Gamma Interferon Impedes the Establishment of Herpes Simplex Virus Type 1 Latent Infection but Has No Impact on Its Maintenance or Reactivation in Mice

Lekstrom-Himes, Julie; LeBlanc, Rona A.; Pesnicak, Lesley; Godleski, Matthew; Straus, Stephen E.

doi:10.1128/jvi.74.14.6680-6683.2000

Cited by 36 publications

(28 citation statements)

References 28 publications

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“…To our knowledge, this is the first direct demonstration that IFN-␥ can block HSV-1 reactivation from latency in neurons. In vivo studies comparing wild-type and IFN-␥ knockout (GKO) mice on a BALB/c background demonstrated more rapid reactivation of HSV-1 from latency following induction by hyperthermic stress (3) or UV-B corneal irradiation (14) in GKO mice. In the former study the overall incidence of reactivation was also increased in IFN-␥-deficient mice, whereas this difference was not observed in the latter study.…”

Section: Discussionmentioning

confidence: 99%

Gamma Interferon Can Prevent Herpes Simplex Virus Type 1 Reactivation from Latency in Sensory Neurons

Liu

Khanna

Carriere

et al. 2001

J Virol

214

177

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We recently demonstrated that CD8؉ T cells could block herpes simplex virus type 1 (HSV-1) reactivation from latency in ex vivo trigeminal ganglion (TG) cultures without destroying the infected neurons. Here we establish that CD8؉ T-cell prevention of HSV-1 reactivation from latency is mediated at least in part by gamma interferon (IFN-␥). We demonstrate that IFN-␥ was produced in ex vivo cultures of dissociated latently infected TG by CD8 ؉ T cells that were present in the TG at the time of excision. Depletion of CD8 ؉ T cells or neutralization of IFN-␥ significantly enhanced the rate of HSV-1 reactivation from latency in TG cultures. When TG cultures were treated with acyclovir for 4 days to insure uniform latency, supplementation with recombinant IFN-␥ blocked HSV-1 reactivation in 80% of cultures when endogenous CD8 ؉ T cells were present and significantly reduced and delayed HSV-1 reactivation when CD8 ؉ T cells or CD45 ؉ cells were depleted from the TG cultures. The effectiveness of recombinant IFN-␥ in blocking HSV-1 reactivation was lost when its addition to TG cultures was delayed by more than 24 h after acyclovir removal. We propose that when the intrinsic ability of neurons to inhibit HSV-1 gene expression is compromised, HSV-specific CD8 ؉ T cells are rapidly mobilized to produce IFN-␥ and perhaps other antiviral cytokines that block the viral replication cycle and maintain the viral genome in a latent state.Following primary infection of epithelial surfaces, herpes simplex virus type 1 (HSV-1) gains access to the termini of sensory neurons, is transported in a retrograde direction to the neuron cell bodies in sensory ganglia, replicates, spreads to other neurons, and establishes a lifelong latent infection in a portion of the neurons. Recurrent HSV-1 disease results from reactivation of latent HSV-1 in sensory neurons followed by anterograde axonal transport to epithelial or epidermal surfaces. Therefore, treatments that block reactivation of HSV-1 from latency could effectively prevent recurrent disease in the face of latent infection. The long-term retention of CD8 ϩ T cells and production of the cytokine gamma interferon (IFN-␥) in the latently infected trigeminal ganglion (TG) suggest a possible role for the immune system in controlling HSV-1 reactivation from latency (4,10,16,20).Ganglionic latency is classically defined as retention of HSV-1 genomes in neurons in the absence of virion production. The definition of latency at the molecular level is currently evolving. Clearly, a family of transcripts called latencyassociated transcripts is produced in abundance in at least a portion of latently infected neurons (6, 7). In addition, transcripts for the HSV-1 ␣ (immediate-early) gene, infected cell protein 4 (ICP4), and ␤ (early) gene thymidine kinase were detected in low abundance in latently infected murine sensory ganglia (13). Most studies have failed to detect latency-associated transcript translation products, and the production of any viral proteins in latently infected neurons is currentl...

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Section: Discussionmentioning

confidence: 99%

Gamma Interferon Can Prevent Herpes Simplex Virus Type 1 Reactivation from Latency in Sensory Neurons

Liu

Khanna

Carriere

et al. 2001

J Virol

214

177

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“…Although PMNs are one of the initial cells that traffic to the cornea [3], CD4 + and CD8 + T lymphocytes are thought to be key components in the development of lesions associated with herpetic stromal keratitis [4][5][6][7]. Th2 cytokines exacerbate HSV-1 infection whereas Th1 cytokines are principally produced by those cells infiltrating the infected tissue and contribute towards resistance to virus replication and spread [8][9][10]. Chemokines expressed locally are likely involved in the recruitment of leukocytes into the site of infection with CCL2 and CXCL10 expressed or up-regulated significantly within the first 36 hr post infection relative to other chemokines including CCL3, CCL5, CXCL1, and CXCL9 [11].…”

Section: Introductionmentioning

confidence: 99%

CD4+ T cell migration into the cornea is reduced in CXCL9 deficient but not CXCL10 deficient mice following herpes simplex virus type 1 infection

Wuest

Farber

Luster

et al. 2006

Cellular Immunology

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The role of CXCL9 and CXCL10 in the ocular immune response to herpes simplex virus type 1 (HSV-1) infection was investigated using mice deficient in either CXCL9 or CXCL10. CXCL10 but not CXCL9 deficient mice showed an increase in sensitivity to ocular virus infection as measured by an elevation in virus titer recovered in the tear film and corneal tissue. The increase in virus was associated with an increase in the expression of the chemokine CCL2 but no significant change in the infiltration of CD4 + T cells or NK cells into the corneal stroma. In contrast, a significant reduction in CD4 + T cell infiltration into the cornea was found in CXCL9 deficient mice following HSV-1 infection consistent with the absence of CXCL9 expression and reduction in expression of other chemokines including CCL3, CCL5, CXCL1, and CXCL10. Collectively, the results suggest a nonredundant role for CXCL9 and CXCL10 in response to ocular HSV-1 infection in terms of controlling virus replication and recruitment of CD4 + T cells into the cornea.

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“…"True" latent HSV-1 infections in humans and in animal models, including mice, have been extensively studied, and the need for immune cells and cytokines-in particular IFN-␥-was postulated (6,12,13,27,31,45,49). Latent HSV-1 infections have three separable phases: establishment, maintenance, and reactivation.…”

Section: Nk Cells or Mature T And B Cells Are Not Required To Resist mentioning

confidence: 99%

Interplay between Alpha/Beta and Gamma Interferons with B, T, and Natural Killer Cells in the Defense against Herpes Simplex Virus Type 1

Vollstedt

Arnold

Schwerdel

et al. 2004

J Virol

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The essential components of the immune system that control primary and chronic infection with herpes simplex virus type 1 (HSV-1) in mice were investigated. Infection within the first few days can be controlled by alpha/beta interferon (IFN-␣/␤) alone without significant contribution of B, T, or NK cells. IFN-␣/␤ and IFN-␥ cooperate in the elimination of virus in the absence of these lymphocytes. In contrast, B, T, or NK cells appear to be required to control persistent infection with HSV-1. These results suggest that distinct and essential immune elements are recruited in a time-dependent fashion to control acute and persistent HSV-1 infection.

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Gamma Interferon Impedes the Establishment of Herpes Simplex Virus Type 1 Latent Infection but Has No Impact on Its Maintenance or Reactivation in Mice

Abstract: Murine models of gamma interferon (IFN-␥

Cited by 36 publications

References 28 publications

Gamma Interferon Can Prevent Herpes Simplex Virus Type 1 Reactivation from Latency in Sensory Neurons

Gamma Interferon Can Prevent Herpes Simplex Virus Type 1 Reactivation from Latency in Sensory Neurons

CD4+ T cell migration into the cornea is reduced in CXCL9 deficient but not CXCL10 deficient mice following herpes simplex virus type 1 infection

Interplay between Alpha/Beta and Gamma Interferons with B, T, and Natural Killer Cells in the Defense against Herpes Simplex Virus Type 1

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