scholarly journals Effect of Apolipoprotein E on the Cerebral Load of Latent Herpes Simplex Virus Type 1 DNA

2006 ◽  
Vol 80 (11) ◽  
pp. 5383-5387 ◽  
Author(s):  
Javier S. Burgos ◽  
Carlos Ramirez ◽  
Isabel Sastre ◽  
Fernando Valdivieso
Keyword(s):  
Nervous System ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Herpes Simplex Virus Type ◽  
Acute Infection ◽  
Wild Type ◽  
Simplex Virus ◽  
The Brain ◽  
Hsv 1

ABSTRACT Herpes simplex virus type 1 (HSV-1) is neurotropic and enters a latent state lasting the lifetime of the host. This pathogen has recently been proposed as a risk factor for Alzheimer's disease (AD) in conjunction with apolipoprotein E4 (ApoE4). In a murine acute infection model, we showed that viral neuroinvasiveness depends directly on the overall ApoE dosage and especially on the presence of isoform ApoE4. If an interaction between ApoE and HSV-1 is involved in AD, it may occur during latency rather than during acute infection. Certainly, ApoE plays an important role in late-onset AD, i.e., at a time in life when the majority of people harbor HSV-1 in their nervous system. In the present work, wild-type, APOE knockout, APOE3, and APOE4 transgenic mice were used to analyze the influence of the ApoE profile on the levels of latent virus DNA. The knockout mice had significantly lower concentrations of the virus in the nervous system than the wild-type mice, while the APOE4 mice had very high levels in the brain compared to the APOE3 animals. ApoE4 seems to facilitate HSV-1 latency in the brain much more so than ApoE3. The APOE dosage correlated directly with the HSV-1 DNA concentration in the brain, strengthening the hypothesis that HSV-1, together with ApoE, might be involved in AD.

scholarly journals The Immune Response to Herpes Simplex Virus Type 1 Infection in Susceptible Mice Is a Major Cause of Central Nervous System Pathology Resulting in Fatal Encephalitis

2008 ◽  
Vol 82 (14) ◽  
pp. 7078-7088 ◽  
Author(s):  
Patric Lundberg ◽  
Chandran Ramakrishna ◽  
Jeffrey Brown ◽  
J. Michael Tyszka ◽  
Mark Hamamura ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Nervous System ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Brain Stem ◽  
Herpes Simplex Virus Type ◽  
Simplex Virus ◽  
The Brain ◽  
Hsv 1

ABSTRACT This study was undertaken to investigate possible immune mechanisms in fatal herpes simplex virus type 1 (HSV-1) encephalitis (HSE) after HSV-1 corneal inoculation. Susceptible 129S6 (129) but not resistant C57BL/6 (B6) mice developed intense focal inflammatory brain stem lesions of primarily F4/80+ macrophages and Gr-1+ neutrophils detectable by magnetic resonance imaging as early as day 6 postinfection (p.i.). Depletion of macrophages and neutrophils significantly enhanced the survival of infected 129 mice. Immunodeficient B6 (IL-7R−/− Kitw41/w41) mice lacking adaptive cells (B6-E mice) and transplanted with 129 bone marrow showed significantly accelerated fatal HSE compared to B6-E mice transplanted with B6 marrow or control nontransplanted B6-E mice. In contrast, there was no difference in ocular viral shedding in B6-E mice transplanted with 129 or B6 bone marrow. Acyclovir treatment of 129 mice beginning on day 4 p.i. (24 h after HSV-1 first reaches the brain stem) reduced nervous system viral titers to undetectable levels but did not alter brain stem inflammation or mortality. We conclude that fatal HSE in 129 mice results from widespread damage in the brain stem caused by destructive inflammatory responses initiated early in infection by massive infiltration of innate cells.

scholarly journals Suppression of Proinflammatory Cytokine Expression by Herpes Simplex Virus Type 1

2004 ◽  
Vol 78 (11) ◽  
pp. 5883-5890 ◽  
Author(s):  
Trine H. Mogensen ◽  
Jesper Melchjorsen ◽  
Lene Malmgaard ◽  
Antonella Casola ◽  
Søren R. Paludan
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Proinflammatory Cytokines ◽  
Herpes Simplex Virus Type ◽  
Cytokine Expression ◽  
Wild Type ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Viral immune evasion strategies are important for establishment and maintenance of infections. Many viruses are in possession of mechanisms to counteract the antiviral response raised by the infected host. Here we show that a herpes simplex virus type 1 (HSV-1) mutant lacking functional viral protein 16 (VP16)—a tegument protein promoting viral gene expression—induced significantly higher levels of proinflammatory cytokines than wild-type HSV-1. This was observed in several cell lines and primary murine macrophages, as well as in peritoneal cells harvested from mice infected in vivo. The enhanced ability to stimulate cytokine expression in the absence of VP16 was not mediated directly by VP16 but was dependent on the viral immediate-early genes for infected cell protein 4 (ICP4) and ICP27, which are expressed in a VP16-dependent manner during primary HSV infection. The virus appeared to target cellular factors other than interferon-induced double-stranded RNA-activated protein kinase R (PKR), since the virus mutants remained stronger inducers of cytokines in cells stably expressing a dominant-negative mutant form of PKR. Finally, mRNA stability assay revealed a significantly longer half-life for interleukin-6 mRNA after infection with the VP16 mutant than after infection with the wild-type virus. Thus, HSV is able to suppress expression of proinflammatory cytokines by decreasing the stability of mRNAs, thereby potentially impeding the antiviral host response to infection.

scholarly journals Eclipse Phase of Herpes Simplex Virus Type 1 Infection: Efficient Dynein-Mediated Capsid Transport without the Small Capsid Protein VP26

2006 ◽  
Vol 80 (16) ◽  
pp. 8211-8224 ◽  
Author(s):  
Katinka Döhner ◽  
Kerstin Radtke ◽  
Simone Schmidt ◽  
Beate Sodeik
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Capsid Protein ◽  
Herpes Simplex Virus Type ◽  
Viral Genome ◽  
Wild Type ◽  
Nuclear Targeting ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Cytoplasmic dynein,together with its cofactor dynactin, transports incoming herpes simplex virus type 1 (HSV-1) capsids along microtubules (MT) to the MT-organizing center (MTOC). From the MTOC, capsids move further to the nuclear pore, where the viral genome is released into the nucleoplasm. The small capsid protein VP26 can interact with the dynein light chains Tctex1 (DYNLT1) and rp3 (DYNLT3) and may recruit dynein to the capsid. Therefore, we analyzed nuclear targeting of incoming HSV1-ΔVP26 capsids devoid of VP26 and of HSV1-GFPVP26 capsids expressing a GFPVP26 fusion instead of VP26. To compare the cell entry of different strains, we characterized the inocula with respect to infectivity, viral genome content, protein composition, and particle composition. Preparations with a low particle-to-PFU ratio showed efficient nuclear targeting and were considered to be of higher quality than those containing many defective particles, which were unable to induce plaque formation. When cells were infected with HSV-1 wild type, HSV1-ΔVP26, or HSV1-GFPVP26, viral capsids were transported along MT to the nucleus. Moreover, when dynein function was inhibited by overexpression of the dynactin subunit dynamitin, fewer capsids of HSV-1 wild type, HSV1-ΔVP26, and HSV1-GFPVP26 arrived at the nucleus. Thus, even in the absence of the potential viral dynein receptor VP26, HSV-1 used MT and dynein for efficient nuclear targeting. These data suggest that besides VP26, HSV-1 encodes other receptors for dynein or dynactin.

scholarly journals A Herpes Simplex Virus Type 1 Latency-Associated Transcript Mutant with Increased Virulence and Reduced Spontaneous Reactivation

1999 ◽  
Vol 73 (2) ◽  
pp. 920-929 ◽  
Author(s):  
Guey-Chuen Perng ◽  
Susan M. Slanina ◽  
Ada Yukht ◽  
Barbara S. Drolet ◽  
William Keleher ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Ocular Infection ◽  
Wild Type ◽  
Simplex Virus ◽  
Spontaneous Reactivation ◽  
Hsv 1

ABSTRACT The herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) gene is essential for efficient spontaneous reactivation of HSV-1 from latency. We previously reported that insertion of the LAT promoter and just the first 1.5 kb of the 8.3-kb LAT gene into an ectopic location in the virus restored wild-type spontaneous reactivation to a LAT null mutant. This mutant, LAT3.3A (previously designated LAT1.5a), thus showed that the expression of just the first 1.5 kb of LAT is sufficient for wild-type spontaneous reactivation. We also showed that in the context of the entire LAT gene, deletion of LAT nucleotides 76 to 447 (LAT mutantdLAT371) had no effect on spontaneous reactivation or virulence. We report here on a LAT mutant designated LAT2.9A. This mutant is similar to LAT3.3A, except that the ectopic LAT insert contains the same 371-nucleotide deletion found in dLAT371. We found that LAT2.9A had a significantly reduced rate of spontaneous reactivation compared to marker-rescued and wild-type viruses. This was unexpected, since the combined results of dLAT371 and LAT3.3A predicted that spontaneous reactivation of LAT2.9A would be wild type. We also found that LAT2.9A was more virulent than wild-type or marker-rescued viruses after ocular infection of rabbits. This was unexpected, since LAT null mutants and LAT3.3A have wild-type virulence. These results suggest for the first time (i) that regions past the first 1.5 kb of LAT can compensate for deletions in the first 1.5kb of LAT and may therefore play a role in LAT dependent spontaneous reactivation and (ii) that regions of LAT affect viral virulence.

scholarly journals A Novel Herpes Simplex Virus Type 1 Transcript (AL-RNA) Antisense to the 5′ End of the Latency-Associated Transcript Produces a Protein in Infected Rabbits

2002 ◽  
Vol 76 (16) ◽  
pp. 8003-8010 ◽  
Author(s):  
Guey-Chuen Perng ◽  
Barak Maguen ◽  
Ling Jin ◽  
Kevin R. Mott ◽  
John Kurylo ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Herpes Simplex Virus Type ◽  
Open Reading Frame ◽  
Wild Type ◽  
Reading Frame ◽  
Viral Virulence ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Following primary ocular infection, herpes simplex virus type 1 (HSV-1) establishes a lifelong latent infection in sensory neurons of the trigeminal ganglia. Latency-associated transcript (LAT), the only known viral gene abundantly transcribed during HSV-1 neuronal latency, is required for high levels of reactivation. Recently we showed that three different mutants that do not alter the LAT promoter but contain deletions within the 5′ end of the primary LAT transcript affect viral virulence (G. C. Perng et al., J. Virol. 75:9018-9028, 2001). In contrast, in LAT-null mutants viral virulence appears unaltered (T. M. Block et al., Virology 192:618-630, 1993; D. C. Bloom et al., J. Virol. 68:1283-1292, 1994; J. M. Hill et al., Virology 174:117-125, 1990; G. C. Perng et al., J. Virol. 68:8045-8055, 1994; F. Sedarati, K. M. Izumi, E. K. Wagner, and J. G. Stevens, J. Virol. 63:4455-4458, 1989). We therefore hypothesized that the 5′ end of LAT and/or an as yet unidentified gene that overlaps part of this region is involved in viral virulence. We report here on the discovery and initial characterization of a novel HSV-1 RNA consistent with such a putative gene. The novel RNA was antisense to the 5′ end of LAT and was designated AL-RNA (anti-LAT sense RNA). The AL-RNA overlapped the core LAT promoter and the first 158 nucleotides of the 5′ end of the primary LAT transcript. AL-RNA was detected in extracts from neuron-like cells (PC-12) infected with wild-type HSV-1 but not in cells infected with a mutant with the AL region deleted. The deletions in each of the above three mutants with altered virulence encompass the 5′ end of the AL-RNA, and these mutants cannot transcribe AL. This supports the hypothesis that the AL gene may play a role in viral virulence. Based on comparison to the corresponding genomic sequence, the AL-RNA did not appear to be spliced. The AL-RNA was polyadenylated and contained an open reading frame capable of encoding a protein 56 amino acids in length with a predicted molecular mass of 6.8 kDa. Sera from three of three rabbits infected with wild-type HSV-1 but not sera from any of three rabbits infected with a mutant with the AL-RNA region deleted recognized the Escherichia coli recombinantly expressed AL open reading frame on Western blots. In addition, four of six rabbits infected with wild-type virus developed enzyme-linked immunosorbent assay titers against one or more AL synthetic peptides. These results suggest that an AL protein is produced in vivo.

scholarly journals Negative regulation of herpes simplex virus type 1 ICP4 promoter by IE180 protein of pseudorabies virus

2004 ◽  
Vol 85 (8) ◽  
pp. 2125-2130 ◽  
Author(s):  
S. Gómez-Sebastián ◽  
E. Tabarés
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Negative Regulation ◽  
Wild Type ◽  
Recombinant Viruses ◽  
Simplex Virus ◽  
Hsv 1

Recombinant pseudorabies viruses (PRVs) gIS8 and N1aHTK were constructed by the insertion of a chimeric gene (α4–TK) from herpes simplex virus type 1 (HSV-1) into wild-type PRV. HSV-1 TK expression by these recombinant viruses resulted in enhanced sensitivity to ganciclovir, compared to that of the wild-type PRV, and was similar to the sensitivity shown by HSV-1. Infection with gIS8 or N1aHTK recombinant viruses led to expression of HSV-1 TK mRNA as an immediate–early (IE) gene, observed by downregulation of the HSV-1 α4 promoter. This negative regulation was due to a PRV IE protein, IE180. IE180, however, does not have all the regulatory functions of the infected-cell protein ICP4, as it does not restore the growth of ICP4-deficient HSV-1 mutants.

scholarly journals Effect of Anti-CXCL10 Monoclonal Antibody on Herpes Simplex Virus Type 1 Keratitis and Retinal Infection

2003 ◽  
Vol 77 (18) ◽  
pp. 10037-10046 ◽  
Author(s):  
Daniel J. J. Carr ◽  
James Chodosh ◽  
John Ash ◽  
Thomas E. Lane
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Inflammatory Response ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Acute Infection ◽  
Corneal Stroma ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT The inflammatory response to acute ocular herpes simplex virus type 1 (HSV-1) infection in mice involves the innate and adaptive immune response, with an associated increase in the secretion of chemokines, including CXCL10 (interferon-inducible protein 10 kDa [IP-10]). Neutralizing antibodies to mouse CXCL10 were used to determine the role of CXCL10 during the acute phase of HSV-1 ocular infection. Treatment of HSV-1-infected mice with antibody to CXCL10 significantly reduced CXCL10 levels in the eye and trigeminal ganglion and reduced mononuclear cell infiltration into the corneal stroma. These results coincided with reduced ICAM-1 and CXCR3 transcript expression, macrophage inflammatory protein-1α and CXCL10 levels, and corneal pathology but increased viral titers in the stroma and trigeminal ganglion. Progression of the virus from the corneal stroma to the retina during acute infection was significantly hindered in anti-CXCL10-treated mice. In addition, colocalization of viral antigen with infiltrating leukocytes in the iris and retina during acute infection suggests that one means by which HSV-1 traffics to the retina involves inflammatory cells (primarily CD11b+ cells). Collectively, the results suggest that CXCL10 expression in the eye initially orchestrates the inflammatory response to acute HSV-1 infection, which facilitates the spread of the virus to other restricted sites within the eye.

scholarly journals Recombinant Herpes Simplex Virus Type 1 Expressing Murine Interleukin-4 Is Less Virulent than Wild-Type Virus in Mice

2001 ◽  
Vol 75 (19) ◽  
pp. 9029-9036 ◽  
Author(s):  
Homayon Ghiasi ◽  
Yanira Osorio ◽  
Guey-Chuen Perng ◽  
Anthony B. Nesburn ◽  
Steven L. Wechsler
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Herpes Simplex Virus Type ◽  
Interleukin 4 ◽  
Wild Type Virus ◽  
Type Virus ◽  
Wild Type ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT The effect of interleukin-4 (IL-4) on herpes simplex virus type 1 (HSV-1) infection in mice was evaluated by construction of a recombinant HSV-1 expressing the gene for murine IL-4 in place of the latency-associated transcript (LAT). The mutant virus (HSV-IL-4) expressed high levels of IL-4 in cultured cells. The replication of HSV-IL-4 in tissue culture and in trigeminal ganglia was similar to that of wild-type virus. In contrast, HSV-IL-4 appeared to replicate less well in mouse eyes and brains. Although BALB/c mice are highly susceptible to HSV-1 infection, ocular infection with HSV-IL-4 resulted in 100% survival. Furthermore, 57% of the mice survived coinfection with a mixture of HSV-IL-4 and a lethal dose of wild-type McKrae, compared with only 10% survival following infection with McKrae alone. Similar to wild-type BALB/c mice, 100% of IL-4−/− mice also survived HSV-IL-4 infection. T-cell depletion studies suggested that protection against HSV-IL-4 infection was mediated by a CD4+-T-cell response.

scholarly journals NF-κB Is Required for Apoptosis Prevention during Herpes Simplex Virus Type 1 Infection

2003 ◽  
Vol 77 (13) ◽  
pp. 7261-7280 ◽  
Author(s):  
Margot L. Goodkin ◽  
Adrian T. Ting ◽  
John A. Blaho
Keyword(s):  
Protein Synthesis ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Infected Cell ◽  
Herpes Simplex Virus Type ◽  
Wild Type ◽  
Tnf Α ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Wild-type herpes simplex virus type 1 (HSV-1) infection triggers apoptosis in human cells. The subsequent synthesis of infected cell proteins between 3 and 6 h postinfection (hpi) acts to block this process from killing the cells. The factors produced during this window also prevent cell death induced by environmental staurosporine or sorbitol (M. Aubert, J. O'Toole, and J. A. Blaho, J. Virol. 73:10359-10370, 1999). We now report that (i) during the prevention window, HSV-1(F) also inhibited apoptosis induced by tumor necrosis factor alpha (TNF-α) plus cycloheximide (CHX) treatment. While deciphering the mechanism of this inhibition, we observed that (ii) the transcription factor NF-κB translocated from the cytoplasm into the nuclei of infected cells, and (iii) this migration initiated at 3 hpi. (iv) The complete inhibition of protein synthesis at 3 hpi by the addition of CHX precluded NF-κB translocation, while CHX additions at 6 hpi or later did not elicit this effect. This result confirms that infected cell protein synthesis is required for the nuclear import of NF-κB. (v) The detection of NF-κB in nuclei correlated with the ability of HSV-1(F), HSV-1(KOS1.1), or HSV-1(R7032), a replication-competent recombinant virus containing a deletion in the gene encoding the gE glycoprotein, to prevent apoptosis. (vi) NF-κB did not bind its κB DNA recognition site and remained cytoplasmic in cells actively undergoing apoptosis following infection with HSV-1(vBSΔ27), a virus with the key regulatory protein ICP27 deleted. (vii) Prestimulation of NF-κB by the addition of a phorbol ester prevented HSV-1(vBSΔ27)-induced apoptosis. (viii) Retention of NF-κB in the cytoplasm by the addition of a pharmacological antagonist of its release from IκBα led to an increase in death factor processing during HSV-1(F) infection. (ix) A novel HEp-2 clonal cell line, termed IκBαDN, was generated which expresses a dominant-negative form of IκBα. Treatment of IκBαDN cells with TNF-α in the absence of CHX resulted in apoptotic death due to the inability of NF-κB to become activated in these cells. Finally, (x) infection of IκBαDN cells with HSV-1(F) or HSV-1(KOS1.1) resulted in apoptosis, demonstrating that (xi) the nuclear translocation of NF-κB between 3 and 6 hpi (the prevention window) is necessary to prevent apoptosis in wild-type HSV-1-infected human HEp-2 cells.

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