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Use of Expresser Cell Lines to Functionally Characterize the Herpes Simplex Virus Transcription-Activating Protein ICP4Persson, Roy H. 12 1900 (has links)
<p>During Herpes Simplex Virus type 1 (HSV-1) infections, many viral proteins are synthesized and several have proven or suspected roles in regulating viral gene expression. To facilitate the study of the individual activity of one such protein, ICP4, the ICP4 gene was cloned in a plasmid vector, and expresser cell lines containing 5-30% of infected cell levels of ICP4 were established. The ICP4 is functional, correctly processed, and located in the cell nuclei. The endogenous ICP4 gene retained its capacity to respond to viral trans-acting factors, since its expression after superinfection with HSV-2 mimicked that of the viral gene. Although cells infected with lCP4 mutant viruses overproduce ICP4 and other immediate-early proteins, cell lines synthesizing a mutant form of ICP4 did not overproduce this protein, suggesting that autoregulation of the lCP4 gene requires more than 30% of the infected cell level of ICP4 or, alternatively, requires the presence of other viral proteins. After superinfection in the presence of an inhibitor of protein synthesis, the endogenous ICP4 is capable of transactivating viral early genes encoding thymidine kinase, lCP6, ICP8, gB, gD, and gE. In contrast, the early gene for the viral alkaline exonuclease, the early-late gene for VP5 and the late genes for p40 and gC, respond poorly or not at all. This demonstrates that most early genes can be induced by ICP4 in the absence of other viral immediate-early proteins, but that early-late and late genes require supplementary factors.</p> / Doctor of Philosophy (PhD)
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Stress hormones epinephrine and corticosterone modulate herpes simplex virus 1 and 2 productive infection and reactivation primarily in sympathetic, not sensory, neuronsIves, Angela M. January 2017 (has links)
Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) infect and establish latency in peripheral neurons, from which they can reactivate to cause recurrent disease throughout the life of the host. Stress is associated with exacerbation of clinical symptoms and induction of recurrences in humans and animal models. The viruses preferentially replicate and establish latency in different subtypes of sensory neurons, as well as in neurons of the autonomic nervous system that are highly responsive to stress hormones. To determine if stress-related hormones modulate productive and latent HSV-1 and HSV-2 infection within sensory and autonomic neurons, we analyzed viral DNA after treatment of primary adult murine neuronal cultures with the stress hormones epinephrine and corticosterone. Both sensory trigeminal (TG) and sympathetic superior cervical ganglia (SCG) neurons expressed adrenergic receptors and glucocorticoid receptor. In productively infected neuronal cultures, epinephrine treatment significantly increased HSV-1 DNA replication and production of viral progeny in SCG neurons, but no significant differences were found in TG neurons. In contrast, corticosterone significantly decreased HSV-2 DNA replication and production of viral progeny in SCG neurons, but not in TG neurons. In quiescently infected neuronal cultures, epinephrine and corticosterone significantly increased HSV-1 reactivation from sympathetic SCG neurons, but not sensory TG neurons. In contrast, corticosterone increased HSV-2 reactivation from both SCG and TG neurons, but epinephrine had no effect. Adrenergic or epinephrine-induced reactivation of HSV-1 in SCG neurons involved activation of several adrenergic receptors, the cyclic AMP response element binding protein (CREB), the transcription factor β-catenin, and the c-Jun N-terminal kinase (JNK). Corticosterone-induced reactivation of HSV-1 in SCG neurons required activation of glucocorticoid receptor (GCR) and transcription factors CREB and JNK. In contrast, corticosterone-induced reactivation of HSV-2 in TG and SCG neurons could utilize either the GCR or mineralocorticoid receptor (MCR) and most likely involves the chromatin remodeling properties of those receptors. Thus, stress-related hormones, epinephrine and corticosterone, selectively modulate productive and quiescent HSV-1 and HSV-2 infections primarily in sympathetic, but not sensory, neurons through different mechanisms. These results have implications for describing a mechanism by which stress-induced reactivation may occur in humans. / Ph. D. / Herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) are major human pathogens, which establish latency in neurons of the peripheral nervous system and reactivate to cause recurrent disease in humans. Physiological stress, which includes the secretion of the stress hormones epinephrine and cortisol, has been associated with increases in severity of clinical signs and increased recurrent disease in humans and animal models of herpetic disease. The mechanism by which physiological stress induces HSV reactivation has been assumed to be through suppression of the immune system. In addition, it has been assumed that sensory neurons harboring latent HSV are the primary source of reactivating virus for recurrent HSV disease. However, my dissertation provides evidence that the stress hormones epinephrine and corticosterone (the rodent equivalent of cortisol) can act on peripheral neurons in which the virus is latent, rather than through immune system suppression. In addition, my dissertation provides evidence that the autonomic nervous system, which modulates the physiological stress response, is an important source of reactivating virus to cause recurrent disease. The molecular pathway by which epinephrine and corticosterone induce HSV reactivation in primary adult murine neurons involves specific receptors, transcription factors, and protein kinases that could potentially be targeted in humans for inhibition of HSV reactivation and prevention of herpetic recurrent disease.
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An investigation of the properties and functions of the herpes associated ubiquitin-specific protease, HauspKathoria, Meeta January 1999 (has links)
No description available.
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Immunology of herpes simplex keratitis and its treatment by corneal transplantationLiu, Lei January 2009 (has links)
Purpose: To investigate the immune responses in cornea, ocular draining lymph nodes and spleen as well as the priming site of HSV-specific lymphocytes and their possible role in HSK development. To explore the possible treatment of HSK by transplanting corneal allograft and collagen artificial cornea. Methods: BALB/c mice corneas were infected with RE strain HSV-1. Immunohistochemistry of eye sections was performed and flow cytometry was carried out for cell suspension of cornea, TG, submandibular ocular draining lymph node (SMDLN),a non-ocular related lymph node and spleen at various times post HSV-1 eye inoculation. Results: There were strong immune responses in ocular draining lymph nodes post HSV-1 ocular infection, with a significant increasing number of innate cells as well as B cells and T cells. These changes were not observed in non-ocular related lymph nodes or spleen. An antigen specific response to HSV-1 antigen stimulation was observed <i>in vitro</i> for crude cells from ocular draining lymph node and to a lesser extent for spleen, but no changes were observed for the cells from non-ocular related lymph node. Interestingly, removal of ocular draining lymph nodes or spleen prior to HSV inoculation did not prevent HSK, but adversely impaired the control of viral replication, which was indicated by severe blepharitis and encephalitis. Both corneal allograft and collagen artificial cornea failed to survive in HSK eye, and retro-corneal membrane and degradation were the main obstacles for artificial cornea. Conclusions: HSV-specific lymphocytes are primed mainly in ocular draining lymph nodes, however, these cells might not be necessarily required for HSK development. Prevention of retro-corneal membrane seems to be important for survival of both corneal allograft and artificial cornea in HSK eyes.
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The effect of X-irradiation on the susceptibility of hela cells to infection by herpes simplex virusLinczer, Marion January 1965 (has links)
Thesis (M.A.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / The general problem of alteration in viral susceptibility by the irradiation of monolayers of tissue cells in culture was examined in this study; specifically an increased susceptibility of HeLa (an established cell line which was derived from an epidermaid carcinoma of the cervix) to destruction by herpes simplex virus (the virus commonly associated with cold sores or fever blisters). The experimental procedures included the study of the radiosensitivity of the cell line, survival curve analyses expressed as the efficiency of plating, that is the per cent of viable cells capable of forming colonies visible to the unaided eye within twelve days, and finally infectivity studies.
Tissue culture has proved to be a very useful tool in the study of radiation effects on tissues of higher animals since the effects of radiation can apparently be explained on the cellular level. Many types of cells have been studied but in all cases the most striking characteristic in irradiated populations is the increased cell size.
Ionizing radiation effects both the reproductive and synthesizing capacity of cells with the former being the more sensitive. Some irradiated cells never divide while others divide several times before reproduction stops. After the cells stop dividing, they continue to grow in size forming giants because synthesis of the cellular constituents continues.
Giant cells resulting from x-irradiation are more readily destroyed by the action of viruses than are non-irradiated cells. PUCK & MARCUS reported that NDV when plated on a mixture of giant and normal cells, destroyed more of the giants than normal cells. An enhancement of cell susceptibility following irradiation was also demonstrated for two enteroviruses by HSIUNG. The increased susceptibility of x-ray-induced giant cells to CPE of virus and the earlier release of virus by such cells was also demonstrated by LEVINE in studies with the Leon strain of type 3 polio. Many tissue culture-virus systems have been used to demonstrate alterations in susceptibility induced by x-irradiation, but few investigators have used a HeLa-HSV system to study this altered susceptibility using low levels of irradiation (50 roentgens to 500 roentgens) [TRUNCATED] / 2031-01-01
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Investigations of Factors Affecting the Transcriptional Regulation of Herpes Simplex Virus Type 1 βγ (Leaky-Late) GenesLown, Rosemary Ann 18 May 1994 (has links)
Herpes simplex virus type 1 (HSV-1) is a virus commonly causing cold sores in humans, however, virulent infections are known to produce debilitating encephalitis and death. HSV-1 transcription is carried out by the host cell RNA polymerase II in a tightly regulated temporal cascade. The first genes transcribed, the a genes, are activated in the absence of viral DNA synthesis. Transcription of the other temporal classes, the β, βγ, and γ genes is dependent upon the protein products of the a genes for activation. The purpose of this study was to investigate the factors that contribute to this rigid regulation of HSV-1 transcription. This investigation sought to identify some of the cellular and viral transcription factors that activate transcription of genes of the later kinetic classes. Two separate approaches were utilized in these investigations. 1) In vitro transcription using a soluble, cell free system to study the transcriptional regulation of the VP5 gene, and 2) DNA competition binding assays to identify and characterize the protein-DNA complexes resulting from interaction between the cisacting DNA sequences of the VP5 gene, other viral genes, and the proteins that bind to them. Attempts at in vitro transcription of β, βγ, and γ genes were unsuccessful. Because these genes require a products for activation, it was necessary to prepare nuclear extracts from infected cells. However, HSV-1 contains endogenous RNase activities which are components of the biochemical machinery by which the virus directs host transcription to the synthesis of viral molecules. The uses of virus deficient in the host shut-off function and various drugs were unsuccessful. Previous work in the Millette laboratory demonstrated a sequence in the VP5 promoter that played a significant role in the up regulation of expression of that gene. DNA binding competition studies using a number of HSV-1 sequences exhibiting partial homology to this sequence demonstrated that these sequences all compete for the binding of the same protein factor. Similarly, a piece of the human immunodeficiency virus (HIV) exhibiting a seven base pair homology also exhibited weak competition.
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Clinical Implications of HIV-1, HSV-2 Co-infection and Opportunities for InterventionTan, Darrell Hoi-San 07 January 2013 (has links)
HSV-2 may have adverse consequences in HIV. I evaluated the impact of HSV-2 co-infection on (highly active antiretroviral therapy)-untreated HIV infection in a systematic review of observational studies (study 1) and a retrospective cohort (study 2). I further evaluated whether HSV reactivation rates in co-infected persons differ by use of suppressive cART (study 3).
Study 1 found modest evidence that HSV-2 seropositivity may be associated with accelerated progression to opportunistic infection or clinical AIDS, but not with increased HIV viral load. Some evidence suggests that HSV-2 disease activity is associated with increased HIV viral load and decreased CD4 counts. Study 2 compared rates of CD4 count change by HSV-2 status (Focus HerpeSelect ELISA) among 218 patients with a past period of ART-untreated follow-up using mixed linear regression models. No significant difference in the rate of CD4 count change was observed in HSV-2 seropositives at +13.6 cells/mm3/year (p=0.12) in univariate analysis, and -4.5 cells/mm3/year (p=0.68) in analysis adjusted for sex, HSV-1, oral and genital HSV symptoms, immigrant status, and immigrant*time interaction. These findings support the need for carefully designed and executed studies of HSV-2 suppression as an adjunctive management strategy for HIV disease, but raise questions regarding the exact mechanism of negative synergy between these viruses and the relative importance of HSV-2 latency and replication in driving these effects.
In Study 3, 44 cART-naïve and 41 treated (HIV RNA<50 copies/mL) HIV+ adults with HSV-1 and/or 2 co-infection collected oral, genital and anal swabs daily for 28 days. Negative binomial models were used to quantify the relationship between cART and HSV shedding (Roche LightCycler HSV1/2). Overall HSV shedding was low, at a median (IQR) of 3.6% (0, 14.3%) of days. No relationship was seen between cART and HSV-1 or 2 shedding in univariate (RR=1.55, 95%CI=0.83,2.87) or multivariate analysis adjusted for sex, baseline CD4, recent immigrant status, and time since HIV diagnosis (aRR=1.05, 95%CI=0.43,2.58). Null results were also observed for HSV-1 and HSV-2 considered separately. That HSV shedding persists despite cART suggests that trials of anti-HSV drugs for improving HIV outcomes may be warranted in such patients.
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The role of the Herpes simplex virus Us3 protein kinase in the prevention of apoptosis /Munger, Joshua Colby. January 2001 (has links)
Thesis (Ph. D.)--University of Chicago, Committee on Virology, 2001. / Includes bibliographical references. Also available on the Internet.
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The role of cyclin D3 in the replicating of Herpes simplex virus 1 /Van Sant, Charles Lewis. January 2001 (has links)
Thesis (Ph. D.)--University of Chicago, Committee on Virology, June 2001. / Includes bibliographical references. Also available on the Internet.
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Clinical Implications of HIV-1, HSV-2 Co-infection and Opportunities for InterventionTan, Darrell Hoi-San 07 January 2013 (has links)
HSV-2 may have adverse consequences in HIV. I evaluated the impact of HSV-2 co-infection on (highly active antiretroviral therapy)-untreated HIV infection in a systematic review of observational studies (study 1) and a retrospective cohort (study 2). I further evaluated whether HSV reactivation rates in co-infected persons differ by use of suppressive cART (study 3).
Study 1 found modest evidence that HSV-2 seropositivity may be associated with accelerated progression to opportunistic infection or clinical AIDS, but not with increased HIV viral load. Some evidence suggests that HSV-2 disease activity is associated with increased HIV viral load and decreased CD4 counts. Study 2 compared rates of CD4 count change by HSV-2 status (Focus HerpeSelect ELISA) among 218 patients with a past period of ART-untreated follow-up using mixed linear regression models. No significant difference in the rate of CD4 count change was observed in HSV-2 seropositives at +13.6 cells/mm3/year (p=0.12) in univariate analysis, and -4.5 cells/mm3/year (p=0.68) in analysis adjusted for sex, HSV-1, oral and genital HSV symptoms, immigrant status, and immigrant*time interaction. These findings support the need for carefully designed and executed studies of HSV-2 suppression as an adjunctive management strategy for HIV disease, but raise questions regarding the exact mechanism of negative synergy between these viruses and the relative importance of HSV-2 latency and replication in driving these effects.
In Study 3, 44 cART-naïve and 41 treated (HIV RNA<50 copies/mL) HIV+ adults with HSV-1 and/or 2 co-infection collected oral, genital and anal swabs daily for 28 days. Negative binomial models were used to quantify the relationship between cART and HSV shedding (Roche LightCycler HSV1/2). Overall HSV shedding was low, at a median (IQR) of 3.6% (0, 14.3%) of days. No relationship was seen between cART and HSV-1 or 2 shedding in univariate (RR=1.55, 95%CI=0.83,2.87) or multivariate analysis adjusted for sex, baseline CD4, recent immigrant status, and time since HIV diagnosis (aRR=1.05, 95%CI=0.43,2.58). Null results were also observed for HSV-1 and HSV-2 considered separately. That HSV shedding persists despite cART suggests that trials of anti-HSV drugs for improving HIV outcomes may be warranted in such patients.
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