Immunity to latent viral infection: many skirmishes but few fatalities

Khanna, Kamal M.; Lepisto, Andrew J.; Hendricks, Robert L.

doi:10.1016/j.it.2004.02.010

Cited by 54 publications

(39 citation statements)

References 38 publications

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“…When these reactivating cells are discovered by the CD8 ϩ T cells, we propose that the reactivation will be inhibited or the cell will be killed by the activated CD8 ϩ T cells before it is able to replicate its DNA and produce new infectious virions. This would be similar to what has been proposed for the control of latent HSV-1 infection in the sensory ganglions, although the effector mechanism may be different as sensory ganglions do not appear to be lost during longterm latent HSV infection (52,53).…”

Section: Discussionsupporting

confidence: 82%

“…It is possible that the latently infected cells are undergoing more spontaneous reactivation, but this process is stopped by the T cell response before the production of infectious virus. This would be analogous to what is believed to be occurring in the ganglion of mice latently infected with HSV-1, where gB-specific CD8 ϩ T cells are constantly activated and prevent the production of new HSV-1 virions (52,53). In our system, we used quantitative RT-PCR to examine the production of viral transcripts and found that IL-15 Ϫ/Ϫ mice indeed had higher levels of the viral transcripts, suggesting more Ag was present.…”

Section: Discussionmentioning

confidence: 60%

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IL-15-Independent Proliferative Renewal of Memory CD8+ T Cells in Latent Gammaherpesvirus Infection

Obar

Crist

Leung

et al. 2004

The Journal of Immunology

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IL-15 is known to be critical in the homeostasis of Ag-specific memory CD8+ T cells following acute viral infection. However, little is known about the homeostatic requirements of memory CD8+ T cells during a latent viral infection. We have used the murine gammaherpesvirus-68 (MHV-68) model system to investigate whether IL-15 is necessary for the maintenance of memory CD8+ T cells during a latent viral infection. IL-15 is not essential either for the initial control of MHV-68 infection or for the maintenance of MHV-68-specific memory CD8+ T cells. Even at 140 days postinfection, the proportion of CD8+ T cells recognizing the MHV-68 epitopes were the same as in control mice. The maintenance of these memory CD8+ T cells was attributable to their ability to turn over in vivo, probably in response to the presence of low levels of Ag. IL-15−/− mice had a significantly higher turnover rate within the virus-specific memory CD8+ T cell population, which was the result of increased levels of viral gene expression rather than an increase in viral load. These cells did not accumulate in the spleens of the IL-15−/− mice due to an increased sensitivity to apoptosis as a result of decreased Bcl-2 levels. Intriguingly, memory CD8+ T cells from latently infected mice failed to undergo homeostatic proliferation in a naive secondary host. These data highlight fundamental differences between memory CD8+ T cells engaged in active immune surveillance of latent viral infections vs memory CD8+ T cells found after acute viral infections.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 60%

IL-15-Independent Proliferative Renewal of Memory CD8+ T Cells in Latent Gammaherpesvirus Infection

Obar

Crist

Leung

et al. 2004

The Journal of Immunology

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“…For example, certain vaccines or delivery methods might produce anti-HSV T lymphocytes that can promote or maintain latency in seropositive individuals by controlling virus reactivation in neurons (30). However, these T cells might also exacerbate corneal disease, especially if virus that persists in the cornea becomes a target for enhanced immunity.…”

Section: Resultsmentioning

confidence: 99%

Herpes keratitis in the absence of anterograde transport of virus from sensory ganglia to the cornea

Polcicova

Biswas

Banerjee

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Herpes stromal keratitis is an immunopathologic disease in the corneal stroma leading to scarring, opacity, and blindness, and it is an important problem in common corneal surgeries. Paradoxically, virus antigens are largely focused in the epithelial layer of the cornea and not in the stromal layer, and viral antigens are eliminated before stromal inflammation develops. It is not clear what drives inflammation, whether viral antigens are necessary, or how viral antigens reach the stroma. It has been proposed that herpes simplex virus (HSV) travels from the corneal epithelium to sensory ganglia then returns to the stroma to cause disease. However, there is also evidence of HSV DNA and infectious virus persistent in corneas, and HSV can be transmitted to transplant recipients. To determine whether HSV resident in the cornea could cause herpes stromal keratitis, we constructed an HSV US9 ؊ mutant that had diminished capacity to move in neuronal axons. US9 ؊ HSV replicated and spread normally in the mouse corneal epithelium and to the trigeminal ganglia. However, US9 ؊ HSV was unable to return from ganglia to the cornea and failed to cause periocular skin disease, which requires zosteriform spread from neurons. Nevertheless, US9 ؊ HSV caused keratitis. Therefore, herpes keratitis can occur without anterograde transport from ganglia to the cornea, probably mediated by virus persistent in the cornea. ocular infection ͉ stroma ͉ neurons ͉ US9 cell-to-cell spread ͉ persistent herpes simplex virus

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“…3b. Thus, Qa-1 b -CD94-NKG2a inhibitory signaling was more effective in the presence of fewer viral Ags, a situation that presumably occurs in the latent TG (28). This could be a major regulatory pathway to inhibit the cytotoxicity of CD8 ϩ T cells in the latent TG, where Ag doses will be low, but presumably not in the acutely inflamed TG, where replicating virus and abundant Ag are still present (28).…”

Section: Discussionmentioning

confidence: 98%

Qa-1b and CD94-NKG2a Interaction Regulate Cytolytic Activity of Herpes Simplex Virus-Specific Memory CD8+ T Cells in the Latently Infected Trigeminal Ganglia

Suvas

Azkur

Rouse

2006

The Journal of Immunology

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After ocular infection, HSV-specific CD8+ T cells migrate to and are specifically retained in the ophthalmic branch of the trigeminal ganglia (TG) even at the time when replicating virus is no longer evident. Virus-specific CD8+ T cells maintain an activation phenotype and secrete IFN-γ in the latent TG. In this report we demonstrated that activated virus-specific memory CD8+ T cells, although potentially cytolytic, also expressed the CD94-NK cell receptor subfamily G2a inhibitory molecule and were unable to exert cytotoxicity when engaged by Qa-1b expressing targets. Interestingly, many neurons in the latent TG expressed Qa-1b, and blocking of Qa-1b/CD94-NKG2a interaction in an ex vivo TG culture resulted in neuronal cell lysis. The expression of the inhibitory CD94-NKG2a molecule could be induced by TGF-β1, which was shown to present as a bioactive molecule in the latent TG. Additionally, CD4+ forkhead/winged helix transcription factor 3+ T cells were also determined in the latent TG. Our results demonstrate the operation of a regulatory system in vivo that serves to protect irreplaceable neurons from destruction by the immune system.

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Immunity to latent viral infection: many skirmishes but few fatalities

Cited by 54 publications

References 38 publications

IL-15-Independent Proliferative Renewal of Memory CD8+ T Cells in Latent Gammaherpesvirus Infection

IL-15-Independent Proliferative Renewal of Memory CD8+ T Cells in Latent Gammaherpesvirus Infection

Herpes keratitis in the absence of anterograde transport of virus from sensory ganglia to the cornea

Qa-1b and CD94-NKG2a Interaction Regulate Cytolytic Activity of Herpes Simplex Virus-Specific Memory CD8+ T Cells in the Latently Infected Trigeminal Ganglia

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