Human cytomegalovirus hyperimmune globulin not only neutralizes HCMV infectivity, but also inhibits HCMV-induced intracellular NF-kappaB, Sp1, and PI3-K signaling pathways.
Inhibition of virus-induced intracellular signaling pathways and viral infectivity are our ultimate goals in the development of effective antiviral agents to control human cytomegalovirus (HCMV) infections. The HCMV hyperimmune globulin may meet such criteria. In a human embryonic lung (HEL) fibroblast culture model, pretreatment of Towne strain HCMV with HCMV hyperimmune globulin was shown to inhibit viral infectivity successfully, as measured by a standard plaque assay. The extracellular viral titers and extracellular viral DNA, as measured by plaque assay and PCR, respectively, were also decreased. In addition, the HCMV hyperimmune globulin prevented HCMV from inducing the intracellular activation of NF-kappaB, Sp-1, and PI3-K signaling pathways. The PI3-K pathway was examined by following phosphorylation (activation) of two of its downstream kinases, Akt and p70S6K. HCMV hyperimmune globulin also prevented the production of immediate early, early, and late viral proteins. These studies show that HCMV hyperimmune globulin neutralization of HCMV prevents the earliest known events observed after viral envelope glycoproteins bind their cell membrane receptors, i.e., NF-kappaB, Sp-1 and PI3-K activation. This suggests that HCMV hyperimmune globulin not only can inhibit viral infectivity, but can also prevent the abnormal cellular signaling that may induce unwanted cellular proliferation or cytokine synthesis.
Andreoni
Kenneth A
KA
Department of Surgery, University of North Carolina, Chapel Hill, North Carolina, USA. kenneth_andreoni@med.unc.edu
Wang
Xin
X
Huang
Shu-Mei
SM
Huang
Eng-Shang
ES
D002213:Capsid / Q000096:biosynthesis; D036022:Capsid Proteins; D003586:Cytomegalovirus Infections / Q000276:immunology*; D004789:Enzyme Activation; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis; D007136:Immunoglobulins / Q000276:immunology*; D016756:Immunoglobulins, Intravenous; D007424:Intracellular Fluid; D008562:Membrane Glycoproteins; D016328:NF-kappa B / Q000276:immunology*; D009500:Neutralization Tests; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000276:immunology*; D016329:Sp1 Transcription Factor / Q000276:immunology*; D015534:Trans-Activators; D014759:Viral Envelope Proteins; D014764:Viral Proteins / Q000096:biosynthesis
D036022:Capsid Proteins; D017874:Immediate-Early Proteins; D007136:Immunoglobulins; D016756:Immunoglobulins, Intravenous; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D016329:Sp1 Transcription Factor; D015534:Trans-Activators; D014759:Viral Envelope Proteins; D014764:Viral Proteins; C088645:IE1 protein, cytomegalovirus; C069186:IE2 protein, Cytomegalovirus; C077406:UL115 protein, Human herpesvirus 5; C415589:UL94 protein, Human cytomegalovirus; C071440:glycoprotein H, Cytomegalovirus; C499358:glycoprotein H, Human cytomegalovirus; C439068:glycoprotein O, cytomegalovirus; C045781:cytomegalovirus-specific hyperimmune globulin; C072218:UL84 protein, Cytomegalovirus; C494918:AKT1 protein, human