Publications by authors named "Mir A Ali"

24 Publications

  • Page 1 of 1

Serum and Cervicovaginal Fluid Antibody Profiling in Herpes Simplex Virus (HSV) Seronegative Recipients of the HSV529 Vaccine.

J Infect Dis 2021 Mar 15. Epub 2021 Mar 15.

Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Previous HSV2 vaccines have not prevented genital herpes. Concerns have been raised about the choice of antigen, the type of antibody induced by the vaccine, and whether antibody is present in the genital tract where infection occurs. We reported results of a trial of an HSV2 replication-defective vaccine, HSV529, that induced serum neutralizing antibody responses in 78% of HSV1 -/HSV2 - vaccine recipients. Here we show that HSV1 -/HSV2 - vaccine recipients developed antibodies to epitopes of several viral proteins; however, fewer antibody epitopes were detected in vaccine recipients compared with naturally infected persons. HSV529 induced antibodies that mediated HSV2-specific NK cell activation. Depletion of gD-binding antibody from sera reduced neutralizing titers by 62% and NK cell activation by 81%. HSV2 gD antibody was detected in cervicovaginal fluid at about one-third the level of that in serum. A vaccine that induces potent serum antibodies transported to the genital tract might reduce HSV genital infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jiab139DOI Listing
March 2021

An integrated disease-specific graded prognostic assessment scale for melanoma: contributions of KPS, CITV, number of metastases, and BRAF mutation status.

Neurooncol Adv 2021 Jan-Dec;3(1):vdaa152. Epub 2020 Nov 12.

Department of Neurosurgery, University of Minnesota, Minneapolis, Minnesota, USA.

Background: Stereotactic radiosurgery (SRS) remains a mainstay therapy in the treatment of melanoma brain metastases (BM). While prognostic scales have been developed for melanoma patients who underwent SRS treatment for BM, the pertinence of these scales in the context of molecularly targeted therapies remains unclear.

Methods: Through a multi-institutional collaboration, we collated the survival patterns of 331 melanoma BM patients with known BRAF mutation status treated with SRS. We established a prognostic scale that was validated in an independent cohort of 174 patients. All patients with BRAF mutations in this series were treated with BRAF inhibitors. Prognostic utility was assessed using Net Reclassification Index (NRI > 0) and integrated discrimination improvement (IDI) metrics.

Results: In a multivariate Cox proportional hazards model, BRAF mutation status, KPS, number of metastases, and cumulative intracranial tumor volume (CITV) independently contributed to survival prognostication for melanoma patients with SRS-treated BM ( < .05 for all variables). These variables were incorporated into a prognostic scale using the disease-specific graded prognostic assessment (ds-GPA) framework. This integrated melanoma ds-GPA scale was validated in 2 independent cohorts collated through a multi-institutional collaboration. In terms of order of prognostic importance, BRAF mutation status exerted the greatest influence on survival, while KPS, the number of metastases, and CITV exhibited comparable, lesser impacts.

Conclusions: Optimal survival prognostication for SRS-treated patients with melanoma BM requires an integrated assessment of patient characteristics (KPS), tumor characteristics (CITV and number of metastases), and the mutational profile of the melanoma (BRAF mutation status).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/noajnl/vdaa152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810198PMC
November 2020

Effect of Bruton tyrosine kinase inhibitor on efficacy of adjuvanted recombinant hepatitis B and zoster vaccines.

Blood 2021 01;137(2):185-189

Hematology Branch, National Heart, Lung, and Blood Institute.

Vaccinations are effective in preventing infections; however, it is unknown if patients with chronic lymphocytic leukemia (CLL) who are treatment naïve (TN) or receiving Bruton tyrosine kinase inhibitors (BTKi's) respond to novel adjuvanted vaccines. Understanding the effect of BTKi's on humoral immunity is timely because BTKi's are widely used and vaccination against coronavirus disease 2019 is urgently needed. In 2 open-label, single-arm clinical trials, we measured the effect of BTKi's on de novo immune response against recombinant hepatitis B vaccine (HepB-CpG) and recall response against recombinant zoster vaccine (RZV) in CLL patients who were TN or on BTKi. The primary end point was serologic response to HepB-CpG (anti-hepatitis B surface antibodies ≥10 mIU/mL) and RZV (≥fourfold increase in anti-glycoprotein E). The response rate to HepB-CpG was lower in patients on BTKi (3.8%; 95% confidence interval [CI], 0.7-18.9) than patients who were TN (28.1%; 95% CI, 15.6-45.4; P = .017). In contrast, the response rate to RZV did not differ significantly between the BTKi (41.5%; 95% CI, 27.8-56.6) and TN cohorts (59.1%; 95% CI, 38.7-76.7; P = .2). BTKi's were associated with a decreased de novo immune response following HepB-CpG, whereas recall immune response following RZV was not significantly affected by BTKi therapy. These trials were registered at www.clinicaltrials.gov as #NCT03685708 (Hep-CpG) and #NCT03702231 (RZV).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020008758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820878PMC
January 2021

Notions of Preprocedural Patient Anxiety in the Realm of IR.

J Vasc Interv Radiol 2020 Feb 26;31(2):336-340.e1. Epub 2019 Jul 26.

Department of Vascular and Interventional Radiology, University of Southern California, Los Angeles, California.

Purpose: To determine the views and current practice preferences of interventional radiologists and allied healthcare providers regarding management of preprocedural anxiety.

Materials And Methods: From March to April 2018, members of the Society of Interventional Radiology were surveyed regarding their opinions in the assessment and management of patient anxiety. Degree of responsibility for the management of anxiety was also queried through the use of a scale (1 = no responsibility; 2 = some responsibility; 3 = major responsibility).

Results: Of 1163 respondents (23.8% response rate), most described preprocedural anxiety as somewhat to very important in their practice (n = 961, 82.6%), somewhat to very important to the patients (n = 1087, 93.5%), and at least sometimes interfering with delivery of care (n = 815, 70.1%). Most respondents did not measure preprocedural anxiety directly (n = 953, 81.9%), but would address it if raised by the patient (n = 911, 82.9%). Patient education (n = 921, 79.1%), medications (n = 801, 68.8%), and therapeutic or empathetic interactions (n = 665, 56.4%) were most preferred to manage anxiety. Radiologists, nurses, patients, primary care providers, family members, and psychologists or psychiatrists were all allocated responsibility to reduce anxiety.

Conclusions: Interventional radiologists and other providers are aware of the importance of preprocedural anxiety. Despite the notion that most radiologists did not address anxiety directly, most indicated a willingness to discuss the issue if raised by patients. Patient education, medications, and several other techniques are preferred to manage preprocedural anxiety. Responsibility to reduce anxiety is perceived to be shared among radiologists, nurses, patients, family members, and other health care providers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jvir.2019.04.007DOI Listing
February 2020

Role of the JNK Pathway in Varicella-Zoster Virus Lytic Infection and Reactivation.

J Virol 2017 09 10;91(17). Epub 2017 Aug 10.

Division of Neuroimmunology and Neuroinfectious Diseases, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Mechanisms of neuronal infection by varicella-zoster virus (VZV) have been challenging to study due to the relatively strict human tropism of the virus and the paucity of tractable experimental models. Cellular mitogen-activated protein kinases (MAPKs) have been shown to play a role in VZV infection of nonneuronal cells, with distinct consequences for infectivity in different cell types. Here, we utilize several human neuronal culture systems to investigate the role of one such MAPK, the c-Jun N-terminal kinase (JNK), in VZV lytic infection and reactivation. We find that the JNK pathway is specifically activated following infection of human embryonic stem cell-derived neurons and that this activation of JNK is essential for efficient viral protein expression and replication. Inhibition of the JNK pathway blocked viral replication in a manner distinct from that of acyclovir, and an acyclovir-resistant VZV isolate was as sensitive to the effects of JNK inhibition as an acyclovir-sensitive VZV isolate in neurons. Moreover, in a microfluidic-based human neuronal model of viral latency and reactivation, we found that inhibition of the JNK pathway resulted in a marked reduction in reactivation of VZV. Finally, we utilized a novel technique to efficiently generate cells expressing markers of human sensory neurons from neural crest cells and established a critical role for the JNK pathway in infection of these cells. In summary, the JNK pathway plays an important role in lytic infection and reactivation of VZV in physiologically relevant cell types and may provide an alternative target for antiviral therapy. Varicella-zoster virus (VZV) has infected over 90% of people worldwide. While primary infection leads to the typically self-limiting condition of chickenpox, the virus can remain dormant in the nervous system and may reactivate later in life, leading to shingles or inflammatory diseases of the nervous system and eye with potentially severe consequences. Here, we take advantage of newer stem cell-based technologies to study the mechanisms by which VZV infects human neurons. We find that the c-Jun N-terminal kinase (JNK) pathway is activated by VZV infection and that blockade of this pathway limits lytic replication (as occurs during primary infection). In addition, JNK inhibition limits viral reactivation, exhibiting parallels with herpes simplex virus reactivation. The identification of the role of the JNK pathway in VZV infection of neurons reveals potential avenues for the development of alternate antiviral drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/JVI.00640-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5553188PMC
September 2017

Ganetespib, an HSP90 inhibitor, kills Epstein-Barr virus (EBV)-infected B and T cells and reduces the percentage of EBV-infected cells in the blood.

Leuk Lymphoma 2017 04 11;58(4):923-931. Epub 2016 Aug 11.

a Laboratory of Infectious Diseases , National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda , MD , USA.

HSP90 inhibitors have been shown to kill Epstein-Barr virus (EBV)-infected cells by reducing the level of EBV EBNA-1 and/or LMP1. We treated virus-infected cells with ganetespib, an HSP90 inhibitor currently being evaluated in multiple clinical trials for cancer and found that the drug killed EBV-positive B and T cells and reduced the level of both EBV EBNA-1 and LMP1. Treatment of cells with ganetespib also reduced the level of pAkt. Ganetespib delayed the onset of EBV-positive lymphomas and prolonged survival in SCID mice inoculated with one EBV-transformed B-cell line, but not another B-cell line. The former cell line showed lower levels of EBNA-1 after treatment with ganetespib in vitro. Treatment of a patient with T-cell chronic active EBV with ganetespib reduced the percentage of EBV-positive cells in the peripheral blood. These data indicate that HSP90 inhibitors may have a role in the therapy of certain EBV-associated diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2016.1213823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358278PMC
April 2017

Education and Communication in an Interprofessional Antimicrobial Stewardship Program.

J Am Osteopath Assoc 2016 Sep;116(9):588-93

Context: Interprofessional education/interprofessional practice (IPE/IPP) is an essential component in medical education and training. A collaborative interprofessional team environment ensures optimal patient-centered care.

Objective: To describe the implementation of 2 interprofessional antimicrobial stewardship program (ASP) teams using IPE/IPP and to assess the acceptance rate by the primary medical and surgical teams of ASP recommendations for antimicrobial interventions.

Methods: A business plan for the ASP was approved at 2 academic medical centers used for the present study. During a 3-year study period, 2 interprofessional ASP teams included an attending physician specializing in infectious disease (ID), an ID physician fellow, an ASP pharmacist, physician residents, medical students, pharmacy residents, and pharmacy students. Educational seminars were presented for all adult-admitting physicians to discuss the need for the ASP and the prospective audit and feedback process. Cases were presented for discussion during ASP/ID rounds and recommendations were agreed upon by the ASP team. A motivational interviewing face-to-face technique was frequently used to convey the ASP team recommendation to the primary medical or surgical team in a noncoercive and educational manner. The ASP team recommendations for ASP interventions were documented in the medical records.

Results: The overall acceptance rate of recommendations by the primary medical and surgical teams were greater than 90% (2051 of 2266). The most frequent interventions provided were streamline therapy (601), route of administration change (452), bug-drug mismatch (190), and discontinuation of therapy (179). Route of administration change was also the most frequently accepted intervention (96%).

Conclusions: The motivational face-to-face communication technique was particularly useful in conveying ASP team member recommendations to the primary medical or surgical teams. Communicating recommendations as a multidisciplinary team in an educational manner seems to have resulted in to greater acceptance of recommendations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7556/jaoa.2016.116DOI Listing
September 2016

Periodic Illness Associated With Epstein-Barr Virus: A New Diagnosis After a 22-Year Follow-up.

Clin Infect Dis 2016 06 29;62(12):1613-4. Epub 2016 Mar 29.

Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciw197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4885657PMC
June 2016

Detection of antibodies to varicella-zoster virus in recipients of the varicella vaccine by using a luciferase immunoprecipitation system assay.

Clin Vaccine Immunol 2014 Sep 2;21(9):1288-91. Epub 2014 Jul 2.

Dental Clinical Research Core, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.

A high-throughput test to detect varicella-zoster virus (VZV) antibodies in varicella vaccine recipients is not currently available. One of the most sensitive tests for detecting VZV antibodies after vaccination is the fluorescent antibody to membrane antigen (FAMA) test. Unfortunately, this test is labor-intensive, somewhat subjective to read, and not commercially available. Therefore, we developed a highly quantitative and high-throughput luciferase immunoprecipitation system (LIPS) assay to detect antibody to VZV glycoprotein E (gE). Tests of children who received the varicella vaccine showed that the gE LIPS assay had 90% sensitivity and 70% specificity, a viral capsid antigen enzyme-linked immunosorbent assay (ELISA) had 67% and 87% specificity, and a glycoprotein ELISA (not commercially available in the United States) had 94% sensitivity and 74% specificity compared with the FAMA test. The rates of antibody detection by the gE LIPS and glycoprotein ELISA were not statistically different. Therefore, the gE LIPS assay may be useful for detecting VZV antibodies in varicella vaccine recipients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00921999.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/CVI.00250-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178563PMC
September 2014

Whole genome mapping of the first reported case of KPC-2-positive Klebsiella pneumoniae ST258 in Nebraska.

Diagn Microbiol Infect Dis 2014 Jul 12;79(3):384-6. Epub 2014 Apr 12.

Center for Research in Anti-Infectives and Biotechnology, Department of Medical Microbiology and Immunology, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68178. Electronic address:

Three ertapenem-resistant Klebsiella pneumoniae carrying bla(KPC-2) were isolated from a single patient in Nebraska over a span of 5 months. A comparative analysis of the genetic relatedness of these isolates was investigated using pulsed-field gel electrophoresis, multilocus sequence typing, and whole genome mapping.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.diagmicrobio.2014.03.023DOI Listing
July 2014

Activation of H2AX and ATM in varicella-zoster virus (VZV)-infected cells is associated with expression of specific VZV genes.

Virology 2014 Mar 29;452-453:52-8. Epub 2014 Jan 29.

Medical Virology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Mammalian cells activate DNA damage response pathways in response to virus infections. Activation of these pathways can enhance replication of many viruses, including herpesviruses. Activation of cellular ATM results in phosphorylation of H2AX and recruits proteins to sites of DNA damage. We found that varicella-zoster (VZV) infected cells had elevated levels of phosphorylated H2AX and phosphorylated ATM and that these levels increased in cells infected with VZV deleted for ORF61 or ORF63, but not deleted for ORF67. Expression of VZV ORF61, ORF62, or ORF63 alone did not result in phosphorylation of H2AX. While BGLF4, the Epstein-Barr virus homolog of VZV ORF47 protein kinase, phosphorylates H2AX and ATM, neither VZV ORF47 nor ORF66 protein kinase phosphorylated H2AX or ATM. Cells lacking ATM had no reduction in VZV replication. Thus, VZV induces phosphorylation of H2AX and ATM and this effect is associated with the presence of specific VZV genes in virus-infected cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.virol.2013.12.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789179PMC
March 2014

Altered antibody profiles against common infectious agents in chronic disease.

PLoS One 2013 2;8(12):e81635. Epub 2013 Dec 2.

Clinical Dental Research Core, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, United States of America.

Despite the important diagnostic value of evaluating antibody responses to individual human pathogens, antibody profiles against multiple infectious agents have not been used to explore health and disease mainly for technical reasons.  We hypothesized that the interplay between infection and chronic disease might be revealed by profiling antibodies against multiple agents. Here, the levels of antibodies against a panel of 13 common infectious agents were evaluated with the quantitative Luciferase Immunoprecipitation Systems (LIPS) in patients from three disease cohorts including those with pathogenic anti-interferon-γ autoantibodies (IFN-γ AAB), HIV and Sjögren's syndrome (SjS) to determine if their antibody profiles differed from control subjects.  The IFN-γ AAB patients compared to controls demonstrated statistically higher levels of antibodies against VZV (p=0.0003), EBV (p=0.002), CMV (p=0.003), and C. albicans (p=0.03), but lower antibody levels against poliovirus (p=0.04). Comparison of HIV patients with blood donor controls revealed that the patients had higher levels of antibodies against CMV (p=0.0008), HSV-2 (p=0.0008), EBV (p=0.001), and C. albicans (p=0.01), but showed decreased levels of antibodies against coxsackievirus B4 (p=0.0008), poliovirus (p=0.0005),   and HHV-6B (p=0.002). Lastly, SjS patients had higher levels of anti-EBV antibodies (p=0.03), but lower antibody levels against several enteroviruses including a newly identified picornavirus, HCoSV-A (p=0.004), coxsackievirus B4 (p=0.04), and poliovirus (p=0.02). For the IFN-γ AAB and HIV cohorts, principal component analysis revealed unique antibody clusters that showed the potential to discriminate patients from controls.  The results suggest that antibody profiles against these and likely other common infectious agents may yield insight into the interplay between exposure to infectious agents, dysbiosis, adaptive immunity and disease activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0081635PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3847058PMC
September 2014

Detection of molluscum contagiosum virus (MCV) DNA in the plasma of an immunocompromised patient and possible reduction of MCV DNA with CMX-001.

J Infect Dis 2012 Mar 19;205(5):794-7. Epub 2012 Jan 19.

Medical Virology Section, Laboratory of Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-8007, USA.

Molluscum contagiosum virus (MCV) is a poxvirus that causes localized papules in healthy persons. We evaluated a woman with severe immunodeficiency and disseminated MCV. During treatment with CMX-001, an antiviral with activity against other poxviruses, MCV DNA was detected in 20% of plasma samples. When the patient was not receiving CMX-001, MCV DNA was detected in 50% of samples. We also noted improvement in warts on her fingers during CMX-001 therapy. Although MCV is caused by direct inoculation of virus into skin in healthy persons, in a severely immunocompromised person MCV DNA was present in blood and may spread by viremia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jir853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3274371PMC
March 2012

Xenotropic murine leukemia virus-related virus is not associated with chronic fatigue syndrome in patients from different areas of the us in the 1990s.

Virol J 2011 Sep 24;8:450. Epub 2011 Sep 24.

Medical Virology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Background: In 2009, xenotropic murine leukemia virus-related virus (XMRV) was reported in 67% of patients with chronic fatigue syndrome (CFS) compared to 4% of controls. Since then numerous reports failed to detect XMRV in other cohorts of CFS patients, and some studies suggested that XMRV sequences in human samples might be due to contamination of these samples with mouse DNA.

Results: We determined the prevalence of XMRV in patients with CFS from similar areas in the United States as the original 2009 study, along with patients with chronic inflammatory disorders and healthy persons. Using quantitative PCR, we initially detected very low level signals for XMRV DNA in 15% of patients with CFS; however, the frequency of PCR positivity was no different between patients with CFS and controls. Repeated attempts to isolate PCR products from these reactions were unsuccessful. These findings were supported by our observations that PHA and IL-2 stimulation of peripheral blood mononuclear cells from patients with apparently low levels of XMRV, which induced virus replication in the 2009 report, resulted in the disappearance of the signal for XMRV DNA in the cells. Immunoprecipitation of XMRV-infected cell lysates using serum from patients from whom we initially detected low levels of XMRV DNA followed by immunoblotting with antibodies to XMRV gp70 protein failed to detect antibody in the patients, although one control had a weak level of reactivity. Diverse murine leukemia virus (MLV) sequences were obtained by nested PCR with a similar frequency in CFS patients and controls. Finally, we did not detect XMRV sequences in patients with several chronic inflammatory disorders including rheumatoid arthritis, Bechet's disease, and systemic lupus erythematosus.

Conclusions: We found no definitive evidence for XMRV DNA sequences or antibody in our cohort of CFS patients, which like the original 2009 study, included patients from diverse regions of the United States. In addition, XMRV was not detected in a cohort of patients with chronic inflammatory disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1743-422X-8-450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210120PMC
September 2011

Insulin degrading enzyme induces a conformational change in varicella-zoster virus gE, and enhances virus infectivity and stability.

PLoS One 2010 Jun 25;5(6):e11327. Epub 2010 Jun 25.

Laboratory of Clinical Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.

Varicella-zoster virus (VZV) glycoprotein E (gE) is essential for virus infectivity and binds to a cellular receptor, insulin-degrading enzyme (IDE), through its unique amino terminal extracellular domain. Previous work has shown IDE plays an important role in VZV infection and virus cell-to-cell spread, which is the sole route for VZV spread in vitro. Here we report that a recombinant soluble IDE (rIDE) enhances VZV infectivity at an early step of infection associated with an increase in virus internalization, and increases cell-to-cell spread. VZV mutants lacking the IDE binding domain of gE were impaired for syncytia formation and membrane fusion. Pre-treatment of cell-free VZV with rIDE markedly enhanced the stability of the virus over a range of conditions. rIDE interacted with gE to elicit a conformational change in gE and rendered it more susceptible to proteolysis. Co-incubation of rIDE with gE modified the size of gE. We propose that the conformational change in gE elicited by IDE enhances infectivity and stability of the virus and leads to increased fusogenicity during VZV infection. The ability of rIDE to enhance infectivity of cell-free VZV over a wide range of incubation times and temperatures suggests that rIDE may be useful for increasing the stability of varicella or zoster vaccines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0011327PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892511PMC
June 2010

The insulin degrading enzyme binding domain of varicella-zoster virus (VZV) glycoprotein E is important for cell-to-cell spread and VZV infectivity, while a glycoprotein I binding domain is essential for infection.

Virology 2009 Apr 23;386(2):270-9. Epub 2009 Feb 23.

Medical Virology Section, Laboratory of Clinical Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Varicella-zoster virus (VZV) glycoprotein E (gE) interacts with glycoprotein I and with insulin degrading enzyme (IDE), which is a receptor for the virus. We found that a VZV gE deletion mutant could only be grown in cells expressing gE. Expression of VZV gE on the surface of cells did not interfere with VZV infection. HSV deleted for gE is impaired for cell-to-cell spread; VZV gE could not complement this activity in an HSV gE null mutant. VZV lacking the IDE binding domain of gE grew to peak titers nearly equivalent to parental virus; however, it was impaired for cell-to-cell spread and for infectivity with cell-free virus. VZV deleted for a region of gE that binds glycoprotein I could not replicate in cell culture unless grown in cells expressing gE. We conclude that the IDE binding domain is important for efficient cell-to-cell spread and infectivity of cell-free virus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797441PMC
http://dx.doi.org/10.1016/j.virol.2009.01.023DOI Listing
April 2009

Varicella-zoster virus immediate-early 63 protein interacts with human antisilencing function 1 protein and alters its ability to bind histones h3.1 and h3.3.

J Virol 2009 Jan 29;83(1):200-9. Epub 2008 Oct 29.

Laboratory of Clinical Infectious Diseases, National Institutes of Health, 10 Center Dr., Building 10, Room 11N234, Bethesda, MD 20892, USA.

Varicella-zoster virus (VZV) immediate-early 63 protein (IE63) is abundantly expressed during both acute infection in vitro and latent infection in human ganglia. Using the yeast two-hybrid system, we found that VZV IE63 interacts with human antisilencing function 1 protein (ASF1). ASF1 is a nucleosome assembly factor which is a member of the H3/H4 family of histone chaperones. IE63 coimmunoprecipitated and colocalized with ASF1 in transfected cells expressing IE63 and in VZV-infected cells. IE63 also colocalized with ASF1 in both lytic and latently VZV-infected enteric neurons. ASF1 exists in two isoforms, ASF1a and ASF1b, in mammalian cells. IE63 preferentially bound to ASF1a, and the amino-terminal 30 amino acids of ASF1a were critical for its interaction with IE63. VZV IE63 amino acids 171 to 208 and putative phosphorylation sites of IE63, both of which are critical for virus replication and latency in rodents, were important for the interaction of IE63 with ASF1. Finally, we found that IE63 increased the binding of ASF1 to histone H3.1 and H3.3, which suggests that IE63 may help to regulate levels of histones in virus-infected cells. Since ASF1 mediates eviction and deposition of histones during transcription, the interaction of VZV IE63 with ASF1 may help to regulate transcription of viral or cellular genes during lytic and/or latent infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/JVI.00645-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2612320PMC
January 2009

The amino terminus of varicella-zoster virus (VZV) glycoprotein E is required for binding to insulin-degrading enzyme, a VZV receptor.

J Virol 2007 Aug 6;81(16):8525-32. Epub 2007 Jun 6.

Laboratory of Clinical Infectious Diseases, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.

Varicella-zoster virus (VZV) glycoprotein E (gE) is required for VZV infection. Although gE is well conserved among alphaherpesviruses, the amino terminus of VZV gE is unique. Previously, we showed that gE interacts with insulin-degrading enzyme (IDE) and facilitates VZV infection and cell-to-cell spread of the virus. Here we define the region of VZV gE required to bind IDE. Deletion of amino acids 32 to 71 of gE, located immediately after the predicted signal peptide, resulted in loss of the ability of gE to bind IDE. A synthetic peptide corresponding to amino acids 24 to 50 of gE blocked its interaction with IDE in a concentration-dependent manner. However, a chimeric gE in which amino acids 1 to 71 of VZV gE were fused to amino acids 30 to 545 of herpes simplex virus type 2 gE did not show an increased level of binding to IDE compared with that of full-length HSV gE. Thus, amino acids 24 to 71 of gE are required for IDE binding, and the secondary structure of gE is critical for the interaction. VZV gE also forms a heterodimer with glycoprotein gI. Deletion of amino acids 163 to 208 of gE severely reduced its ability to form a complex with gI. The amino portion of IDE, as well an IDE mutant in the catalytic domain of the protein, bound to gE. Therefore, distinct motifs of VZV gE are important for binding to IDE or to gI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/JVI.00286-07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1951364PMC
August 2007

Absence or overexpression of the Varicella-Zoster Virus (VZV) ORF29 latency-associated protein impairs late gene expression and reduces VZV latency in a rodent model.

J Virol 2007 Feb 6;81(4):1586-91. Epub 2006 Dec 6.

Laboratory of Clinical Infectious Diseases, Bldg. 10, Room 11N234, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.

Varicella-zoster virus (VZV) ORF29 encodes the viral single-stranded DNA binding protein and is expressed during latency in human ganglia. We constructed an ORF29 deletion mutant virus and showed that the virus could replicate only in cells expressing ORF29. An ORF29-repaired virus, in which ORF29 was driven by a cytomegalovirus promoter, grew to peak titers similar to those seen with the parental virus. The level of ORF29 protein in cells infected with the repaired virus was greater than that seen with parental virus. Infection of cells with either the ORF29 deletion or repaired virus resulted in similar levels of VZV immediate-early proteins but reduced levels of glycoprotein E compared to those observed with parental virus. Cotton rats infected with the ORF29 deletion mutant had a markedly reduced frequency of latent infection in dorsal root ganglia compared with those infected with parental virus (P < 0.00001). In contrast, infection of animals with the ORF29 deletion mutant resulted in a frequency of ganglionic infection at 3 days similar to that seen with the parental virus. Animals infected with the ORF29-repaired virus, which overexpresses ORF29, also had a reduced frequency of latent infection compared with those infected with parental virus (P = 0.0044). These studies indicate that regulation of ORF29 at appropriate levels is critical for VZV latency in a rodent model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/JVI.01220-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1797561PMC
February 2007

Insulin degrading enzyme is a cellular receptor mediating varicella-zoster virus infection and cell-to-cell spread.

Cell 2006 Oct;127(2):305-16

Laboratory of Clinical Infectious Diseases, Medical Virology Section, National Institutes of Health, Bethesda, MD, 20892 USA.

Varicella-zoster virus (VZV) causes chickenpox and shingles. While varicella is likely spread as cell-free virus to susceptible hosts, the virus is transmitted by cell-to-cell spread in the body and in vitro. Since VZV glycoprotein E (gE) is essential for virus infection, we postulated that gE binds to a cellular receptor. We found that insulin-degrading enzyme (IDE) interacts with gE through its extracellular domain. Downregulation of IDE by siRNA, or blocking of IDE with antibody, with soluble IDE protein extracted from liver, or with bacitracin inhibited VZV infection. Cell-to-cell spread of virus was also impaired by blocking IDE. Transfection of cell lines impaired for VZV infection with a plasmid expressing human IDE resulted in increased entry and enhanced infection with cell-free and cell-associated virus. These studies indicate that IDE is a cellular receptor for both cell-free and cell-associated VZV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2006.08.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125743PMC
October 2006

Varicella-zoster virus expressing HSV-2 glycoproteins B and D induces protection against HSV-2 challenge.

Vaccine 2004 Jun;22(20):2558-65

Division of Infectious Diseases and Immunology, School of Medicine, Saint Louis University, St. Louis, MO, USA.

A recombinant Oka (ROka) varicella-zoster virus (VZV) vaccine was constructed that expresses herpes simplex virus type 2 (HSV-2) glycoproteins B (gB) and D (gD). Guinea pigs received one of four inocula: (a). uninfected cells, (b). recombinant Oka VZV infected cells, (c). recombinant Oka VZV expressing HSV-2 gB/gD (ROka-gB2/gD2) infected cells, or (d) heat-inactivated ROka-gB2/gD2 infected cells. Only animals inoculated with ROka-gB2/gD2 developed high titers of neutralizing antibodies to HSV-2. Animals immunized with ROka-gB2/gD2 had reduced mortality after intravaginal challenge with HSV-2 compared with animals that received ROka or heat-inactivated ROka-gB2/gD2. Animals immunized with ROka-gB2/gD2 had reduced lesions scores for the first 2 weeks after challenge, and reduced shedding of HSV-2 on Days 5 and 7 after challenge, compared to the other two groups. These data show that recombinant VZV expressing HSV-2 antigens must be infectious to offer significant protection against challenge with HSV-2, and that ROka-gB2/gD2 has promise as a candidate HSV-2 vaccine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vaccine.2003.12.010DOI Listing
June 2004

Chronic active Epstein-Barr virus infection associated with mutations in perforin that impair its maturation.

Blood 2004 Feb 23;103(4):1244-52. Epub 2003 Oct 23.

Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Chronic active Epstein-Barr virus infection (CAEBV) is a rare disease in which previously healthy persons develop severe, life-threatening illness. Mutations in the perforin gene have been found in familial hemophagocytic lymphohistiocytosis, which shares some features with CAEBV. We studied a patient who died at age 18, 10 years after the onset of CAEBV. The patient had high titers of antibodies to EBV, EBV RNA in lymph nodes, T-cell lymphoproliferative disease, and hemophagocytic lymphohistiocytosis. DNA sequencing showed novel mutations in both alleles of the perforin gene that resulted in amino acid changes in the protein. The quantity of the native form of perforin from the patient's stimulated peripheral blood mononuclear cells (PBMCs) was extremely low and immunoblotting showed accumulation of an uncleaved precursor form of perforin. Stimulated PBMCs from the patient were defective for Fas-independent cytotoxicity. These data imply that mutations in this patient resulted in reduced perforin-mediated cytotoxicity by his lymphocytes. This is the first case in which perforin mutations have been shown to result in accumulation of the uncleaved, immature form of perforin. Mutations in the perforin gene are associated with some cases of CAEBV with hemophagocytic lymphohistiocytosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2003-06-2171DOI Listing
February 2004
-->