Intracellular Reovirus Survives Cytotoxic T Lymphocyte-mediated Lysis of its Host Cell

Howell, Donna; Martz, Eric

doi:10.1099/0022-1317-68-11-2899

Cited by 14 publications

(7 citation statements)

References 36 publications

(22 reference statements)

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“…First, killing of infected cells does not always lead to the elimination of infectious viruses. For example, both intracellular fully formed reovirus and Hepatitis B Viruses have been shown to survive the destruction of the infected cells by exposure to CTLs (57,58). Conversely, a decrease in viral replication can occur without killing infected cells.…”

Section: Discussionmentioning

confidence: 96%

Herpes Simplex Virus GenesUs3,Us5, andUs12Differentially Regulate Cytotoxic T Lymphocyte-Induced Cytotoxicity

2006

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Many viruses, including Herpes Simplex Virus (HSV), have developed strategies to avoid detection by cytotoxic T lymphocytes (CTLs). In this article, we evaluated the role of individual HSV-1 genes in preventing cytolysis and apoptosis, and in decreasing viral yield after CTL exposure of HSV-infected fibroblasts, using viruses deleted for the immune evasion gene Us12 or one of the two antiapoptotic genes Us3 and Us5. To evaluate CTL-mediated apoptosis, we used a flow cytometry assay measuring active caspase-3 in target cells. This assay was more sensitive than the chromium release assay used to evaluate cytolysis, and measured a different aspect of CTL cytotoxicity. Although virus with deletion of Us12 was markedly defective in the ability to prevent lysis of target fibroblasts, it retained most of its ability to protect target fibroblasts from CTL-induced apoptosis. Virus with deletion of Us3 was also defective in the ability to prevent lysis of target fibroblasts, yet such virus protected target fibroblasts from CTL-induced apoptosis as well as wild-type viruses. In contrast, Us5-deleted virus showed defects in the ability to protect target fibroblasts from both cytolysis and apoptosis after CTL attack. In addition, the replication of Us12-deleted virus was reduced compared with wild-type virus in fibroblasts subjected to CTL attack 6 h after infection, but showed equivalent replication when CTL attack occurred later. In contrast, Us3- or Us5-deleted virus showed no measurable defect in their ability to replicate in fibroblasts under CTL attack. Our data suggest that cytolysis, apoptosis, and viral yield do not necessarily correlate in infected cells under CTL attack. Furthermore, the Us3, Us5, and Us12 viral genes each have unique inhibitory effects on the different T lymphocyte cytotoxic effects. Taken together, these results suggest that HSV evasion of cellular immunity is multifacterial and complex, and relies on the partially redundant activities of various individual HSV proteins.

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Section: Discussionmentioning

confidence: 96%

Herpes Simplex Virus GenesUs3,Us5, andUs12Differentially Regulate Cytotoxic T Lymphocyte-Induced Cytotoxicity

2006

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“…IL 2 has been shown to enhance the expression of cytoplasmic granules [22] The conventional concept that CTL reduce the yield of virus by lysing infected cells in situ before intact virus can be assembled is attractive but lacks formal proof. In addition, it has been shown at least in one case that intracellular reovirus survives CTL-mediated lysis of its host cells [51].…”

Section: Discussionmentioning

confidence: 99%

Expression of cytoplasmic granules with T cell‐associated serine proteinase‐1 activity in Ly‐2(CD8) T lymphocytes responding to lymphocytic choriomeningitis virus in vivo

et al. 1989

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Monoclonal antibodies (mAb) with specificity for the T cell-associated serine proteinase-1 of the mouse (MTSP-1) were used to study expression and storage of this enzyme in T lymphocytes during lymphocytic choriomeningitis (LCM) virus infection in vivo. Immunohistochemical analysis of splenic tissue at the peak of LCM virus-specific T cell-mediated cytolytic responses, i.e., at day 7 post infection, revealed high numbers of MTSP-1+ T lymphocytes in the interfollicular T cell-dependent area of the spleen. More than 50% of Ly-2+(CD8+) cells but only low numbers of Ly-2-(CD8-) cells, previously enriched by flow cytofluorometry, contained large amounts of cytoplasmic granules which stained both with MTSP-1-specific mAb and the esterase substrate N-alpha-benzyloxycarbonyl-L-lysine thiobenzyl ester. These data demonstrate that in vivo generated LCM virus-induced cytolytic T lymphocytes develop cytoplasmic storage granules containing MTSP-1 and suggest that the mechanism of granule exocytosis is operative in vivo; possibly MTSP-1 is one effector molecule participating in the Ly-2+(CD8+) T lymphocyte-mediated control of virus infection.

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“…In a previous study, we were unable to detect inactivation of fully assembled, encapsidated intracellular reovirus by CTL (20). However, the most important role for nucleic acid fragmentation would likely be to act on the viral genome while it is in a replicative, exposed state, namely the eclipse phase.…”

Section: Introductionmentioning

confidence: 84%

“…An attractive hypothesis is that CTL induce DNA (and perhaps RNA) fragmentation as a virus-control mechanism (8,20,27,32). In a previous study, we were unable to detect inactivation of fully assembled, encapsidated intracellular reovirus by CTL (20).…”

Section: Introductionmentioning

confidence: 99%

How Do CTL Control Virus Infections? Evidence for Prelytic Halt of Herpes simplex

Martz¹,

Gamble²

1992

Viral Immunology

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Cytotoxic T lymphocytes (CTL) induce in target cells a rapid, prelytic fragmentation of target cell DNA, accompanied by apoptosis. In contrast, complement and (with a few exceptions) chemical and physical means of inducing cytolysis induce necrosis, without DNA fragmentation. The function of the unusual DNA fragmentation induced by CTL remains to be elucidated. The major recognized function of CTL is in halting virus infections. Earlier, we proposed that CTL might halt virus infections prelytically, by fragmenting viral and cellular nucleic acids, and that in this case, cytolysis per se might be a less important function of CTL. We report here experiments designed to detect prelytic halt of virus replication. We employed in vivo-like conditions: fibroblast targets (difficult to lyse) were infected with herpes simplex virus (HSV), then incubated at low E/T cell ratios overnight. At the highest E/T ratios which produced less than 10% CTL-induced lysis, plaque-forming unit yield was reduced by about 50%. At higher E/T ratios which lysed 1/6 to 1/3 of the infected target cells, 3/4 to 9/10 of the virus production was prevented. The discrepancy between the level of lysis and the reduction in virus yield is evidence for significant CTL-induced prelytic halt of HSV replication. At present, it is unclear whether the antiviral effect observed involves an activity of CTL distinct from their lytic ability, such as their DNA fragmenting ability.

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Intracellular Reovirus Survives Cytotoxic T Lymphocyte-mediated Lysis of its Host Cell

Cited by 14 publications

References 36 publications

Herpes Simplex Virus GenesUs3,Us5, andUs12Differentially Regulate Cytotoxic T Lymphocyte-Induced Cytotoxicity

Herpes Simplex Virus GenesUs3,Us5, andUs12Differentially Regulate Cytotoxic T Lymphocyte-Induced Cytotoxicity

Expression of cytoplasmic granules with T cell‐associated serine proteinase‐1 activity in Ly‐2(CD8) T lymphocytes responding to lymphocytic choriomeningitis virus in vivo

How Do CTL Control Virus Infections? Evidence for Prelytic Halt of Herpes simplex

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