DNA vaccines and immunity to herpes simplex virus.
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Animals↗
Biomedical subjects
B T Rouse
Publications and source records attributed to B T Rouse.
Protection by minigenes: a novel approach of DNA vaccines.
To test the principle that genetically engineered epitopes in a plasmid DNA can efficiently induce specific immunity, a minigene cassette encoding cytotoxic T lymphocyte (CTL), helper T and B cell epitopes from herpes simplex virus (HSV) was constructed and placed in an expression vector named pcMini. Following immunizations with pcMini, mice developed epitope-specific CTLs comparable to the response induced by live HSV. Less effective but detectable antibody, lymphoproliferation, and T cell cytokine responses were also produced. In addition, pcMini-primed mice elicited a recall response upon restimulation with recombinant vaccinia virus expressing HSV antigen. The protection provided by minigene vaccination was significant, although not as efficient as live virus vaccine. The DNA minigene approach may prove useful to define and induce immune responses against minimal antigenic determinants.
Animals↗
Immune induction and modulation by topical ocular administration of plasmid DNA encoding antigens and cytokines.
In this article, the authors investigated if administration of eukaryotic expression plasmid DNA delivered to the ocular surface provided a means of inducing and modulating the immune response to herpes simplex virus (HSV). Topical application of gB DNA led to the development of HSV specific systemic humoral and cellular immunity. In addition, mucosal antibody was induced at both proximal and distal locations. Topically gB DNA immunized animals were protected against lethal challenge via either the systemic or the vaginal mucosal routes. Ocular pre-exposure to DNA encoding the cytokines interleukin (IL)-4 or IL-10, but not IL-2 or interferon-gamma, modulated the severity of the immunoinflammatory response to subsequent corneal infection with HSV. The present results indicate that the ocular surface provides a readily accessible site for DNA immunization and is suitable for both immune induction and modulation of the nature of the immune response that is induced.
Adjuvants, Immunologic↗
Herpes simplex virus latency and the immune response.
Following infection, herpes simplex virus establishes latency in the nervous system and recurrences of lytic replication occur periodically. Molecular events which may determine how virus enters latency, how it is maintained and what occurs during reactivation have been investigated. The role of the immune response in limiting infection of the nervous system, influencing the latent state and removing virus from peripheral sites following reactivation has also been studied.
Herpes Simplex↗
Modulation of virus-induced delayed-type hypersensitivity by plasmid DNA encoding the cytokine interleukin-10.
This report evaluates the efficacy of eukaryotic expression plasmids encoding cytokines at modulating the induction and expression of cutaneous delayed-type hypersensitivity (DTH) responses to virus infections. Mice given a single intramuscular administration of cytokine DNA were subsequently infected with either herpes simplex virus (HSV) or vaccinia virus, then tested for DTH. Responses in animals given interleukin-10 DNA were markedly suppressed for at least 5 weeks after pretreatment. Animals also expressed diminished T-cell proliferative responses and modest changes in the balance of T helper type 1 and 2 T-cell reactions. Treatment of animals already sensitized to express DTH, also showed inhibited responses, these taking 6-7 days after treatment to become apparent. Our results show the potency and convenience of plasmid DNA encoding cytokines to modulate inflammatory reactions. Advantages and risks of the cytokine DNA approach are briefly discussed.
Animals↗
Herpes simplex virus replication-induced expression of chemokines and proinflammatory cytokines in the eye: implications in herpetic stromal keratitis.
On infection of the cornea with herpes simplex virus (HSV), an immunopathologic response termed herpetic stromal keratitis (HSK) ensues. This response is mediated primarily by CD4+ T cells and only occurs if mice are infected with replication-competent virus, although replication-defective mutants induce cellular immune responses following infection. To determine the consequences of HSV replication in the cornea, which is crucial for HSK manifestation, corneas infected with productive virus and replication-defective mutants were analyzed for chemokines and proinflammatory cytokine mRNA expression by RT-PCR at various times. While productive infection resulted in rapid upregulation and sustained expression of such chemokines as N51/KC, macrophage inflammatory protein-1beta (MIP-1beta), MIP-2, and monocyte chemotactic protein-1 (MCP-1) and such cytokines as interleukin-1 (IL-1), IL-6, IL-12, and tumor necrosis factor-alpha (TNF-alpha), expression of such inflammatory mediators was minimal and transient after unproductive infection. Expression of MIP-1alpha and lymphotactin along with a biphasic expression of IL-6 and MIP-2 were seen only with productive infection. Initial PMN recruitment into the cornea was approximately 50-fold greater with productive infection than with unproductive infection. These data suggest that a replication-induced proinflammatory milieu in the cornea is crucial for the subsequent progression of HSK possibly because of enhancement of the expression of corneal agonists that drive HSK manifestation.
Animals↗
Modulation of viral immunoinflammatory responses with cytokine DNA administered by different routes.
The efficacy of plasmid DNA encoding cytokine administered by different routes, systemic or surface exposure, was evaluated and compared for their modulating effects on subsequent lesions caused by infection with herpes simplex virus (HSV). Systemic or topical administration of both interleukin-4 (IL-4) and IL-10 DNA but not IL-2 DNA caused a long-lasting suppression of HSV-specific delayed-type hypersensitivity response. IL-4 or IL-10 DNA preadministration also modulated the expression of immunoinflammatory lesions associated with corneal infection of HSV. Suppression of ocular lesions required that the DNA be administered to the nasal mucosa or ocular surfaces and was not evident after intramuscular administration. The modulating effect of IL-10 DNA was most evident after topical ocular administration, whereas the effects of IL-4 DNA given by both routes appeared to be equal. Preexposure of IL-4 DNA, but not IL-10 DNA, resulted in a significant change in Th subset balance following HSV infection. Our results indicate that the modulating effect of IL-4 or IL-10 DNA may proceed by different mechanisms. Furthermore, our results suggest that surface administration of cytokine DNA is a convenient means of modulating immunoinflammatory lesions.
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DNA vaccines for the prophylaxis and modulation of HSV infections.
There is currently no acceptable vaccine available for the control of herpes simplex virus (HSV) infection. This review discusses the reasons for the past failures and evaluates the prospect that a fresh approach, such as that provided by plasmid DNA encoding viral proteins, could provide a solution. The issues addressed include immune responses generated by plasmids encoding glycoproteins of HSV, the mechanism of HSV, the nature of the response in neonates, mucosal barrier immunity, attempts at improving immunogenicity of DNA vaccines and the immunomodulation potential with DNA encoding cytokines. The review concludes that DNA vaccines against HSV may merit evaluation in man, but DNA vaccine research may be more useful for uncovering mechanisms by which the immune system functions against HSV infection.
Journal Article↗
A skeptical look at viral immune evasion.
In the past several years, many viral gene products have been found to encode proteins which interfere with immune defense mechanisms. Whether these interactions between virus and immune system components are actually evasion mechanisms used during viral infections in their natural hosts remains to be proven. In vitro studies do, however, reveal several tactics which may aid viral replication and dissemination by interfering with components of both the innate and adaptive immune systems. In this manuscript, we discuss the more intensively studied of these putative in vitro evasion tactics and ponder their relevance in in vivo situations.
Antibody Formation↗
DNA immunization of neonates induces immunity despite the presence of maternal antibody.
Neonatal animals were not considered as suitable vaccine recipients either because of immune immaturity or because passively delivered antibody interferes with immune induction. In this report, we evaluated the response of neonatal mice to immunization with naked DNA encoding a herpes simplex virus (HSV) protein, and determined if maternally derived HSV antibody interfered with immunogenicity. Our results show that neonatal mice develop effective humoral and T cell responses after immunization with either DNA or inactivated vaccines. The nature of the responses to HSV immunization, however, was more Th2-like in neonates than in adults. Whereas neonatal mice from HSV-naive mothers responded well to both DNA and inactivated vaccines, only DNA immunization induced effective immunity in neonates born to immune mothers. Our results indicate that DNA vaccines might provide a useful means of immunizing young animals that still possess high levels of potentially interfering maternal antibody.
Animals↗
Suppression of ongoing ocular inflammatory disease by topical administration of plasmid DNA encoding IL-10.
Ocular infection with herpes simplex virus leads to an inflammatory lesion in the cornea orchestrated by CD4+ Th1 lymphocytes. This immunopathologic disease, called herpetic stromal keratitis, is an important cause of impaired vision. In this study, we set out to determine whether established lesions of herpetic stromal keratitis could be controlled by topically administering naked plasmid DNA encoding cytokines to the corneal surface. A single topical administration of DNA encoding IL-10 was beneficial to the majority (75%) of treated animals, and 50% (vs 10% in controls) resolved their lesions completely over a 23-day observation period. Topical ocular application of DNA encoding foreign proteins was also shown to be an effective means of inducing systemic and mucosal immune responses. The direct application of DNA encoding cytokines may represent an additional therapeutic option for the management of immunoinflammatory disease.
Administration, Topical↗
Regression of tumors in mice vaccinated with professional antigen-presenting cells pulsed with tumor extracts.
Vaccination with tumor extracts circumvents the need to identify specific tumor rejection antigens and extends the use of active immunotherapy to the vast majority of cancers, in which specific tumor antigens have not yet been identified. In this study we examined the efficacy of tumor vaccines comprised of unfractionated tumor material presented by professional antigen-presenting cells (APC): dendritic cells (DC) or macrophages (M phi). To enhance the relevance of these studies for human patients we used 2 poorly immunogenic murine tumor models and evaluated the effectiveness of the vaccination protocols in tumor-bearing animals. APC (in particular DC) pulsed with unfractionated extracts from these "poorly immunogenic" tumors were highly effective in eliciting tumor-specific cytotoxic T lymphocytes. A measurable CTL response could be detected after even a single immunization with tumor extract-pulsed DC. DC or M phi pulsed with tumor extract were also effective vaccines in tumor-bearing animals. In the murine bladder tumor (MBT-2) model a modest extension of survival and 40% cure rate was seen in the animal groups immunized with DC or M phi pulsed with MBT-2 tumor extract. DC or M phi pulsed with B16/F10.9 tumor extract were also remarkably effective in the B16 melanoma lung metastasis model, as shown by the observation that treatment with APC caused a significant reduction in lung metastases. Cumulatively, the CTL and immunotherapy data from the two murine tumor systems suggest that APC (in particular DC) pulsed with unfractionated cell extracts as a source of tumor antigen may be equally or more effective than genetically modified tumor vaccines.
Animals↗
On the essential involvement of neutrophils in the immunopathologic disease: herpetic stromal keratitis.
Corneal infection with herpes simplex virus-1 in immunocompetent mice induces an immunopathologic response termed herpetic stromal keratitis (HSK). The earliest sign of disease is neutrophil infiltration, which lasts for 48 to 72 h and then disappears. However, a secondary neutrophil infiltration, this time more massive, occurs, beginning 8 to 9 days postinfection, a time in which HSK becomes clinically evident. The role of neutrophils in HSK expression was investigated by eliminating such cells using a specific mAb (RB6-8C5). In neutrophil-depleted immunocompetent mice, virus replicated more abundantly, but no effects on HSK expression were observed, possibly because sustained neutropenia could not be maintained. However, using a severe combined immunodeficient mouse model, in which HSK does not occur unless given adoptive transfer of CD4+ T cells, the effects of neutrophil depletion were more pronounced. There were significantly less incidence and severity of HSK in CD4+ T cell-reconstituted severe combined immunodeficient mice that were depleted of neutrophils as compared with controls. Neutrophil-depleted mice displayed moderate to severe periocular skin lesions, progressively became cachetic, and developed signs of encephalitis. Virus was recovered at higher titers and for longer periods from eyes of neutrophil-depleted animals. Brain virus titers were also significantly higher on day 12 postinfection as compared with control animals. These results suggest that herpes simplex virus infection of the cornea rapidly invokes recruitment of neutrophils that may aid in viral clearance, and that neutrophils directly or indirectly serve as agonists in perpetuating a CD4+ T cell-mediated inflammatory reaction.
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Enhancement of immune response to naked DNA vaccine by immunization with transfected dendritic cells.
Immunization with plasmid DNA encoding various proteins promises to be a valuable vaccine approach especially if its immunogenicity could be optimized. In this study we show that the intramuscular delivery in dendritic cells (DC) of naked plasmid DNA encoding two proteins of herpes simplex virus (HSV) leads to the induction of significantly enhanced levels of resistance to viral challenge. Whereas DC transfected in vitro with DNA induced enhanced immunity, similarly transfected macrophage (M phi) populations lacked immunogenicity even though plasmid expression occurred in vitro. The enhanced immunity induced by DC-delivered DNA appeared to be associated mainly with an increased Th1 CD4+ T cell response. Our results add evidence that DC are the essential antigen-presenting cell types involved in immune responses to intramuscularly administered DNA vaccines.
Animals↗
Immunopathogenesis of herpetic ocular disease.
Herpes viruses are among the most prevalent of human virus infections. Productive replication of herpes simplex virus (HSV) is usually confined to mucocutaneous sites by the rapid deployment of innate and adaptive immune responses. Infection invariably results in establishment of latency and in some cases results in periodic reactivation of the virus. This article focuses primarily on ocular herpes with emphasis on the pathogenesis of stromal keratitis. Herpetic stromal keratitis (HSK) is an immunopathologic disease, which indeed is one of the leading causes of blindness in the Western world. The mechanisms by which HSV infection in human beings results in HSK is not well understood but studies using the mouse model has clearly indicated the role of T-cell-mediated immune response as the cause for ocular damage. We, in this article, attempt to provide an interpretive synthesis on different aspects of HSK pathogenesis, reviewing what is currently known and speculating on mysterious issues, such as, whether HSK represents a virus-induced autoimmune disease. We also discuss aspects of remission of the disease.
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Protective immunity against herpes simplex virus (HSV) type 1 following oral administration of recombinant Salmonella typhimurium vaccine strains expressing HSV antigens.
Salmonella typhimurium strains expressing foreign antigens of various pathogens are capable of eliciting antigen-specific humoral and cellular immune responses. Attenuated S. typhimurium strain chi4550 (delta(cya) delta(crp) delta(asd)) was used as an expression vector for herpes simplex virus (HSV) antigens. Genes encoding glycoprotein D (gD) and the immediate-early protein ICP27 of HSV-1 were cloned and expressed in plasmid pYA292 (asd+) and subsequently placed into chi4550. Following two oral immunizations, the protective efficacy of recombinant strains against zosteriform challenge with HSV-1 was measured in 3-4-week-old BALB/c mice. Levels of protection observed were 77% with the ICP27 construct but only 31% with the gD construct. Zosteriform protection correlates with a CD4+-mediated delayed-type hypersensitivity (DTH) reaction against HSV. Accordingly, significant DTH was observed only in mice immunized orally with the S. typhimurium ICP27 construct. ELISA analysis of antigen-specific humoral responses failed to detect serum antibody responses following oral administration although recombinant S. typhimurium were isolated from spleens of orally dosed mice up to day 30. Intravenous (i.v.) immunization with the gD-expressing construct did, however, induce detectable serum antibody responses. Some humoral IgA responses against gD in faecal samples were detected as early as 3 weeks post-oral immunization while those induced by the i.v. route were slightly lower. These data suggest that recombinant S. typhimurium HSV antigens are capable of inducing immunity against HSV, some aspects of which are protective against HSV challenge.
Administration, Oral↗
Induction of mucosal immunity against herpes simplex virus by plasmid DNA immunization.
The ability of mucosally delivered plasmid DNA encoding glycoprotein B (gB) of herpes simplex virus type 1 (HSV-1) to generate systemic as well as distal mucosal immunity was evaluated. BALB/c mice were immunized intranasally (i.n.) with gB DNA or DNA expressing beta-galactosidase (beta-Gal). Two days following immunization, gB and beta-Gal gene expression was detected by reverse transcription (RT)-PCR in lungs and cervical lymph nodes (CLN). Histological analysis showed that beta-Gal protein was expressed in vivo in the lungs and the CLN of animals immunized with i.n. administered beta-Gal DNA. The immune responses generated by i.n. administration of gB DNA with or without cholera toxin (CT) were compared to those generated by intramuscular (i.m.) gB DNA and i.n. live HSV administration. Three i.n. doses of gB DNA over a 3-week period resulted in a distal mucosal immunoglobulin A (IgA) response. In addition, the mucosal IgA response was enhanced by coadministration of CT with gB DNA. The i.m. route of immunization induced a strong IgG response in the serum and vagina but was inefficient in generating a mucosal IgA response. Antigen-specific cytokine ELISPOT analyses as well as the serum IgG1/IgG2a ratio indicated induction of stronger Th2 responses following the additional i.n. administration of CT compared to i.n. or i.m. gB DNA or i.n. live HSV immunization. In addition, mucosal immunization with gB DNA induced anti-HSV cell-mediated immunity in vivo as measured by delayed-type hypersensitivity. Although i.n. DNA immunization was an effective means of inducing mucosal antibody, it was inferior to i.m. DNA delivery in providing protection against lethal HSV challenge via the vaginal route. In addition, both i.m. and i.n. plasmid immunizations failed to generate an immune barrier to viral invasion of the mucosa.
Administration, Intranasal↗
DNA vaccines -- a modern gimmick or a boon to vaccinology?
The reports in 1993 that naked DNA encoding viral genes conferred protective immunity came as a surprise to most vaccinologists. This review analyses the expanding number of examples where plasmid DNA induces immune responses. Issues such as the type of immunity induced, mechanisms of immune protection, and how DNA vaccines compare with other approaches are emphasized. Additional issues discussed include the likely means by which DNA vaccines induce CTL, how the potency and type of immunity induced can be modified, and whether DNA vaccines represent a practical means of manipulating unwanted immune response occurring during immunoinflammatory diseases. It seems doubtful if DNA vaccines will replace currently effective vaccines, but they may prove useful for prophylactic use against some agents that at present lack an effective vaccine. DNA vaccines promise to be valuable to manipulate the immune response in situations where responses to agents are inappropriate or ineffective.
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