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PubMed1990

Viral reactivation as a cause of unexplained fever in patients with progressive metastatic breast cancer.

Patients suffering from metastatic breast cancer and recurrent fever were investigated for viral reactivation or new viral infection as a possible cause of these febrile episodes. Three groups of patients were included in the study: (a) patients under adjuvant chemotherapy with cyclophosphamide, methotrexate and fluoruracil, (b) patients with stable metastatic disease treated with cyclophosphamide, fluoruracil and Adriamycin or mitoxantrone and (c) patients with progressive metastatic disease who also received the latter treatment. During the time of observation, patients under adjuvant chemotherapy did not present with fever or asymptomatic viral reactivation or bacterial infections at all. Out of 7 patients with stable disease, 2 had bacterial infections that coincided with the leukocyte nadir, and 1 presented with asymptomatic reactivation of cytomegalovirus. In contrast, fever in 9 of 11 patients with progressive disease was associated with a reactivation of herpes simplex virus (HSV) and in 3 of them with a consecutive reactivation of varicella zoster virus (VZV). The increase in complement-fixing anti-HSV or anti-VZV antibodies occurred in close association with a rise of the respective preexisting antibodies of the IgG class. In addition, HSV-infected cells were recovered from the urine of 7 patients with progressive disease further corroborating the serological data. Incidentally, natural killer cell activity, which has been postulated to be connected with the defense against viral infections, was found to be significantly lower in the group of patients with progressive disease, as compared to the group of patients under adjuvant chemotherapy (P less than 0.05) or to the group of patients with stable disease (P less than 0.05). We conclude that unexplained fever in patients with progressive metastatic breast cancer may result from viral reactivation.

Antibodies, Viral↗

PubMed2001

[Hemophagocytosis during multiple organ failure: M-CSF overproduction or viral reactivation?].

OBJECTIVE: This study was aimed to assess the potential role of M-CSF and viral reactivation in the genesis of haemophagocytosis during the multiple organ failure (MOF) syndrome. METHODS: Twenty-five patients (mean age: 60 +/- 16 years; Apache II: 23 +/- 5) sustaining MOF with an unexplained thrombocytopenia were studied. In each patient, a bone marrow aspirate, serum M-CSF concentration, and a virological examination (Herpes viruses) were obtained on admission. In addition, 20 patients (mean age: 57 +/- 15 years; Apache II: 24 +/- 7) with at least two organ failures but no thrombocytopenia constituted the control group. Circulating M-CSF levels and the frequency of virus reactivation were compared between groups. RESULTS: Haemophagocytosis was diagnosed in 11/25 patients (44%). No viral reactivation was found. Serum M-CSF concentrations were higher in the presence of haemophagocytosis (699 +/- 242 vs 438 +/- 157 IU.mL-1; p < 0.05). Ferritin levels were also increased in the presence of a macrophage activation (3,258 +/- 2,807 vs. 520 +/- 280 mg.L-1; p < 0.0001). In contrast, both circulating M-CSF and ferritin levels were similar between thrombocytopenic patients with no hemophagocytosis and controls. CONCLUSIONS: This study confirmed the high incidence of haemophagocytosis in critically ill patients sustaining MOF. In this setting, circulating M-CSF levels were markedly elevated, whereas no Herpes viruses reactivation was found.

Aged↗

PubMed1992

Risk factors for viral reactivation following bone marrow transplantation.

The identification of risk factors for viral reactivation following transplantation is essential in order that antiviral prophylactic regimes may be allocated rationally. In the pretransplant period qualitative serological assessment of recipient and donor is informative with regard to the risk of post-transplant reactivation and disease. In addition, the quantitative level of herpes simplex virus (HSV) IgG in the pretransplant recipient is predictive of post-transplant HSV excretion, although this relationship does not exist for other viruses of the herpes group. We discuss the value of surveillance cultures for cytomegalovirus in the post-transplant period in predicting the development of CMV disease, and how this may allow effective intervention to prevent what is a major cause of morbidity and mortality in the transplant population.

Antibodies, Viral↗

PubMed1989

Correlation between the induction of heat shock protein 70 and enhanced viral reactivation in mammalian cells treated with ultraviolet light and heat shock.

Enhanced viral reactivation (EVR) is considered to be one manifestation of an inducible response to DNA damage in mammalian cells analogous to the SOS response in Escherichia coli. EVR is characterized by the increased survival of ultraviolet (UV)-irradiated virus in cells which have been pretreated with DNA-damaging agents or by another type of cellular stress, heat shock (HS). In this study, we have analyzed the induction of nuclear proteins from Vero cells treated with either UV or HS, with the goal of identifying the protein(s) which mediate the EVR response. Results of 2-dimensional protein gel electrophoresis and fluorographic analysis of [35S]methionine-labeled nuclear proteins showed that UV-irradiation caused the increased synthesis of five proteins at 4-9 h after treatment. At 19-24 h, one of these proteins was still being synthesized at a higher level in UV-irradiated cells, and there were nine additional proteins whose syntheses were enhanced over control levels. In contrast, HS induced only one Mr 72,000 nuclear protein whose synthesis was maximal during the 4-9-h labeling period and corresponded to one of the proteins induced by UV at 19-24 h. Subsequent Western and Northern blot analyses have confirmed that this protein is a member of the heat shock protein (hsp) 70 family. Elevated nuclear levels of this protein correlated temporally with the maximum EVR response induced by each treatment (4 h after HS and 24 h after UV). Since the kinetics of EVR is different following UV and HS and parallels the difference in the induction of nuclear levels of hsp70 following each treatment, the results suggest that hsp70 may be involved in mediating the EVR response. In addition, this protein may also play a role in the recovery of DNA synthesis in UV-irradiated cells.

Blotting, Northern↗

PubMed1986

Benzo[a]pyrene diol epoxide induces viral reactivation at concentrations that block DNA elongation in mammalian cells.

The survival of UV-irradiated Simian virus 40 (SV40) in CV-1P African green monkey kidney cells treated with (+/-)7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BP-diol epoxide I) was studied. Enhanced survival of UV damaged SV40 was detected when CV-1P cells were treated with dose levels of BP-diol epoxide I corresponding to the exponential portion (0.33-1.11 microM) of a CV-1P cell survival curve. Dose levels of BP-diol epoxide I corresponding to the shoulder region (less than or equal to 0.16 microM) of a CV-1P survival curve did not induce viral reactivation. The shoulder region concentrations of BP-diol epoxide I selectively inhibited DNA initiation while the concentrations on the exponential portion of the curve preferentially inhibited DNA elongation. It was shown in a time course of enhanced viral survival at 0.66 microM BP-diol epoxide I that the reactivation response was fully induced by 24 h. In conclusion, the viral reactivation response was associated with concentrations of BP-diol epoxide I which induced lethal damage and preferentially inhibited DNA elongation.

Animals↗

PubMed1992

Uracil in OriS of herpes simplex 1 alters its specific recognition by origin binding protein (OBP): does virus induced uracil-DNA glycosylase play a key role in viral reactivation and replication?

We have recently demonstrated that mammalian uracil-DNA glycosylase activity is undetectable in adult neurons. On the basis of this finding we hypothesized that uracil, derived either from oxidative deamination of cytosine or misincorporation of dUMP in place of dTMP during DNA repair by the unique nuclear DNA polymerase present in adult neurons, DNA polymerase beta, might accumulate in neuronal DNA. Uracil residues could also arise in the herpes simplex 1 (HSV1) genome during latency in nerve cells. We therefore suggest a role for the virus encoded uracil-DNA glycosylase in HSV1 reactivation and in the first steps of DNA replication. We show here 1) that the viral DNA polymerase incorporates dUTP in place of dTTP with a comparable efficiency in vitro; 2) that virus specific DNA/protein interactions between the virus encoded origin binding protein and its target DNA sequence is altered by the presence of uracil residues in its central region TCGCA. Thus uracil, present in viral OriS or other key sequences could hamper the process leading to viral reactivation. Hence, HSV1 uracil-DNA glycosylase, dispensable in viral proliferation in tissue culture, could be essential in neurons for the "cleansing" of the viral genome of uracil residues before the start of replication.

Base Sequence↗

PubMed2004

Bupropion (Zyban, Wellbutrin) inhibits nicotine-induced viral reactivation in herpes simplex virus type 1 latent rabbits.

We reported that nicotine applied via a transdermal patch (21 mg/day) induced viral reactivation and ocular shedding in herpes simplex virus type 1 (HSV-1) latent rabbits. One possible mechanism of action involves the release of catecholamines and other similar agents, triggering HSV reactivation. Bupropion (Zyban, Wellbutrin), a non-nicotine aid to smoking cessation, inhibits neuronal uptake of norepinephrine, serotonin, and dopamine. To determine whether bupropion inhibits HSV reactivation, rabbits latent with HSV-1 were grouped (at least 10 rabbits/group) and treated as follows: nicotine patch (transdermal delivery) and bupropion [Zyban sustained-release tablets (150 mg) twice a day (oral)], nicotine patch only, Zyban tablets only [twice a day (oral)], nicotine patch with oral placebo [twice a day (oral)], or no drug treatment. Eyes were swabbed for 22 consecutive days. The appearance of HSV-1 in the tear film was significantly less frequent in the bupropion-treated rabbits, in terms of positive rabbits/total rabbits, positive eyes/total eyes, and positive swabs/total swabs. Nicotine-treated rabbits had 78/440 (17.7%) positive/total swabs, and nicotine/placebo-treated rabbits had 149/792 (18.8%) positive/total swabs, whereas bupropion-treated rabbits had 23/440 (5.2%), and nicotine/bupropion-treated rabbits had 47/792 (5.9%) positive/total swabs. Thus, bupropion significantly reduces nicotine-induced HSV reactivation in latent rabbits.

Animals↗

PubMed2006

BK viral reactivation in cardiac transplant patients: evidence for a double-hit hypothesis.

BACKGROUND: BK nephropathy is a significant cause of renal dysfunction in renal allograft recipients. The question of whether BK viral infection plays a role in renal dysfunction in cardiac transplantation patients remains to be answered. METHODS: We prospectively examined the prevalence of BK viral reactivation in the setting of cardiac transplantation and performed a cross-sectional analysis of 111 cardiac transplantation patients. We also assessed the prevalence of viremia in a cohort of 29 renal transplant recipients. RESULTS: We found urinary decoy cells in 28 cardiac transplantation patients. Of these, 14 patients had evidence of BK viral DNA in the urine. None, however, had evidence of BK viremia. Mean age, gender, levels of pre- and post-transplant serum creatinine, cardiopulmonary bypass time, and ischemic time were not significantly different between the groups. We found that 7 of 29 renal transplant recipients studied had BK viral DNA in their urine. CONCLUSION: These findings are evidence of BK virus reactivation in the setting of cardiac transplantation at a percentage similar to that seen in renal allograft recipients. In contrast to renal allograft recipients, none had evidence of viremia. Thus, even in the setting of established BK virus reactivation, immunosuppression in combination with renal allograft dysfunction and renal ischemic injury is usually insufficient to cause BK viremia and nephropathy, and it appears that a second, organ-specific hit is necessary, such as kidney inflammation, kidney ischemia, or donor-recipient human leukocyte antigen mismatch.

Adult↗

PubMed1996

Delayed facial palsy after acoustic neuroma resection: the role of viral reactivation.

Delayed facial palsy after acoustic neuroma resection may occur in up to 15% of cases. Prognosis is generally good if the palsy does not progress to total paralysis. However, a delayed palsy with subsequent total paralysis has a more variable final outcome, which ranges from normal function to permanent total paralysis. This delayed paralysis has been attributed to edema from surgical manipulation of the facial nerve. Steroids and intraoperative decompression of the meatal foramen have been used with some success, but some cases remain refractory to these measures. Herpes simplex virus and varicella-zoster virus are ubiquitous in the population and remain in a latent state in neural ganglia. These viruses are reactivated during times of stress. Trigeminal nerve surgery (partial sensory rhizotomy and microvascular decompression) stimulates reactivation of herpes simplex with manifestations in the sensory distribution of the trigeminal nerve in 38-94% of procedures. Prevention of this reactivation has been demonstrated in placebo-controlled trials by using prophylactic acyclovir. We present a patient who underwent translabyrinthine resection of an intracanalicular acoustic neuroma and in whom developed otalgia, vesicles on the ear canal and the ipsilateral buccal mucosa, and progressive facial palsy the week after surgery. Serologic evaluation confirmed the diagnosis of herpes zoster oticus. Reactivation of latent virus apparently occurred as a result of surgical manipulation of the facial nerve. This parallels viral reactivation seen in trigeminal nerve surgery. We propose a new theory for an additional cause of delayed facial palsy after acoustic neuroma resection-reactivation of latent herpesvirus resulting from surgical trauma. Acyclovir should be evaluated in clinical trials for a prophylactic role in patients undergoing acoustic neuroma resection or a therapeutic role in patients in whom a delayed postoperative facial palsy develops.

Cranial Nerve Neoplasms↗

PubMed2006

A case of drug-induced hypersensitivity syndrome showing transient immunosuppression before viral reactivation during treatment for pemphigus foliaceus.

Drug-induced hypersensitivity syndrome (DIHS) is one of the most severe drug adverse reactions, with characteristic biphasic symptoms. Reactivation of human herpesvirus-6 (HHV-6) is frequently observed, although the cause of DIHS is still unknown. A patient developed DIHS during treatment with diaminodiphenylsulphone for pemphigus foliaceus. The number of lymphocytes in his peripheral blood, and titres of serum total IgG and IgM and anti-desmoglein1 antibody transiently decreased just before reactivation of HHV-6, cytomegalovirus and Epstein-Barr virus. This observation suggests that transient suppression of both cellular and humoral immunity may trigger viral reactivation, which leads to the development of the second phase of DIHS.

Administration, Oral↗

PubMed1994

RAZ, an Epstein-Barr virus transdominant repressor that modulates the viral reactivation mechanism.

Epstein-Barr virus (EBV) is associated with the development of several types of human cancers and is an important cause of lymphomas in immunocompromised hosts. Expression of the EBV BZLF1 immediate-early gene product (Z) triggers disruption of latency in EBV-infected cells. Z is a member of the b-Zip family of proteins and binds to AP-1-like sites in early viral promoters. Here we show that a viral RNA related to Z, in which there is replacement of the transactivation domain of Z by fusion through alternate splicing with a portion of another EBV transactivator, BRLF1 (R), can repress Z function. This differentially spliced mRNA is predicted to express a novel chimeric protein which we call RAZ for R and Z. RAZ retains the dimerization and DNA-binding domains of Z but loses its transactivation domain. We show that in vitro the RAZ protein acts transdominantly to repress transactivation of early promoters by Z. Repression is produced by dimerization of RAZ with Z resulting in RAZ:Z heterodimers that can no longer bind to Z-binding sites despite retention of the DNA-binding domains in both proteins. Deletion of the R domain of RAZ restores the ability of the truncated RAZ homodimers and RAZ:Z heterodimers to bind to DNA. A biologic effect of RAZ was shown by cotransfection of latently infected Raji cells with Z and RAZ expression clones; RAZ diminished viral reactivation induced by Z, as indicated by amount of early replicative antigens (EA-D) detected. The RAZ protein presents a model for transcriptional control unique among the herpesvirus and distinct from analogous viral and cellular repressors. RAZ, by limiting the availability of Z protein, is likely to modulate EBV reactivation.

Alternative Splicing↗

PubMed1974

Latent ganglionic infection with herpes simplex virus types 1 and 2: viral reactivation in vivo after neurectomy.

Inoculation of the cornea, lip, or footpad of mice with herpes simplex virus type 1 resulted in a latent infection of the local sensory ganglia. Inoculation of the vagina and cervix with herpes simplex virus type 2, as well as type 1, also induced a latent ganglionic infection. With the use of sciatic nerve section as a stimulus, a reproducible model of viral reactivation in vivo was established.

Animals↗

PubMed2003

Relapsing herpes simplex encephalitis: pathological confirmation of viral reactivation.

This case is reported to raise awareness of herpes simplex encephalitis as a persisting brain disorder. A 66 year old immunocompetent man developed status epilepticus and died of pneumonia in the course of progressive hemiparesis, cognitive decline, and atrophy of the brain over a five year period after herpes simplex encephalitis. In addition to a completely destroyed left temporal lobe, necropsy revealed active encephalitis consisting of necrosis and lymphocyte infiltration with a large number of intranuclear inclusions in the neurones and glial cells in the markedly oedematous parenchyma of the right frontal and parietal lobes. Herpes simplex virus type 1 (HSV-1) antigen was detected by immunohistochemistry, HSV-1 DNA by in situ hybridisation, and herpes simplex virus nucleocapsids by electronmicroscopy. These clinical and pathological findings suggest that direct viral reactivation might result in a relapse of herpes simplex encephalitis, causing progressive clinical deterioration associated with the persistence of HSV-1 in the brain. This is the first case report demonstrating HSV-1 antigen, HSV-1 DNA, and herpes simplex virus nucleocapsids in a case of relapsing herpes simplex encephalitis.

Atrophy↗

PubMed2003

The herpes simplex virus type 1 ICP0 promoter is activated by viral reactivation stimuli in trigeminal ganglia neurons of transgenic mice.

Herpes simplex virus type 1 (HSV-1) causes a latent infection in sensory ganglia neurons in humans and in the mouse model. The ability of the virus to latently infect neurons and reactivate is central to the ability of HSV-1 to remain in the human population and spread to new hosts. It is possible that neuronal transcriptional proteins control latency and reactivation by modulating activation of the HSV-1 immediate-early (IE) gene ICP0. We have previously shown that factors in trigeminal ganglia neurons can differentially activate the IE ICP0 promoter and the IE ICP4 promoter in developing trigeminal ganglia neurons of transgenic mice. Ultraviolet (UV) irradiation and hyperthermic stress have been shown to result in HSV-1 reactivation from sensory neurons in the mouse model. Reporter transgenic mice were exposed to UV irradiation or hyperthermia to test whether stimuli that are known to reactivate HSV-1 could activate viral IE promoters in the absence of viral proteins. Measurement of beta-galactosidase activity in trigeminal ganglia from these transgenic mice indicated that the ICP0 promoter activity was significantly increased by both UV irradiation and hyperthermia. The IE genes ICP4 and ICP27 and the late gene gC reporter transgenes failed to be activated in parallel experiments. These results suggest that the ICP0 promoter is a target for activation by host transcription factors in sensory neurons that have undergone damage. It further suggests the possibility that activation of ICP0 gene expression by neuronal transcription factors may be important in reactivation of HSV-1 in neurons.

Animals↗

PubMed2006

Histone deacetylase inhibitors induce apoptosis with minimal viral reactivation in cells infected with Kaposi's sarcoma-associated herpesvirus.

Kaposi's sarcoma-associated herpesvirus (KSHV) latently infects tumor cells in patients with Kaposi's sarcoma and primary effusion lymphoma (PEL). The purpose of this study was to determine whether histone deacetylase inhibitors (HDAI) could induce apoptosis, with minimal viral replication, in cells latently infected with KSHV. Four HDAI (depsipeptide, suberoylanilide hydroxamic acid, MS-275, and trichostatin A) were studied in two PEL B cell lines (BCBL-1, BC-3). As expected, histone hyperacetylation was readily induced in all PEL cells exposed to HDAI. HDAI also triggered KSHV reactivation in a time- and dose-dependent manner. Flow cytometric and transmission electron microscopic studies, however, revealed that reactivation occurred in only a minor percentage (3-14%) of treated cells. Importantly, and in contrast to viral reactivation, HDAI induced apoptotic cell death in a dose-dependent manner in a large percentage (up to 90%) of KSHV-infected cells. In summary, all four HDAI tested induced histone hyperacetylation in all cells, KSHV reactivation in a minority of cells, and apoptotic cell death in a majority of cells latently infected with KSHV. These findings suggest that HDAI may be a therapeutic option for patients with KSHV-mediated diseases by rendering cells infected with KSHV susceptible to apoptosis.

Antiviral Agents↗

PubMed1999

Transcriptional activation by the product of open reading frame 50 of Kaposi's sarcoma-associated herpesvirus is required for lytic viral reactivation in B cells.

Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is a lymphotropic virus strongly linked to the development of KS, an endothelial cell neoplasm frequent in persons with AIDS. Reactivation from latency in B cells is thought to be an important antecedent to viral spread to endothelial cells during KS pathogenesis. Earlier experiments have posited a role for the transcriptional activator encoded by KSHV open reading frame 50 (ORF50) in such reactivation, since ectopic overexpression of this protein induces reactivation in latently infected B cells. Here we have explored several aspects of the expression, structure, and function of this protein bearing on this role. The ORF50 gene is expressed very early in lytic reactivation, before several other genes implicated as candidate regulatory genes in related viruses, and its expression can upregulate their promoters in transient assays. The protein is extensively phosphorylated in vivo and bears numerous sites for phosphorylation by protein kinase C, activators of which are potent stimulators of lytic induction. The C terminus of the ORF50 protein contains a domain that can strongly activate transcription when targeted to DNA; deletion of this domain generates an allele that expresses a truncated protein which retains the ability to form multimers with full-length ORF50 and functions as a dominant-negative protein. Expression of this allele in latently infected cells ablates spontaneous reactivation from latency and strikingly suppresses viral replication induced by multiple stimuli, including phorbol ester, ionomycin, and sodium butyrate. These results indicate that the ORF50 gene product plays an essential role in KSHV lytic replication and are consistent with its action as a putative molecular switch controlling the induction of virus from latency.

Amino Acid Sequence↗

PubMed2005

Viral reactivation and pseudotype production in an in vitro superinfection system with two different strains of HIV-1.

Viral production and variability of HIV-1 is normally high in vivo causing the necessary conditions for cellular superinfection. In order to evaluate the superinfection dynamics in vitro, H9HTLVIIIB cell line was superinfected with HIVMN. Superinfected cells showed nearly 50% cell mortality at day 1 post-superinfection (ps), which increased significantly up to day 4 ps. Superinfecting genome was detectable until day 10 ps. The superinfecting strain was found in the supernatant only on day 1 ps, but was recovered up to day 4 ps by coculture with non-infected cells. The existing strain (HIVHXB2) was recovered throughout the studied period. Pseudotype formation by the HIVHXB2 genome and envelope proteins of the superinfecting strain (HIVMN) was observed from day 1 to 6 ps. Viral production was increased by 1.7 LOG in superinfected cells from day 1 ps. Both viral production increase and pseudotype formation could be relevant for HIV pathogenesis in vivo.

Cell Line↗

PubMedDate not supplied

The roles of inflammation, STAT transcription factors, and nerve growth factor in viral reactivation and herpes keratitis.

Nerve growth factor (NGF) has an inhibitory effect while inflammatory cytokines may stimulate herpes simplex virus (HSV) reactivation. NGF binds to its receptor trkA on terminal axons and signals the neuron cell body in the ganglion. Many cytokines may also signal neurons through their specific receptors, affecting STAT transcription factors within the cell bodies. We studied the effects of trigeminal ganglion (TG) explantation, a powerful HSV reactivation stimulus, on the NGF/trkA and the JAK/STAT signaling pathways. Immunohistochemistry and gel shifting experiments were performed using anti-STAT, anti-trkA, or negative control antibodies on mouse TGs. The expression of neuronal trkA was greatly reduced or eliminated by 3 days postexplantation. In contrast, the expression of STAT1, STAT3, and STAT5b, as well as phosphotyrosine-STAT3 were relatively preserved in these explanted TGs. Gel-shifting experiments indicated that TG nuclear extracts bind specifically to the HSV-1 LAT promoter, an important viral gene that regulates reactivation. STAT1, but not STAT3 or STAT5b, was detected as a component of this LAT binding complex. These studies suggest that the inhibitory effects of NGF/trkA signaling are lost after TG explantation while STAT expression is maintained, allowing HSV-1 reactivation to proceed.

Animals↗