteasome-dependent protein degradation by the Gly-Ala repeat domain of the Epstein-Barr virus nuclear antigen 1. Herpes simplex virus encephalitis in human UNC-93B deficiency. [PubMed: 20061127] 118. [PubMed: 17991806] 102. et al. 93:10990–5. Private specificities of CD8 T cell responses control patterns of heterologous immunity. et al. Riddell SR. 319:921–6. 2006. Identification of host proteins required for HIV infection through a functional genomic screen. [PubMed: 8756719] 110. [PubMed: 8187174] 119. 115:3602–12. Immunol Rev. Proc Natl Acad Sci U S A. Gilbert MJ. et al. Comprehensive analysis of human endogenous retrovirus transcriptional activity in human tissues with a retrovirus-specific microarray. The SEROCO Study Group. et al. 86:367–77. Casrouge A. Sharipo A. Cytomegalovirus selectively blocks antigen processing and presentation of its immediate-early gene product. Genetic determinants of HIV-1 infection and progression to AIDS: susceptibility to HIV infection. Human cytomegalovirus inhibits antigen presentation by a sequential multistep process. 2003. Wilkins C. Annu Rev Genet. 2006. 314:308–12. 14:123–31. Curr Opin Immunol. et al. Plachter B. 79:341–52. Fujinami RS. [PubMed: 16973841] 112. [PubMed: 19317737] 114. 226:29–40. de Vries JE. 2007. Hill AV. et al. 7:861–71. [PubMed: 8855296] 120. et al. Blood. Kim SK. Aspects of genetic susceptibility to human infectious diseases. Hubert JB. 40:469–86. 73(Pt B): 155–78. Nat Rev Microbiol. et al. [PubMed: 18617886] 107. Clute SC. [PubMed: 9430231] Nat Rev Immunol. Koppelman B. 5:555–63. Greenberg PD. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiplyexposed individuals to HIV-1 infection. [PubMed: 16308574] 103. Pathogenic epitopes. Tissue Antigens. Goulder PJ. 2005. [PubMed: 15596828] 116. Interleukin-10 down-regulates MHC class II alphabeta peptide complexes at the plasma membrane of monocytes by affecting arrival and recycling. 1996.

2001. Kieff E. Science. [PubMed: 14722312] 129. EMBO J. HLA and hepatitis B nfection. 2:110–5. available in PMC 2014 January 23. Bochud PY. A whole-genome association study of major determinants for host control of HIV-1. Ge D. J Virol. Aderem A. 2008. [PubMed: 16113477] 140. [PubMed: 9384576] 124. et al. Respiratory mucosal immunization with reovirus serotype 1/L stimulates virus-specific humoral and cellular immune responses. 317:944–7. 2007. Epstein-Barr virus-induced gene 3 and the p35 subunit of interleukin 12 form a novel heterodimeric hematopoietin. 196:505–9. [PubMed: 19759533] 136. 2009. J Infect Dis. 461:798–801. Cuff CF. 78:1582–90. et al. Holmes EC. Moskophidis D. OAS-1 and PKR. Cebra JJ.Rouse and Sehrawat Page 18 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript 123. 33:224–30. 73:7633–40. 1997. [PubMed: 12944978] 138. [PubMed: 17641165] 134. Co-localization of HIV-1 Nef with the AP-2 adaptor protein complex correlates with Nef-induced CD4 down-regulation. 1997. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Gao X. Polymorphisms in interferon-induced genes and the outcome of hepatitis C virus infection: roles of MxA. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. [PubMed: 17624834] 131. 2:e53. Influence of the route of infection on development of T-cell receptor beta-chain repertoires of reovirus-specific cytotoxic T lymphocytes. et al. including double-positive (CD4(+)/ CD8(+)) T cells. Smith J. et al. Lechner F. 344:1194–1195. Rothlin CV. Author manuscript. [PubMed: 9342359] 126. Nature. 2005. HLA class II genes determine the natural variance of hepatitis C viral load. 362:758–61. Koelle DM. 94:12041–6. Almarri AB JR. Proc Natl Acad Sci U S A. [PubMed: 19230159] 139. 461:399–401. 26 (Suppl 4):D45–8. J Virol. [PubMed: 10438854] 128. Hepatology. [PubMed: 7934542] 132. Magaret AS. Fanning LJ. [PubMed: 16789835] 130. Lemke G. Knapp S. Cunningham C. Pathogenesis of respiratory syncytial virus infection in the murine model. [PubMed: 8469287] 127. Nat Med. [PubMed: 18785840] 125. Birkenbach M. Wald A. Proc Am Thorac Soc. 1999. . Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. et al. 11:1290–2. 2008. 1994. Epidemiology of influenza. 2009. 8:327– 36. Nat Rev Immunol. Pircher H. Fellay J. Nature. Thomas DL. 1993. 2008. Le Goffic R. Detrimental contribution of the Toll-like receptor (TLR)3 to influenza A virusinduced acute pneumonia. 62:307–28. Genes Immun. [PubMed: 16288280] 133. Zinkernagel RM. Monto AS. 16:6964–76. Graham BS. AIDS restriction HLA allotypes target distinct intervals of HIV-1 pathogenesis. Peebles RS Jr. [PubMed: 19684573] 137. Nature. Evolutionary history and phylogeography of human viruses. [PubMed: 18421305] Nat Rev Immunol. 2007. Lancet. PLoS Pathog. [PubMed: 11124840] 135. 2003. et al. Periwal SB. 2005. Annu Rev Microbiol. Devergne O. Fulton JR. et al. 2006. Polymorphisms in TLR2 are associated with increased viral shedding and lesional rate in patients with genital herpes simplex virus Type 2 infection. Vaccine. 4:411–9. Immunobiology of the TAM receptors. Greenberg ME. et al. 2004.

different type of T helper (Th) cell responses are induced. which form immune complexes that are deposited in certain tissues such as glomeruli of kidneys and blood vessels to cause immune complex (IC) disease. . Innate cells recognize viral replication intermediates and secrete pro-inflammatory cytokines. Th cells after migrating to the site of infection also contribute to the tissue damage. Cytopathic virus kills infected cells from which cellular contents including proteases and lysosomal enzymes are released which digest the matrix and create an inflammatory milieu. In conditions where the control of aggressive Th cells and CD8+ T cells by regulatory T (Treg) cells is impaired and other inhibitory pathways fail to curtail them. Viral antigens are taken up by antigen-presenting cells (APCs) and carried to local draining lymph nodes (LNs). tissue damage is the main consequence of viral infection. which in addition to helping clear the virus contributes to tissue damage. Neutrophils attracted early after infection release inflammatory mediators. Author manuscript.Rouse and Sehrawat Page 19 NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 1. available in PMC 2014 January 23. thereby contributing to tissue damage. Regulatory cytokines are shown in green. Depending on the cytokine milieu created in the draining LN. Th cells also provide help to B cells to secrete antibodies (Abs). Primed CD8+ T cells migrate to the site of infection and kill virally infected cells. Nat Rev Immunol. Immunity or tissue damage following viral infection NIH-PA Author Manuscript Virus (cytopathic or non-cytopathic) upon entry into the host replicates at the tissue site.

2 respectively deliver inhibitory signals to the effector cells and control their inflammatory activity and subsequent tissue damage. Inadequate control (shown by dashed lines) exerted by these pathways under some circumstances results in uncontrolled T cell activation and proliferation causing excessive tissue damage. Question marks (?) are typed next to the receptor pair interaction where in vivo extensive studies have not been performed.1/7. Inhibitory mechanisms to limit tissue damage caused by T cells Effector T cells upregulate inhibitory receptors such as PD1. LAG3. available in PMC 2014 January 23. TIM3. . CTLA4 and others such as adenosine receptors (not shown) on their surface. Author manuscript. galectin-9 and MHC class II and B7. Nat Rev Immunol. activated TReg cells specialized innate cells or highly polarized plastic effector cells that can make anti-inflammatory cytokines inhibit effector cell responses (shown by thick lines). Ligation of these receptors to PDL1.Rouse and Sehrawat Page 20 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 2. Additionally.

Abbreviations used: IRAK-M. Inflammatory and anti-inflammatory mechanism induced after viral infection are enlisted. CTLA-4. which resides in the host either as an subclinical infection. B. . A simplified representation of how the balance between immunity and immunopathology following viral infection may depend upon the balance of anti. Nod like receptor X1. It can be either viral clearance or immunity to re-infection. ring finger containing domain125. Author manuscript. NLRX1. IL-1R associated kinase-restricted to monocytes/ macrophages. NIH-PA Author Manuscript Nat Rev Immunol. DUBA. Balance between pro-inflammatory and anti-inflammatory mechanisms may decide the outcome viral infection NIH-PA Author Manuscript A. viral clearance with excessive tissue damage or persistence of the pathogen.Rouse and Sehrawat Page 21 NIH-PA Author Manuscript Figure 3. RNF125. Cytotoxic T cell lymphocyte antigen-4. Deubiquitinase enzyme A. an opportunist or tissue damaging agent. available in PMC 2014 January 23.and proinflammatory mechanisms.

EBI3 protein related to p40 subunit of IL-23and IL-27 122. HIV and influenza virus Escape removal by antibodies and CTLs and emergence of variants 124 Viral homologues of host regulatory proteins CMV CMV IL-10-like protein competes with host IL-10 for binding IL-10 receptor 25 EBV IL-10 homologue. pp65 prevents activation of IRF3 119.Rouse and Sehrawat Page 22 Table 1 Virus and host features that favour tissue damage NIH-PA Author Manuscript Feature NIH-PA Author Manuscript Virus Effect on host Refs HCV Blocks RIG-I pathway by degrading IPS1 117 Influenza A virus NS1 protein inhibits RIG-I by direct interaction Paramyxovirus V protein inhibits RIG-I by interacting with MDA5 HIV and human Herpesviru Inhibit IRF3 Hantaan virus. US6 blocks TAP-mediated peptide transport.122 HIV Nef protein inhibits cell surface expression of CD4 and MHC class I molecules 123 Infidel replication machinery and variants HCV. CCHFV and Borna disease virus Viral RNA is undetectable by PRRs owing to removal of 5′ triphosphates HSV ICP47 blocks TAP-mediated peptide transport 118 CMV US3 inhibits tapasin. Author manuscript.112 HSV-1 and VZV Increased encephalitis 74.120 EBV EBNA1 inhibits the proteasome.112 WNV Decreased encephalitis 94 Influenza virus Decreased acute pneumonia 129 HSV-2 Increased genital lesions and viral shedding 130 Viral evasion strategies Interference with innate immune responses Interference with antigen processing and presentation Dose of infection* High Low Route or location of infection NIH-PA Author Manuscript Host genetic susceptibility Defective type I and II IFNs TLR3 polymorphism or Deficiency TLR2 polymorphism Nat Rev Immunol. gp40 retains MHC class I molecules in ER. IL-10 homologue downregulates MHC class II expression 121. . available in PMC 2014 January 23.125 HBV Immunopathology of the liver 92 Influenza virus Inadequate CD8+ T cell response 91 LCMV Induces CTL exhaustion 126 HBV Immunopathology of the liver 92 LCMV Choriomeningitis 98 Intratracheal Reovirus Virus-specific IgA and double-positive (CD4+CD8+) T cell responses 127 Oral versus footpad Reovirus Restricted CD8+ T cell repertoire induced by oral infection 128 Intracranial versus Intravenous LCMV CD8+ T cell-mediated lethal choriomeningitis occurs on intracranial infection and viral persistence occurs on intravenous infection 98 Poliovirus Increased susceptibility to paralysis 71 HSV and VZV Increased susceptibility to encephalitis 74.

respiratory syncytial virus. dengue haemorrhagic fever. varicella zoster virus. EBNA1. CTL. GG genotype in 3′ UTR of OAS1 and CT genotype at −168 of PKR give rise to selflimiting disease 135. TT genotype associated with persistent infection and poor response to treatment 135. herpes simplex virus.139 Adult EBV. IPS1. IFNB-promoter stimulator 1. TLR. WNV. PRR. lymphocytic choriomeningitis virus. EBI3. ICP47. CMV. hepatitis B virus. VZV. Nef. infected cell protein 47.Rouse and Sehrawat Page 23 NIH-PA Author Manuscript Feature Virus Effect on host Refs HLA-DR7 versus HLA-DR2 HBV Chronic carrier versus viral clearance 131 CCR5Δ32bp HIV Resistance to macrophage-infecting virus 109 HLA-B35 versus HLA-B57 HIV Rapid versus delayed progression to AIDS 132 HLA complex P5 rs2395029 HIV TT versus GG genotype: high versus lower viral load at set point 133 HLA-C 5′ region 9264942 HIV TT versus CC genotype: high versus lower viral load at set point 133 HLA-DQB1*031 and HLA-DRB1*11 HCV Spontaneous resolution 134 IL-28B polymorphism HCV CC genotype associated with spontaneous resolution and response to treatment. HBV. Crimean-Congo haemorrhagic fever virus. CC-chemokine receptor 5. CMV. Toll-like receptor. measles virus and mumps virus Increased susceptibility to infection 72. available in PMC 2014 January 23. untranslated region. Author manuscript. dengue shock syndrome. IRF3. protein kinase R. negative factor. HSV. hepatitis C virus. simian immunodeficiency virus89 and HCV12 has no effect on the host response. interferon-regulatory factor 3. CCR5. 0AS1 and PKR Polymorphisms Age when infected NIH-PA Author Manuscript Prior infection CCHFV. EBV.138 EBV Influenza virus Increased susceptibility to infection as immune responses to M protein cross-react with BMLF1 of EBV 102 Flaviviruses Dengue virus DHF or DSS 100 MXA. RSV. EBV-induced gene 3. transporter associated with antigen processing. . LCMV. RSV and influenza virus Increased susceptibility to infection 81. 2′5′ oligoadenylate synthetase 1. HCV. interleukin. pattern recognition receptor. UTR. Epstein-Barr virus nuclear antigen 1. choriomeningitis virus. West Nile virus. IFN. retinoic acid-inducible gene I. TAP. OAS1. ER. NIH-PA Author Manuscript Nat Rev Immunol.101 Old VZV.136 HCV TT genotype at −88 in MXA. endoplasmic reticulum.136 Young Influenza virus and RSV Increased susceptibility to infection (in RSV because of inadequate type 1 immune response 138. PKR. MXA. * Dose of infection with lentiviruses88. VZV. RIG-I. DSS. IL. interferon. cytotoxic T lymphocyte. melanoma differentiation-associated gene 5. MDA5. DHF. Epstein-Barr virus. myxoma resistance protein A.