scholarly journals Recombinant Herpes Simplex Virus Type 1 (HSV-1) Codelivering Interleukin-12p35 as a Molecular Adjuvant Enhances the Protective Immune Response against Ocular HSV-1 Challenge

2005 ◽  
Vol 79 (6) ◽  
pp. 3297-3308 ◽  
Author(s):  
Yanira Osorio ◽  
Homayon Ghiasi
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Replication ◽  
Recombinant Virus ◽  
Neutralizing Antibody ◽  
Antibody Titers ◽  
Ifn Γ ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT An important aspect of ocular herpes simplex virus type 1 (HSV-1) vaccine development is identification of an appropriate adjuvant capable of significantly reducing both virus replication in the eye and explant reactivation in trigeminal ganglia. We showed recently that a recombinant HSV-1 vaccine expressing interleukin-4 (IL-4) is more efficacious against ocular HSV-1 challenge than recombinant viruses expressing IL-2 or gamma interferon (IFN-γ) (Y. Osorio and H. Ghiasi, J. Virol. 77:5774-5783, 2003). We have now constructed and compared recombinant HSV-1 viruses expressing IL-12p35 or IL-12p40 molecule with IL-4-expressing HSV-1 recombinant virus. BALB/c mice were immunized intraperitoneally with IL-12p35-, IL-12p40-, IL-12p35+IL-12p40-, or IL-4-expressing recombinant HSV-1 viruses. Controls included mice immunized with parental virus and mice immunized with the avirulent strain KOS. The efficacy of each vaccine in protecting against ocular challenge with HSV-1 was assessed in terms of survival, eye disease, virus replication in the eye, and explant reactivation. Neutralizing antibody titers, T-cell responses, and expression of 32 cytokines and chemokines were also evaluated. Mice immunized with recombinant HSV-1 expressing IL-12p35 exhibited the lowest virus replication in the eye, the most rapid virus clearance, and the lowest level of explant reactivation. The higher efficacy against ocular virus replication and explant reactivation correlated with higher neutralizing antibody titers, cytotoxic-T-lymphocyte activities, and IFN-γ expression in recombinant HSV-1 expressing IL-12p35 compared to other vaccines. Mice immunized with both IL-12p35 and IL-12p40 had lower neutralizing antibody responses than mice immunized with IL-12p35 alone. Our results confirm that recombinant virus vaccines expressing cytokine genes can enhance the overall protection against infection, with the IL-12p35 vaccine being the most efficacious of those tested. Collectively, the results support the potential use of IL-12p35 as a vaccine adjuvant, without the toxicity-associated concerns of IL-12.

scholarly journals Comparison of Adjuvant Efficacy of Herpes Simplex Virus Type 1 Recombinant Viruses Expressing TH1 and TH2 Cytokine Genes

2003 ◽  
Vol 77 (10) ◽  
pp. 5774-5783 ◽  
Author(s):  
Yanira Osorio ◽  
Homayon Ghiasi
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Herpes Simplex Virus Type ◽  
Recombinant Virus ◽  
Recombinant Viruses ◽  
Ifn Γ ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT The adjuvant effects of cytokines in humoral and cell-mediated immunity to herpes simplex virus type 1 (HSV-1) have been examined in mice using HSV-1 recombinant viruses expressing murine interleukin-2 (IL-2), IL-4, or gamma interferon (IFN-γ) gene. Groups of naive BALB/c mice were immunized intraperitoneally with one or three doses of the HSV-1 recombinant viruses expressing IL-2, IL-4, or IFN-γ or with parental control virus. Despite similar replication kinetics, these three recombinant viruses elicited different immune responses to HSV-1 on immunization. Immunization with the recombinant virus expressing IL-4 elicited a humoral response of greater magnitude than immunization with the recombinant viruses expressing IL-2 or IFN-γ or with parental virus. In contrast, immunization with recombinant virus expressing IL-2 elicited a higher cytotoxic T-cell response than immunization with viruses expressing IL-4 or IFN-γ. Stimulation in vitro of splenocytes obtained from the mice immunized with UV-inactivated HSV-1 McKrae resulted in a TH1 pattern of cytokine expression irrespective of the recombinant virus used in the immunization. As observed for the parental virus, both CD4+ and CD8+ T cells contributed equally to the production of IL-2 by the splenocytes of mice immunized with any of the three recombinant viruses. However, the pattern of IFN-γ production by CD4+ and CD8+ T cells differed according to the recombinant virus used. After lethal ocular challenge, all immunized mice were protected completely against death and manifestations of eye disease caused by HSV-1, which are typical responses in unimmunized mice. Mice immunized with IL-4-expressing virus cleared the virus from their eyes more rapidly than mice immunized with IL-2- or IFN-γ-expressing virus. Taken together, our results suggest that, in contrast to IFN-γ which did not exhibit an adjuvant effect, both IL-4 and IL-2 act as adjuvants in immunization with HSV, with IL-4 showing greater efficacy.

Effect of a combination therapy between IL-12 and soluble IL-4 receptor (sIL-4R) onCandida albicansand herpes simplex virus type 1 infections in thermally injured mice

2002 ◽  
Vol 48 (10) ◽  
pp. 886-894 ◽  
Author(s):  
Makiko Kobayashi ◽  
Hitoshi Takahashi ◽  
David N Herndon ◽  
Richard B Pollard ◽  
Fujio Suzuki
Keyword(s):  
T Cells ◽  
Candida Albicans ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Herpes Simplex Virus Type ◽  
Cell Responses ◽  
Ifn Γ ◽  
Simplex Virus ◽  
Hsv 1

The effectiveness of a combination using IL-12 and soluble IL-4 receptor (sIL-4R) to treat severe infections of herpes simplex virus type 1 (HSV-1) and Candida albicans in thermally injured mice was investigated. Although sIL-4R decreased burn-associated type 2 T-cell responses, the effect of sIL-4R was minimal on the morbidity and mortality of thermally injured mice exposed to 250 times LD50of HSV-1 or 10 times LD50of C. albicans. Compared with 100% mortality in control mice, mortality for HSV-1 and C. albicans was 40 and 20%, respectively, in thermally injured mice that received IL-12 and sIL-4R in combination. After stimulation with anti-CD3 monoclonal antibody, splenic T cells from thermally injured mice exposed to large amounts of HSV-1 or C. albicans did not produce gamma interferon (IFN-γ) into their culture fluids. However, IFN-γ was produced by splenic T cells from thermally injured and infected mice treated with IL-12 and sIL-4R in combination. These results suggest that therapeutic treatment with a combination of IL-12 and sIL-4R may be effective by inducing type 1 T-cell responses in thermally injured mice exposed to large amounts of HSV-1 or C. albicans.Key words: burn, IL-12, soluble IL-4 receptor, herpesvirus, Candida albicans.

scholarly journals Alpha/Beta Interferon and Gamma Interferon Synergize To Inhibit the Replication of Herpes Simplex Virus Type 1

2002 ◽  
Vol 76 (22) ◽  
pp. 11541-11550 ◽  
Author(s):  
Bruno Sainz ◽  
William P. Halford
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Herpes Simplex Virus Type ◽  
Vero Cells ◽  
Ifn Γ ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT In vivo evidence suggests that T-cell-derived gamma interferon (IFN-γ) can directly inhibit the replication of herpes simplex virus type 1 (HSV-1). However, IFN-γ is a weak inhibitor of HSV-1 replication in vitro. We have found that IFN-γ synergizes with the innate IFNs (IFN-α and -β) to potently inhibit HSV-1 replication in vitro and in vivo. Treatment of Vero cells with either IFN-β or IFN-γ inhibits HSV-1 replication by <20-fold, whereas treatment with both IFN-β and IFN-γ inhibits HSV-1 replication by ∼1,000-fold. Treatment with IFN-β and IFN-γ does not prevent HSV-1 entry into Vero cells, and the inhibitory effect can be overcome by increasing the multiplicity of HSV-1 infection. The capacity of IFN-β and IFN-γ to synergistically inhibit HSV-1 replication is not virus strain specific and has been observed in three different cell types. For two of the three virus strains tested, IFN-β and IFN-γ inhibit HSV-1 replication with a potency that approaches that achieved by a high dose of acyclovir. Pretreatment of mouse eyes with IFN-β and IFN-γ reduces HSV-1 replication to nearly undetectable levels, prevents the development of disease, and reduces the latent HSV-1 genome load per trigeminal ganglion by ∼200-fold. Thus, simultaneous activation of IFN-α/β receptors and IFN-γ receptors appears to render cells highly resistant to the replication of HSV-1. Because IFN-α or IFN-β is produced by most cells as an innate response to virus infection, the results imply that IFN-γ secreted by T cells may provide a critical second signal that potently inhibits HSV-1 replication in vivo.

scholarly journals Reactivation of Expression from Quiescent Herpes Simplex Virus Type 1 Genomes in the Absence of Immediate-Early Protein ICP0

2007 ◽  
Vol 81 (21) ◽  
pp. 11781-11789 ◽  
Author(s):  
Chris M. Preston
Keyword(s):  
Gene Expression ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Replication ◽  
Human Fibroblasts ◽  
Protein Icp0 ◽  
Simplex Virus ◽  
Null Mutants ◽  
Hsv 1

ABSTRACT Model systems have previously been developed in which herpes simplex virus (HSV) is retained in human fibroblasts in a nonreplicating state known as quiescence. The HSV type 1 (HSV-1) immediate-early (IE) protein ICP0, an important activator of gene expression, reactivates the quiescent genome and promotes the resumption of virus replication. Previous studies reported that infection with ICP0-null HSV-1 mutants fails to reactivate quiescent HSV, even when the mutant itself undergoes productive replication, leading to the hypothesis that quiescent genomes exist in a silent configuration in which they are shielded from trans-acting factors. I reinvestigated these findings, using HSV-1 mutants with lesions in the transcription activators VP16, ICP0, and ICP4 to establish quiescent infection at high efficiency. Superinfection with ICP0-null HSV-1 mutants at a low multiplicity of infection (MOI), so that individual plaques were formed, reactivated expression from the quiescent genome, demonstrating that the requirement for ICP0 is not absolute. The previously reported failure to observe reactivation by ICP0-null mutants was shown to be a consequence of either a low initial MOI or a high superinfecting MOI. Competition between viral genomes at the level of gene expression and virus replication, especially when ICP0 was absent, was demonstrated during reactivation and also during normal infection of human fibroblasts. The results show that the multiplicity-dependent phenotype of ICP0-null mutants limits the efficiency of reactivation at low MOIs and that competition between genomes occurs at high MOIs. The conclusion that quiescent HSV genomes are extensively silenced and intrinsically insensitive to trans-acting factors must be reevaluated.

Neutralization Antibody to Herpes Simplex Virus Type 1 in Bell's Palsy

1988 ◽  
Vol 97 (6_suppl3) ◽  
pp. 18-21 ◽  
Author(s):  
Koshiro Nakamura ◽  
Naoaki Yanagihara
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Complement Fixation ◽  
Bell’S Palsy ◽  
Bell's Palsy ◽  
Geometric Means ◽  
Antibody Titers ◽  
Simplex Virus ◽  
Hsv 1

In 45 patients with Bell's palsy of recent onset, the neutralization antibody titers to herpes simplex virus type 1 (HSV-1) were assayed by a microtiter technique. As a control, the neutralization antibody titers of 50 normal subject were assayed. Complement fixation tests also were performed. The geometric means of the neutralization antibody titers of the patients appeared higher at all times than those of the normal subjects. Significant change in the neutralization antibody titer suggesting a recent infection of HSV-1 was seen in seven patients (15.6%), while the complement fixation test demonstrated significant change in only one patient (2.2%). The higher geometric means of the neutralization antibody titers in the patients was thought to indicate that reactivation of the HSV-1 infection was responsible for the onset of Bell's palsy.

scholarly journals Infection of BALB/c Mice with a Herpes Simplex Virus Type 1 Recombinant Virus Expressing IFN-γ Driven by the LAT Promoter

Virology ◽  
2002 ◽  
Vol 302 (1) ◽  
pp. 144-154 ◽  
Author(s):  
Homayon Ghiasi ◽  
Yanira Osorio ◽  
Yahya Hedvat ◽  
Guey-Chuen Perng ◽  
Anthony B. Nesburn ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Recombinant Virus ◽  
Ifn Γ ◽  
Simplex Virus

scholarly journals Primary herpes simplex virus type 1 infection of the eye triggers similar immune responses in the cornea and the skin of the eyelids

2002 ◽  
Vol 83 (7) ◽  
pp. 1579-1590 ◽  
Author(s):  
Thomas H. Stumpf ◽  
Rachel Case ◽  
Carolyn Shimeld ◽  
David L. Easty ◽  
Terry J. Hill
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Immune Responses ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Disease Process ◽  
Ifn Γ ◽  
Simplex Virus ◽  
Hsv 1

Herpetic stromal keratitis (HSK) and blepharoconjunctivitis in humans are thought partly to result from immunopathological responses to herpes simplex virus type 1 (HSV-1). The corneas of NIH mice were inoculated with HSV-1 (strain McKrae) and mice were examined for signs of disease and infection on days 1, 4, 7, 10, 14 and 21. The eyes and eyelids of infected and control mice were processed for immunohistochemistry and double stained for viral antigens and one of the following cell surface markers (Gr-1, F4/80, CD4, CD8, CD45R or MHC class II) or one of the following cytokines (IL-2, IL-4, IL-6, IL-10, IL-12 or IFN-γ). All infected mice developed signs of HSK by day 4 and blepharitis by day 7 and these both persisted until day 21, when signs of resolution where apparent. Virus was detected during the first week of infection and became undetectable by day 10. Large numbers of Gr-1+ cells (neutrophils) infiltrated infected corneas and eyelids in areas of viral antigen and CD4+ T cells increased significantly in number after virus clearance. In both sites, the predominant cytokines were IL-6, IL-10, IL-12 and IFN-γ, with few IL-2+ and IL-4+ cells. These observations suggest that the immune responses in the cornea are similar to those in the eyelids but, overall, the responses are not clearly characterized as either Th1 or Th2. In both sites, the neutrophil is the predominant infiltrating cell type and is a likely source of the cytokines observed and a major effector of the disease process.

scholarly journals Dendritic Cells Are Required for Optimal Activation of Natural Killer Functions following Primary Infection with Herpes Simplex Virus Type 1

2009 ◽  
Vol 83 (7) ◽  
pp. 3175-3186 ◽  
Author(s):  
Sadik H. Kassim ◽  
Naveen K. Rajasagi ◽  
Barry W. Ritz ◽  
Stephen B. Pruett ◽  
Elizabeth M. Gardner ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Nk Cells ◽  
Nk Cell ◽  
Ifn Γ ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Natural killer (NK) cells play an important role in the optimal clearance of herpes simplex virus type 1 (HSV-1) infection in mice. Activated NK cells function via cytokine secretion or direct cytolysis of target cells; dendritic cells (DCs) are thought to make critical contributions in the activation of both of these functions. Yet, the magnitude and physiological relevance of DC-mediated NK cell activation in vivo is not completely understood. To examine the contribution of DC help in regulating NK cell functions after infection with HSV-1, we utilized a transgenic mouse model that allows the transient ablation of DCs. Using this approach, it was found that the gamma interferon (IFN-γ) expression potential of NK cells is quantitatively and qualitatively impaired in the absence of DCs. With regard to priming of NK cytolytic functions, the ablation of DCs did not significantly affect cytotoxic protein expression by NK cells. An in vivo cytolytic assay did, however, reveal impairments in the magnitude of NK cell cytotoxicity. Overall, this study provides direct evidence that functional DCs are required for optimal IFN-γ expression and cytolytic function by NK cells following infection with HSV-1.

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

2017 ◽  
Vol 91 (15) ◽  
Author(s):  
Dhong Hyun Lee ◽  
Homayon Ghiasi
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Replication ◽  
M2 Macrophages ◽  
Herpes Simplex Virus 1 ◽  
M1 Macrophages ◽  
Cytokines And Chemokines ◽  
Ifn Γ ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT 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-γ) 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-γ DNA, which enhances the development of M1 macrophages, increased virus replication in the eye; increased latency; and also increased CD4, CD8, IFN-γ, 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-γ,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.

scholarly journals Transient IFN-γ synthesis in the lymph node draining a dermal site loaded with UV-irradiated herpes simplex virus type 1: an NK- and CD3-dependent process regulated by IL-12 but not by IFN-α/β

2000 ◽  
Vol 81 (10) ◽  
pp. 2365-2373 ◽  
Author(s):  
S. Riffault ◽  
C. Carrat ◽  
G. Milon ◽  
B. Charley ◽  
J. H. Colle
Keyword(s):  
Lymph Node ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Ifn Γ ◽  
Β Receptor ◽  
Simplex Virus ◽  
Hsv 1

Our previous studies have shown that UV-inactivated, non-replicating herpes simplex virus type 1 (UV-HSV-1) triggers early and transient synthesis of IFN-α/β in the mouse regional lymph node when delivered upstream (i.e. in the ear dermis). In this study, it is demonstrated, by use of a quantitative RT–PCR readout assay, that IFN-γ mRNA expression was rapidly and transiently upregulated in draining lymph nodes when UV-HSV-1 was delivered in the ear dermis of C57Bl/6 mice. An increased number of IFN-γ-producing cells was also detected in the lymph node by flow cytometric analysis. Two different subsets of cells, namely DX5+ NK cells and CD3ϵ+ T cells, accounted for this early IFN-γ synthesis. Prompt upregulation of IFN-α and IL-12p40 mRNA was also recorded. We took advantage of IFN-α/β-receptor knockout and wild-type 129 mice to study a potential role of IFN-α/β in the signalling pathway leading to IFN-γ transcription/translation. IFN-γ mRNA upregulation still occurred in IFN-α/β-receptor−/− mice, showing that IFN-α/β was dispensable. The use of IL-12-neutralizing antibodies, prior to UV-HSV-1 delivery, confirmed the major role played by IL-12 in the early/transient IFN-γ burst.

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