Improved Protection from Primary Ocular HSV-1 Infection and Establishment of Latency Using Multigenic DNA Vaccines

Osorio, Yanira; Cohen, Jacob; Ghiasi, Homayon

doi:10.1167/iovs.03-0828

Cited by 32 publications

(37 citation statements)

References 75 publications

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“…1B and Table 1). Previously, it was shown that rIL-2/IL-2 monoclonal antibody (MAb) complexes increase the bio- The complete ORF of IL-2 or IL-4 was cloned into the VR-1055 vector as we described previously (22). Female BALB/c mice were injected 3 times with 100 g of IL-2 or IL-4 DNA.…”

Section: Resultsmentioning

confidence: 99%

“…The complete open reading frame (ORF) of murine IL-2 or the IL-2A, IL-2B, IL-2A1, or IL-2A2 fragment, as well as that of full-length IL-2 with one mutation or three mutations, was cloned into the BamHI site of the VR-1055 expression vector as we described previously (22). Full-length natural murine IL-2 and its various forms used in this study were synthesized by GenScript (Piscataway, NJ).…”

Section: Ethicsmentioning

confidence: 99%

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Role of Interleukin-2 and Herpes Simplex Virus 1 in Central Nervous System Demyelination in Mice

Mott

Zandian

Allen

et al. 2013

J Virol

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We have reported previously that ocular infection of different strains of mice with recombinant herpes simplex virus 1 (HSV-1) constitutively expressing interleukin-2 (IL-2) provokes central nervous system (CNS) demyelination and optic neuropathy, as determined by changes in visual evoked cortical potentials and pathological changes in the optic nerve and CNS, whereas recombinant viruses expressing IL-4, gamma interferon, IL-12p35, IL-12p40, or IL-12p70 do not induce this neuropathy. The goal of this study was to dissect the mechanism underlying the interplay between the immune system (elevation of IL-2) and an environmental factor (infection with HSV-1) that elicits this pathology. Similar results were obtained upon delivery of IL-2 into the mouse brain using osmotic minipumps or injection of mice with recombinant IL-2 protein, IL-2 DNA, or IL-2 synthetic peptides prior to infection with wild-type (wt) HSV-1 strains McKrae and KOS. The critical role of IL-2 is further supported by our data, indicating that a single mutation at position T27A in IL-2 completely blocks the HSV-1-induced pathology. This study shows a novel model of autoimmunity in which viral infection and enhanced IL-2 cause CNS demyelination. Several lines of evidence implicate interleukin-2 (IL-2) in the pathology of multiple sclerosis (MS) (1-4). Patients with MS have elevated levels of IL-2 in their sera and cerebrospinal fluid (CSF) (1-4). The soluble IL-2 receptor (sIL-2R) is also elevated in the sera and CSF of patients with MS (3, 5-10). These clinical findings of elevated IL-2 levels (and lower than normal IL-4 levels) in the sera of MS patients suggest a possible link between IL-2 and the onset of MS. Furthermore, supernatants harvested from T lymphocytes of MS patients cause damage to myelin and glial cells in vitro (11,12), suggesting that the MS T lymphocytes produce demyelination factors and are activated in vivo.In order to investigate the role of cytokines in demyelination in a viral model of MS, we had constructed a panel of recombinant herpes simplex virus 1 (HSV-1) isolates that constitutively express murine cytokines, including IL-2 (13), IL-4, gamma interferon (IFN-␥), . Using these viruses, we have shown that infection of different strains of mice with a recombinant HSV-1 strain constitutively expressing IL-2 (HSV-IL-2), but not HSV-IL-4, HSV-IFN-␥, HSV-IL-12p35, or HSV-IL12p40, results in demyelination of the optic nerves (ONs), the spinal cords (SCs), and the brains of the infected mice, as determined by histologic examination of tissues obtained at necropsy (17,18). In addition, the HSV-IL-2-infected mice developed optic neuropathy, as determined by changes in the visual evoked cortical potentials (VECPs) (18). Using knockout mice, depletion, and transfer studies, we found that both CD8 ϩ and CD4 ϩ T cells contributed to HSV-IL-2-induced central nervous system (CNS) demyelination, with CD8 ϩ T cells being the primary inducers (19). We have also found that infection of mice with a recombinant HSV-1 isolate expressing IL-12p...

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Section: Resultsmentioning

confidence: 99%

Section: Ethicsmentioning

confidence: 99%

Role of Interleukin-2 and Herpes Simplex Virus 1 in Central Nervous System Demyelination in Mice

Mott

Zandian

Allen

et al. 2013

J Virol

Self Cite

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“…Purified DNA (100 g in a total volume of 50 l PBS) was injected i.m. into each quadriceps using a 27-gauge needle on day 0, day 14, and day 28, as described previously (63,107). For negative controls, mice were injected with either diluent or empty-vector DNA.…”

Section: Methodsmentioning

confidence: 99%

Roles of M1 and M2 Macrophages in Herpes Simplex Virus 1 Infectivity

Lee

Ghiasi

2017

J Virol

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Macrophages are the predominant infiltrate in the corneas of mice that have been ocularly infected with herpes simplex virus 1 (HSV-1). However, very little is known about the relative roles of M1 (classically activated or polarized) and M2 (alternatively activated or polarized) macrophages in ocular HSV-1 infection. To better understand these relationships, we assessed the impact of directed M1 or M2 activation of RAW264.7 macrophages and peritoneal macrophages (PM) on subsequent HSV-1 infection. In both the RAW264.7 macrophage and PM in vitro models, HSV-1 replication in M1 macrophages was markedly lower than in M2 macrophages and unstimulated controls. The M1 macrophages expressed significantly higher levels of 28 of the 32 tested cytokines and chemokines than M2 macrophages, with HSV-1 infection significantly increasing the levels of proinflammatory cytokines and chemokines in the M1 versus the M2 macrophages. To examine the effects of shifting the immune response toward either M1 or M2 macrophages in vivo, wild-type mice were injected with gamma interferon (IFN-␥) DNA or colony-stimulating factor 1 (CSF-1) DNA prior to ocular infection with HSV-1. Virus replication in the eye, latency in trigeminal ganglia (TG), and markers of T cell exhaustion in the TG were determined. We found that injection of mice with IFN-␥ DNA, which enhances the development of M1 macrophages, increased virus replication in the eye; increased latency; and also increased CD4, CD8, IFN-␥, and PD-1 transcripts in the TG of latently infected mice. Conversely, injection of mice with CSF-1 DNA, which enhances the development of M2 macrophages, was associated with reduced virus replication in the eye and reduced latency and reduced the levels of CD4, CD8, IFN-␥,and PD-1 transcripts in the TG. Collectively, these results suggest that M2 macrophages directly reduce the levels of HSV-1 latency and, thus, T-cell exhaustion in the TG of ocularly infected mice.IMPORTANCE Our findings demonstrate a novel approach to further reducing HSV-1 replication in the eye and latency in the TG by modulating immune components, specifically, by altering the phenotype of macrophages. We suggest that inclusion of CSF-1 as part of any vaccination regimen against HSV infection to coax responses of macrophages toward an M2, rather than an M1, response may further improve vaccine efficacy against ocular HSV-1 replication and latency.KEYWORDS macrophages, infectivity, latency, exhaustion, HSV-1, CSF-1, IFN-␥, polarized, primary infection, reactivation M acrophage infiltrates play key roles in the immune defense system and are a central component of the innate immune system (1-4). Macrophages exhibit a wide variety of critically important functions, including phagocytosis, cytokine/chemokine secretion, and tumor cytotoxicity (5, 6). Resident macrophages are not detectable in the corneas of naive mice (7, 8), and we have confirmed the lack of resident macrophages in the corneas of uninfected mice by immunostaining using anti-F4/80, as well as anti-CD11b, antib...

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“…Genetic immunization offers some advantages over other available vaccination methods, including presentation of native form of the protein, inducing CD8 + T lymphocytes proliferation and the ease in manipulation and production. Several successful reports have now described the use of DNA immunization in inducing effective immune responses against many pathogens (1,8,9). Regarding immunization against viruses, it seems that DNA vaccination is one of the most important approaches in developing effective vaccine production.…”

Section: Introductionmentioning

confidence: 99%

The Effect of Glycoprotein B DNA Immuniation on HSV-l Lethal Infection of BALB/c Mice

et al. 2010

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Background and Aims: Glycoprotein B (gB) is among the most important immunogenic proteins of HSV-1 that is now being used as recombinant vaccine to induce protectively against the virus. It is believed that gB is responsible for induction of neutralizing antibody and up to 90% of CTL (Cytotoxic T Cell) activity against HSV-1 in some haplotypes. Methods: In the present study the antibody titer induced by a gB based DNA vaccine and the protective effect of the candidate vaccine in BALB/c mice in comparison with those induced by the whole virus were evaluated. DNA plasmid carrying full-length of gB-1 was constructed and its ability to express the protein was confirmed by immunofluorescence test. Results: Humoral immune response and protective effect of the constructed vector were evaluated in BALB/c mice. Conclusion:The neutralizing antibody titer induced by the DNA vaccine was significantly lower than the one induced by the whole virus, although, both of vaccines could confer 100% protectively against HSV-1 challenge.

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Improved Protection from Primary Ocular HSV-1 Infection and Establishment of Latency Using Multigenic DNA Vaccines

Abstract: The 5gP DNA vaccine appeared to be more effective than the corresponding protein subunit vaccine, regardless of adjuvant. Emulsification of the 5gP protein in ISA 720 appeared to be more effective than emulsification in Freund's adjuvant.

Cited by 32 publications

References 75 publications

Role of Interleukin-2 and Herpes Simplex Virus 1 in Central Nervous System Demyelination in Mice

Role of Interleukin-2 and Herpes Simplex Virus 1 in Central Nervous System Demyelination in Mice

Roles of M1 and M2 Macrophages in Herpes Simplex Virus 1 Infectivity

The Effect of Glycoprotein B DNA Immuniation on HSV-l Lethal Infection of BALB/c Mice

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