Processing of human cytomegalovirus glycoprotein B in recombinant adenovirus-infected cells

Marshall, Gary S.; Fenger, Denice P.; Stout, Gordon G.; Knights, Mari E.; Hunt, Lawrence A.

doi:10.1099/0022-1317-77-7-1549

Cited by 12 publications

(7 citation statements)

References 33 publications

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“…Second, in contrast to their findings, we failed to see processing of ⌬gB c508s or ⌬gB c550s , as evidenced by cleavage into the SU and TM components of gB. Cleavage of gB has been shown to occur in a distal compartment of the secretory system that appears to be closely apposed to the trans-Golgi network (32). In our study, image analysis of these gB mutant molecules following transient expression in COS-7 cells revealed that they were retained within the ER and failed to colocalize with cellular markers of more distal sites in the secretory pathway (data not shown).…”

Section: Discussioncontrasting

confidence: 53%

Antigenic Domain 1 Is Required for Oligomerization of Human Cytomegalovirus Glycoprotein B

Britt

Jarvis

Drummond

et al. 2005

J Virol

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Section: Discussioncontrasting

confidence: 53%

Antigenic Domain 1 Is Required for Oligomerization of Human Cytomegalovirus Glycoprotein B

Britt

Jarvis

Drummond

et al. 2005

J Virol

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“…Thus, it was hypothesized that in situ production of cIFN-␣ from the DEF201 construct would offer protection against PTV respiratory route challenge in hamsters. Compared to recombinant bacterially derived cIFN-␣ protein, DEF201 use offers distinct advantages that include (i) low manufacturing costs, (ii) enhanced stability, (iii) ease of administration, (iv) single dosing, and (v) native glycosylation, as seen for other proteins (1,14).…”

Section: Discussionmentioning

confidence: 99%

Extended Protection against Phlebovirus Infection Conferred by Recombinant Adenovirus Expressing Consensus Interferon (DEF201)

Gowen

Ennis²,

Sefing

et al. 2012

Antimicrob Agents Chemother

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Punta Toro virus (PTV; Bunyaviridae, Phlebovirus) is related to Rift Valley fever virus (RVFV), a pathogenic agent which causes severe disease in humans and livestock primarily in the sub-Saharan region of Africa. The recent range expansion of RVFV and the potential for its intentional release into naïve populations pose a significant threat to public health and agriculture. Studies modeling disease in rodents and nonhuman primates have shown that PTV and RVFV are highly sensitive to the antiviral effects of alpha interferon (IFN-␣), an important component of the innate antiviral host response. While recombinant IFN-␣ has high therapeutic value, its utility for the treatment of neglected tropical diseases is hindered by its short in vivo half-life and costly production of longer-lasting pegylated IFNs. Here, we demonstrate extended preexposure protection against lethal PTV challenge following a single intranasal administration of DEF201, which is a replication-deficient human adenovirus type 5 vector engineered to constitutively express consensus IFN-␣ (cIFN-␣) from transduced host cells. DEF201 was also efficacious when administered within 24 h as a postexposure countermeasure. Serum concentrations of cIFN-␣ could be detected as early as 8 h following treatment and persisted for more than 1 week. The prolonged antiphlebovirus prophylactic effect, low production costs, and ease of administration make DEF201 a promising agent for intervention during natural disease outbreaks and for countering possible bioterrorist acts. R ift Valley fever virus (RVFV; Bunyaviridae, Phlebovirus) has been the cause of numerous devastating epizootics throughout sub-Saharan Africa and, more recently, the Arabian Peninsula (3). It is a mosquito-borne virus that causes significant losses in livestock characterized by dramatic "abortion storms" resulting in near-complete mortality in newborn animals (5). RVFV transmission to humans occurs through the bites of infected mosquitoes or contact with tissue from infected animals. Because the virus is also infectious by the airborne route, it poses a potential bioterrorism threat, which is amplified by the fact that mosquitoes native to the United States can readily transmit RVFV and serve as vectors (24). Presently, there are no FDA-approved vaccines or antivirals to prevent or treat RVFV infection, which underscores the urgent need to develop new antiviral therapies.Several reports suggest that RVFV is sensitive to the effects of alpha interferon (IFN-␣) (15,16,18), a potent cytokine essential to the control of viral replication and dissemination (20). Studies employing the closely related Punta Toro virus (PTV), a less biohazardous, more accessible model for RVFV infection, have also demonstrated sensitivity toward agents that elicit type I IFN responses (8,22). In addition, a recent report described the antiphlebovirus activity of human consensus IFN-␣ (cIFN-␣) in cell culture and its prophylactic and therapeutic efficacy in hamsters challenged with PTV (10). Because recombinant IFN prote...

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“…Interestingly, both the 160-kDa and the 55-kDa gB subunits were phosphorylated, indicating that some level of gB undergoes phosphorylation during the maturation process prior to proteolytic processing. Since gB proteolysis is known to occur in the TGN (23) a proportion of gB is phosphorylated within the endoplasmic reticulum or Golgi before it reaches the TGN. HCMV expression of the mimic-phosphorylated form of gB (gBAsp 900 ) increases localization of gB to the TGN.…”

Section: Resultsmentioning

confidence: 99%

Phosphorylation of Human Cytomegalovirus Glycoprotein B (gB) at the Acidic Cluster Casein Kinase 2 Site (Ser ₉₀₀ ) Is Required for Localization of gB to the trans- Golgi Network and Efficient Virus Replication

Jarvis¹,

Jones²,

Drummond³

et al. 2004

J Virol

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Human cytomegalovirus (HCMV) glycoprotein B (gB), encoded by the UL55 open reading frame, is an essential envelope glycoprotein involved in cell attachment and entry. Previously, we identified residue serine 900 (Ser 900 ) as a unique site of reversible casein kinase 2 phosphorylation in the cytoplasmic domain of HCMV gB. We have also recently shown that gB is localized to the trans-Golgi network (TGN) in HCMV-permissive cells, thereby identifying the TGN as a possible site of virus envelopment. The aim of the current study was to determine the role of Ser 900 phosphorylation in transport of gB to the TGN and in HCMV biogenesis. Recombinant HCMV strains were constructed that expressed gB molecules containing either an aspartic acid (gBAsp 900 ) or alanine residue (gBAla 900 ) substitution at Ser 900 to mimic the phosphorylated or nonphosphorylated form, respectively. Immunofluorescence analysis of the trafficking of gB mutant molecules in fibroblasts infected with the HCMV recombinants revealed that gBAsp 900 was localized to the TGN. In contrast, gBAla 900 was partially mislocalized from the TGN, indicating that phosphorylation of gB at Ser 900 was necessary for TGN localization. The increased TGN localization of gBAsp 900 was due to a decreased transport of the molecule to post-TGN compartments. Remarkably, the substitution of an aspartic acid residue for Ser 900 also resulted in an increase in levels of progeny virus production during HCMV infection of fibroblasts. Together, these results demonstrate that phosphorylation of gB at Ser 900 is necessary for gB localization to the TGN, as well as for efficient viral replication, and further support the TGN as a site of HCMV envelopment.Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus that can cause devastating disease, primarily in immunosuppressed individuals such as AIDS patients, patients undergoing iatrogenic immunosuppression, and neonates (26). HCMV is an enveloped DNA virus consisting of a large (230 kb) encapsidated genome wrapped within an inner proteinaceous tegument and an outer lipid envelope studded with viral glycoproteins (24). Currently, a "reenvelopment" model is believed to most accurately describe the assembly process of HCMV, as well as many other herpesviruses. In this model, after initial encapsidation within the nucleus, the nucleocapsid enters the cytoplasm by a process of envelopment and deenvelopment at the inner and outer nuclear membranes, respectively. Final envelopment and acquisition of tegument by the cytoplasmic nucleocapsid are then believed to occur at specific membranes of the cellular secretory system. Studies from a number of laboratories indicate that the final envelopment of many herpesviruses, including varicella-zoster virus (VZV), pseudorabies virus (PRV) and herpes simplex virus type 1 (HSV-1), occurs at the trans-Golgi network (TGN) (8,14,15,30,35,36). Consistent with the TGN site of virus assembly, the major envelope glycoproteins of these herpesviruses have been shown to accumulate at the TGN (1, 2, 37). ...

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Processing of human cytomegalovirus glycoprotein B in recombinant adenovirus-infected cells

Cited by 12 publications

References 33 publications

Antigenic Domain 1 Is Required for Oligomerization of Human Cytomegalovirus Glycoprotein B

Antigenic Domain 1 Is Required for Oligomerization of Human Cytomegalovirus Glycoprotein B

Extended Protection against Phlebovirus Infection Conferred by Recombinant Adenovirus Expressing Consensus Interferon (DEF201)

Phosphorylation of Human Cytomegalovirus Glycoprotein B (gB) at the Acidic Cluster Casein Kinase 2 Site (Ser ₉₀₀ ) Is Required for Localization of gB to the trans- Golgi Network and Efficient Virus Replication

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Processing of human cytomegalovirus glycoprotein B in recombinant adenovirus-infected cells

Cited by 12 publications

References 33 publications

Antigenic Domain 1 Is Required for Oligomerization of Human Cytomegalovirus Glycoprotein B

Antigenic Domain 1 Is Required for Oligomerization of Human Cytomegalovirus Glycoprotein B

Extended Protection against Phlebovirus Infection Conferred by Recombinant Adenovirus Expressing Consensus Interferon (DEF201)

Phosphorylation of Human Cytomegalovirus Glycoprotein B (gB) at the Acidic Cluster Casein Kinase 2 Site (Ser 900 ) Is Required for Localization of gB to the trans- Golgi Network and Efficient Virus Replication

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Phosphorylation of Human Cytomegalovirus Glycoprotein B (gB) at the Acidic Cluster Casein Kinase 2 Site (Ser ₉₀₀ ) Is Required for Localization of gB to the trans- Golgi Network and Efficient Virus Replication