Innate Immune Response of the Human Host to Exposure with Herpes Simplex Virus Type 1: In Vitro Control of the Virus Infection by Enhanced Natural Killer Activity via Interleukin-15 Induction

Ahmad, Ali; Sharif-Askari, Ehssan; Fawaz, Lama; Menezes, José

doi:10.1128/jvi.74.16.7196-7203.2000

Cited by 67 publications

(49 citation statements)

References 69 publications

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“…Five micrograms of cellular DNA was used in PCR amplification of the Escherichia coli ␤-galactosidase DNA sequences with Pfu Turbo DNA polymerase (Stratagene). One-tenth of each reaction mixture was then electrophoresed in a 1.5% agarose gel and Southern blotted before probing with an internal primer labeled with 32 P. The sequences of the primers were as follows: 5Ј-actatcccgaccgccttact; 3Ј-gctggtttccatcagttgct; internal probe, ttcaacatcagccgctacag.…”

Section: Methodsmentioning

confidence: 99%

“…In addition to IFN-␥-mediated antiviral effects, the direct lytic activity of NK cells toward virally infected cells constitutes an important antiviral host defense mechanism. Recent in vitro studies with human peripheral blood mononuclear cells (PBMCs) have indicated that a wide variety of viruses that infect human PBMCs induce expansion of NK cells with heightened lytic activity that can be effectively abrogated by using antibodies against IL-15, further supporting an important role for IL-15 in NK-mediated antiviral activity (19,20,32,33).…”

Section: Comparison Of Chemokine Expression Profiles In Tissues Of Inmentioning

confidence: 99%

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Comparative assessment of virulence of recombinant vaccinia viruses expressing IL-2 and IL-15 in immunodeficient mice

Perera

Goldman

Waldmann

2001

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

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Contributed by Thomas A. Waldmann, February 16, 2001 IL-2 and -15 belong to the four ␣-helix bundle family of cytokines and display a spectrum of overlapping immune functions because of shared signal transducing receptor components of the IL-2 receptor complex. However, recent evidence suggests a nonredundant unique role for IL-15 in the establishment and perhaps maintenance of peripheral natural killer (

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Section: Methodsmentioning

confidence: 99%

Section: Comparison Of Chemokine Expression Profiles In Tissues Of Inmentioning

confidence: 99%

Comparative assessment of virulence of recombinant vaccinia viruses expressing IL-2 and IL-15 in immunodeficient mice

Perera

Goldman

Waldmann

2001

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

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“…21 PBMCs (monocytes/macrophages, NK cells, and g/d TCR þ T lymphocytes) provide another line of cellular innate defenses and react to virus infections by expressing several cytokines (IFNa, b, and g, TNFa, IL15 and IL18) with antiviral activity. [10][11][12][13][14][15][16][17] We thus analyzed expression of these cytokines' mRNAs by PBMCs, 12 h after OV injection in control rats and in rats that had been pretreated with CPA. As expected under normal circumstances (ie saline-treated rats), IFNa, IFNb, IFNg, TNFa, and IL-15 mRNA production by PBMCs was significantly induced by the intraneoplastic injection of oncolytic HSV, while production of IL-18 mRNA was unchanged (compare the ÀCPA lanes for HBSS versus hrR3 groups in Figure 7b).…”

Section: The Cpa Effect Is Replicated In Athymic Ratsmentioning

confidence: 99%

Altered expression of antiviral cytokine mRNAs associated with cyclophosphamide's enhancement of viral oncolysis

et al. 2004

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Oncolytic viruses (OVs) are being used as anticancer agents in preclinical and clinical trials. Propagation of OVs inside infected tumors is critical to their efficacy and is mediated by the productive generation of progeny OVs within infected tumor cells. In turn, this progeny can spread the infection to other tumor cells in successive rounds of oncolysis. Previously, we had found that, in rats, cyclophosphamide (CPA) pretreatment increased infection of brain tumors by an intra-arterially administered herpes simplex virus type 1 OV, because it inhibited activation of complement responses, mediated by innate IgM. We also have previously shown that other pharmacologic inhibitors of complement, such as cobra venom factor (CVF), allowed for increased infection. However, in these studies, further inhibition of complement responses by CVF did not result in additional infection of brain tumor cells or in propagation of OV to surrounding tumor cells. In this study, we sought to determine if CPA did lead to increased infection/propagation from initially infected tumor cells. Unlike our results with CVF, we find that CPA administration does result in a time-dependent increase in infection of tumor cells, suggestive of increased propagation, in both syngeneic and athymic models of brain tumors. This increase was due to increased survival of OV within infected tumors and brain surrounding tumors. CPA's effect was not due to a direct enhancement of viral replication in tumor cells, rather was associated with its immunosuppressive effects. RT-PCR analysis revealed that CPA administration resulted in impaired mRNA production by peripheral blood mononuclear cells (PBMCs) of several cytokines (interferons a/b, interferon g, TNFa, IL-15, and IL-18) with anti-HSV function. These findings suggest that the CPA-mediated facilitation of OV intraneoplastic propagation is associated with a general decrease of antiviral cytokines mRNAs in PBMCs. These findings not only suggest a potential benefit for the addition of transient immunosuppression in clinical applications of oncolytic HSV therapy, but also suggest that innate immunomodulatory pathways may be amenable to manipulation, in order to increase OV propagation and survival within infected tumors.

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“…5 Innate immune responses against wild-type HSV1 include: (1) activation of the complement cascade, 6,7 (2) activation of macrophages, recruitment, activation, and maturation of NK cells, CD4+ CD11c-type 2 DC precursors, 8,9 and gd, extrathymicderived, T cells, [10][11][12] and (3) generation and secretion of a variety of cytokines and chemokines that orchestrate the above activities. [13][14][15][16][17][18][19][20] The objective of these responses is to limit the initial infection of a tissue, abrogate further propagation of the virus, and begin maturation of dendritic and/or dendritic-like cells that will then activate antigenspecific T cells as well the maturation of B cells to begin production of high-affinity, high-avidity IgG. 21 Like many other viruses, virulent forms of HSV-1 have evolved several molecular mechanisms to evade and escape such host responses.…”

Section: Introductionmentioning

confidence: 99%

Effects of innate immunity on herpes simplex virus and its ability to kill tumor cells

et al. 2003

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Several clinical trials have or are being performed testing the safety and efficacy of different strains of oncolytic viruses (OV) for malignant cancers. OVs represent either naturally occurring or genetically engineered strains of viruses that exhibit relatively selective replication in tumor cells. Several types of OV have been derived from herpes simplex virus 1 (HSV1). Tumor oncolysis depends on the processes of initial OV infection of tumor, followed by subsequent propagation of OV within the tumor itself. The role of the immune responses in these processes has not been extensively studied. On the contrary, effects of the immune response on the processes of wild-type HSV1 infection and propagation in the central nervous system have been studied and described in detail. The first line of defense against a wild-type HSV1 infection in both naive and immunized individuals is provided by innate humoral (complement, cytokines, chemokines) and cellular (macrophages, neutrophils, NK cells, gd T cells, and interferon-producing cells) responses. These orchestrate the lysis of virions and virus-infected cells as well as provide a link to effective adaptive immunity. The role of innate defenses in curtailing the oncolytic effect of genetically engineered HSV has only recently been studied, but several of the same host responses appear to be operative in limiting anticancer effects by the replicating virus. The importance of this knowledge lies in finding avenues to modulate such initial innate responses, in order to allow for increased oncolysis of tumors while minimizing host toxicity. Gene Therapy (2003) 10, 983-990.

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Innate Immune Response of the Human Host to Exposure with Herpes Simplex Virus Type 1: In Vitro Control of the Virus Infection by Enhanced Natural Killer Activity via Interleukin-15 Induction

Cited by 67 publications

References 69 publications

Comparative assessment of virulence of recombinant vaccinia viruses expressing IL-2 and IL-15 in immunodeficient mice

Comparative assessment of virulence of recombinant vaccinia viruses expressing IL-2 and IL-15 in immunodeficient mice

Altered expression of antiviral cytokine mRNAs associated with cyclophosphamide's enhancement of viral oncolysis

Effects of innate immunity on herpes simplex virus and its ability to kill tumor cells

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