Effector CD4<sup>+</sup>T-Cell Involvement in Clearance of Infectious Herpes Simplex Virus Type 1 from Sensory Ganglia and Spinal Cords

Johnson, Alison J.; Chu, Chin Fun; Milligan, Gregg N.

doi:10.1128/jvi.01159-08

Cited by 58 publications

(51 citation statements)

References 69 publications

(81 reference statements)

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“…The role of CD4 ϩ T cells in VZV replication in human ganglia remains to be determined, but CD4 ϩ T cells are important in clearing ganglia infected by other neurotropic viruses (30,61,63). We also detected NK cells, B cells, and macrophages, but not dendritic cells.…”

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confidence: 74%

Characterization of the Host Immune Response in Human Ganglia after Herpes Zoster

Gowrishankar

Steain

Cunningham

et al. 2010

J Virol

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Varicella-zoster virus (VZV) causes varicella (chicken pox) and establishes latency in ganglia, from where it reactivates to cause herpes zoster (shingles), which is often followed by postherpetic neuralgia (PHN), causing severe neuropathic pain that can last for years after the rash. Despite the major impact of herpes zoster and PHN on quality of life, the nature and kinetics of the virus-immune cell interactions that result in ganglion damage have not been defined. We obtained rare material consisting of seven sensory ganglia from three donors who had suffered from herpes zoster between 1 and 4.5 months before death but who had not died from herpes zoster. We performed immunostaining to investigate the site of VZV infection and to phenotype immune cells in these ganglia. VZV antigen was localized almost exclusively to neurons, and in at least one case it persisted long after resolution of the rash. The large immune infiltrate consisted of noncytolytic CD8؉ T cells, with lesser numbers of CD4 ؉ T cells, B cells, NK cells, and macrophages and no dendritic cells. VZV antigen-positive neurons did not express detectable major histocompatibility complex (MHC) class I, nor did CD8 ؉ T cells surround infected neurons, suggesting that mechanisms of immune control may not be dependent on direct contact. This is the first report defining the nature of the immune response in ganglia following herpes zoster and provides evidence for persistence of non-latency-associated viral antigen and inflammation beyond rash resolution.Varicella-zoster virus (VZV) is a highly species-specific human alphaherpesvirus that infects a majority of the world's population. VZV causes two clinically significant diseases; varicella (chicken pox) and herpes zoster (shingles) (5,8,19). Varicella is characterized by widespread cutaneous vesicular lesions and is a consequence of primary VZV infection in VZV-naïve individuals. While varicella is a relatively mild disease in immunocompetent children, it can cause significant morbidity in healthy adults and is frequently life threatening in immunocompromised individuals (3,4,22). The innate and adaptive immune responses act to eliminate replicating virus during varicella, but not all virus is cleared during this time, with some presumed to access nerve axons in the skin, enabling transport to neurons in sensory ganglia, where the virus is able to establish a lifelong latent infection (5,8,12,13,20,32). An alternative possibility is that virus is transported to ganglia via hematogenous spread (36). The ability of VZV to establish latency in the host is critical to the success of this virus as a human pathogen.VZV reactivation from latency (herpes zoster) causes serious disease in older and immunocompromised individuals and is characterized by vesicular skin rash in a dermatomal distribution with preceding and concomitant pain (7,10,21,68). During reactivation, sensory ganglia are sites of viral replication, where an intense inflammatory response is induced and widespread necrosis of glial cells and neur...

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confidence: 74%

Characterization of the Host Immune Response in Human Ganglia after Herpes Zoster

Gowrishankar

Steain

Cunningham

et al. 2010

J Virol

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“…ϩ T cells were shown to be critically important for virus clearance from sensory neurons of HSV-1-infected mice (28). To assess the activation of CD4 ϩ and CD8 ϩ T cells, we used purified gC-2 and gD-2 antigen.…”

Section: Discussionmentioning

confidence: 99%

Immunization with a Vaccine Combining Herpes Simplex Virus 2 (HSV-2) Glycoprotein C (gC) and gD Subunits Improves the Protection of Dorsal Root Ganglia in Mice and Reduces the Frequency of Recurrent Vaginal Shedding of HSV-2 DNA in Guinea Pigs Compared to Immunization with gD Alone

Awasthi

Lubinski

Shaw

et al. 2011

J Virol

115

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Attempts to develop a vaccine to prevent genital herpes simplex virus 2 (HSV-2) disease have been only marginally successful, suggesting that novel strategies are needed. Immunization with HSV-2 glycoprotein C (gC-2) and gD-2 was evaluated in mice and guinea pigs to determine whether adding gC-2 to a gD-2 subunit vaccine would improve protection by producing antibodies that block gC-2 immune evasion from complement. Antibodies produced by gC-2 immunization blocked the interaction between gC-2 and complement C3b, and passive transfer of gC-2 antibody protected complement-intact mice but not C3 knockout mice against HSV-2 challenge, indicating that gC-2 antibody is effective, at least in part, because it prevents HSV-2 evasion from complement. Immunization with gC-2 also produced neutralizing antibodies that were active in the absence of complement; however, the neutralizing titers were higher when complement was present, with the highest titers in animals immunized with both antigens. Animals immunized with the gC-2-plus-gD-2 combination had robust CD4؉ T-cell responses to each immunogen. Multiple disease parameters were evaluated in mice and guinea pigs immunized with gC-2 alone, gD-2 alone, or both antigens. In general, gD-2 outperformed gC-2; however, the gC-2-plus-gD-2 combination outperformed gD-2 alone, particularly in protecting dorsal root ganglia in mice and reducing recurrent vaginal shedding of HSV-2 DNA in guinea pigs. Therefore, the gC-2 subunit antigen enhances a gD-2 subunit vaccine by stimulating a CD4 ؉ T-cell response, by producing neutralizing antibodies that are effective in the absence and presence of complement, and by blocking immune evasion domains that inhibit complement activation.

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“…Despite the prominent roles of cytotoxic CD8 + T cells and neutralizing antibodies in controlling viral infections, there is growing evidence for an antiviral role of CD4 + helper T cells, not only in provision of help to other effector cells, but also in exertion of direct antiviral functions either by secretion of cytokines or exertion of cytotoxicity [1]. CD4 + T-cell-mediated protective immunity has been reported Correspondence: Prof. Annette Oxenius e-mail: oxenius@micro.biol.ethz.ch for a number of viral infections [2][3][4][5]; however, the antiviral effector mechanisms exerted by CD4 + T cells in vivo have remained poorly characterized.Cytomegalovirus (CMV) is a β-herpes virus that infects a majority of the human population worldwide. After resolution of primary infection, this large DNA β-herpes virus establishes a life-long persistence in its host.…”

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Adoptive transfer of cytomegalovirus‐specific effector CD4⁺T cells provides antiviral protection from murine CMV infection

et al. 2013

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Cytomegalovirus (CMV) infects a majority of the human population and establishes a lifelong persistence. CMV infection is usually asymptomatic but the virus carries pathogenic potential and causes severe disease in immunocompromised individuals. T-cell-mediated immunity plays an essential role in control of CMV infection and adoptive transfer of CMVspecific CD8 + T cells restores viral immunity in immunosuppressed patients but a role for CD4 + T cells remains elusive. Here, we analyzed in adoptive transfer studies the features and antiviral functions of virus-specific CD4 + T cells during primary murine CMV (MCMV) infection. MCMV-specific CD4 + T cells expanded upon MCMV infection and displayed an effector phenotype and function. Adoptive transfer of in vivo activated MCMV-specific CD4 + T cells to immune-compromised mice was protective during pathogenic MCMVinfection and IFN-γ was a crucial mediator of this protective capacity. Moreover, cotransfer of low doses of both MCMV-specific CD4 + T cells and CD8 + T cells synergized in control of lytic viral replication in immune-compromised mice. Our data reveal a pivotal antiviral role for virus-specific CD4 + T cells in protection from pathogenic CMV infection and provide evidence for their antiviral therapeutic potential. Keywords: Adoptive immunotherapy r CD4 + T cells r Cytomegalovirus infectionAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionImmunity to viral infections relies on effector mechanisms exerted by different components of the immune system. Despite the prominent roles of cytotoxic CD8 + T cells and neutralizing antibodies in controlling viral infections, there is growing evidence for an antiviral role of CD4 + helper T cells, not only in provision of help to other effector cells, but also in exertion of direct antiviral functions either by secretion of cytokines or exertion of cytotoxicity [1]. CD4 + T-cell-mediated protective immunity has been reported Correspondence: Prof. Annette Oxenius e-mail: oxenius@micro.biol.ethz.ch for a number of viral infections [2][3][4][5]; however, the antiviral effector mechanisms exerted by CD4 + T cells in vivo have remained poorly characterized.Cytomegalovirus (CMV) is a β-herpes virus that infects a majority of the human population worldwide. After resolution of primary infection, this large DNA β-herpes virus establishes a life-long persistence in its host. CMV infection is usually clinically silent in healthy individuals. Nevertheless, CMV-infected immunosuppressed patients, such as hematopoietic BM or solid organ transplant recipients, suffer from CMV disease with potentially * These authors have contributed equally to this work.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 2886-2895 Immunity to Infection 2887 severe clinical outcome [6]. Cellular immunity is important to control CMV infection [7,8] Results Expansion, activation, and phenotype of M25-specific CD4 + T cells during acute ...

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Effector CD4⁺T-Cell Involvement in Clearance of Infectious Herpes Simplex Virus Type 1 from Sensory Ganglia and Spinal Cords

Cited by 58 publications

References 69 publications

Characterization of the Host Immune Response in Human Ganglia after Herpes Zoster

Characterization of the Host Immune Response in Human Ganglia after Herpes Zoster

Immunization with a Vaccine Combining Herpes Simplex Virus 2 (HSV-2) Glycoprotein C (gC) and gD Subunits Improves the Protection of Dorsal Root Ganglia in Mice and Reduces the Frequency of Recurrent Vaginal Shedding of HSV-2 DNA in Guinea Pigs Compared to Immunization with gD Alone

Adoptive transfer of cytomegalovirus‐specific effector CD4⁺T cells provides antiviral protection from murine CMV infection

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Effector CD4+T-Cell Involvement in Clearance of Infectious Herpes Simplex Virus Type 1 from Sensory Ganglia and Spinal Cords

Cited by 58 publications

References 69 publications

Characterization of the Host Immune Response in Human Ganglia after Herpes Zoster

Characterization of the Host Immune Response in Human Ganglia after Herpes Zoster

Immunization with a Vaccine Combining Herpes Simplex Virus 2 (HSV-2) Glycoprotein C (gC) and gD Subunits Improves the Protection of Dorsal Root Ganglia in Mice and Reduces the Frequency of Recurrent Vaginal Shedding of HSV-2 DNA in Guinea Pigs Compared to Immunization with gD Alone

Adoptive transfer of cytomegalovirus‐specific effector CD4+T cells provides antiviral protection from murine CMV infection

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Effector CD4⁺T-Cell Involvement in Clearance of Infectious Herpes Simplex Virus Type 1 from Sensory Ganglia and Spinal Cords

Adoptive transfer of cytomegalovirus‐specific effector CD4⁺T cells provides antiviral protection from murine CMV infection