The Cysteine-Rich Region and Secreted Form of the Attachment G Glycoprotein of Respiratory Syncytial Virus Enhance the Cytotoxic T-Lymphocyte Response despite Lacking Major Histocompatibility Complex Class I-Restricted Epitopes

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148

115

Respiratory syncytial virus (RSV) readily infects and reinfects during infancy and throughout life, despite maternal antibodies and immunity from prior infection and without the need for significant antigenic change. RSV has two neutralization antigens, the F and G virion glycoproteins. G is expressed in both membrane-bound (mG) and secreted (sG) forms. We investigated whether sG might act as a decoy for neutralizing antibodies by comparing the in vitro neutralization of wild-type (wt) RSV versus recombinant mG RSV expressing only mG. wt RSV indeed was less susceptible than mG RSV to monovalent G-specific and polyvalent RSV-specific antibodies, whereas susceptibility to F-specific antibodies was equivalent. This difference disappeared when the virus preparations were purified to remove sG. Thus, sG appears to function as a neutralization decoy. We evaluated this effect in vivo in mice by comparing the effects of passively transferred antibodies on the pulmonary replication of wt RSV versus mG RSV. Again, wt RSV was less sensitive than mG RSV to G-specific and RSV-specific antibodies; however, a similar difference was also observed with F-specific antibodies. This confirmed that sG helps wt RSV evade the antibodydependent restriction of replication but indicated that in mice, it is not acting primarily as a decoy for G-specific antibodies, perhaps because sG is produced in insufficient quantities in this poorly permissive animal. Rather, we found that the greater sensitivity of mG versus wt RSV to the antiviral effect of passively transferred RSV antibodies required the presence of inflammatory cells in the lung and was Fc␥ receptor dependent. Thus, sG helps RSV escape the antibody-dependent restriction of replication via effects as an antigen decoy and as a modulator of leukocytes bearing Fc␥ receptors.Human respiratory syncytial virus (RSV) is the leading viral agent of serious pediatric respiratory tract disease worldwide (10). Yearly infections and deaths due to RSV worldwide are estimated to be 64 million and 160,000, respectively (53). A striking feature of RSV is its ability to infect neonates and infants very early in life despite the presence of maternally derived virus-neutralizing serum antibodies. Indeed, the peak of serious RSV disease occurs at 2 months of age, a time in life when maternal antibodies protect infants against most other pathogens. Another striking characteristic of RSV is its ability to reinfect and cause disease throughout life, sometimes even during the same epidemic season, despite having only a single serotype (17,19,20,22; reviewed in reference 10). The ability of RSV to infect very early in life despite maternal antibodies and to reinfect throughout life despite immunity from prior infection accounts for much of its impact on human health.RSV has two major virion envelope proteins, the fusion F and major attachment G glycoproteins, which are the two viral neutralization antigens. The full-length RSV membranebound G protein (mG), which is anchored by a transmembrane domain near t...

Section: Discussionmentioning

confidence: 99%

The Secreted Form of Respiratory Syncytial Virus G Glycoprotein Helps the Virus Evade Antibody-Mediated Restriction of Replication by Acting as an Antigen Decoy and through Effects on Fc Receptor-Bearing Leukocytes

Bukreyev

Yang

Fricke

et al. 2008

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148

115

“…The lack of neutralizing antibody induction by hMPV G was demonstrated recently by our group using purified hMPV G protein as an immunogen in cotton rats (Ryder et al, unpublished) and by another group using a recombinant parainfluenza virus vector to deliver hMPV G protein in hamsters (33). The role of hMPV G protein in viral pathogenesis is still not defined, although it is presumed to be an attachment protein, possibly with immunomodulation properties based on its homology with the RSV G protein (8,30,39).…”

Section: Discussionmentioning

confidence: 99%

An Alphavirus Replicon-Based Human Metapneumovirus Vaccine Is Immunogenic and Protective in Mice and Cotton Rats

Mok

Tollefson²,

Podsiad³

et al. 2008

Human metapneumovirus (hMPV) is a recently discovered paramyxovirus that causes upper and lower respiratory tract infections in infants, the elderly, and immunocompromised individuals worldwide. Here, we developed Venezuelan equine encephalitis virus replicon particles (VRPs) encoding hMPV fusion (F) or attachment (G) glycoproteins and evaluated the immunogenicity and protective efficacy of these vaccine candidates in mice and cotton rats. VRPs encoding hMPV F protein, when administered intranasally, induced F-specific virus-neutralizing antibodies in serum and immunoglobulin A (IgA) antibodies in secretions at the respiratory mucosa. Challenge virus replication was reduced significantly in both the upper and lower respiratory tracts following intranasal hMPV challenge in these animals. However, vaccination with hMPV G protein VRPs did not induce neutralizing antibodies or protect animals from hMPV challenge. Close examination of the histopathology of the lungs of VRP-MPV F-vaccinated animals following hMPV challenge revealed no enhancement of inflammation or mucus production. Aberrant cytokine gene expression was not detected in these animals. Together, these results represent an important first step toward the use of VRPs encoding hMPV F proteins as a prophylactic vaccine for hMPV.

“…A number of reports of studies using rAd-based vaccines describe similar findings that Ad vectors induce potent transgene product-specific antibody and/or CD8 T-cell responses but no overly potent CD4 T-cell responses in experimental animal systems (reviewed in reference 38). Second, it has been proposed that RSV G has an immunomodulatory effect on both innate and adaptive immunity (7,32). For example, Bukreyev et al showed that the secreted form of G and the cysteine-rich region have a positive modulatory effect on cytotoxic T-lymphocyte function, which is independent of virus titers and RSV-induced inflammation (7).…”

Section: Discussionmentioning

confidence: 99%

Single Intranasal Immunization with Recombinant Adenovirus-Based Vaccine Induces Protective Immunity against Respiratory Syncytial Virus Infection

Kim

Lee

et al. 2008

Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract disease in infancy and early childhood. Despite its importance as a pathogen, there is no licensed vaccine against RSV. The G glycoprotein of RSV, a major attachment protein, is a potentially important target for protective antiviral immune responses. Here, a recombinant replication-deficient adenovirus-based vaccine, rAd/3xG, expressing the soluble core domain of G glycoprotein (amino acids 130 to 230) engineered by codon optimization and tandem repetition for higher-level expression, was constructed and evaluated for its potential as an RSV vaccine in a murine model. A single intranasal immunization with rAd/3xG provided potent protection against RSV challenge which lasted for more than 10 weeks. Strong mucosal immunoglobulin A responses were also induced by a single intranasal immunization but not by intramuscular or oral administration of rAd/3xG. Interestingly, neither gamma interferon-nor interleukin-4-producing CD4 T cells directed to I-E d -restricted epitope were detected in the lungs of rAd/3xG-immune mice upon challenge, whereas priming with vaccinia virus expressing RSV G (vvG) elicited strong Th1/Th2 mixed CD4 T-cell responses. Lung eosinophilia and vaccine-induced weight loss were significantly lower in the rAd/3xG-immune group than in the vvG-primed group. Together, our data demonstrate that a single intranasal administration of rAd/3xG elicits beneficial protective immunity and represents a promising vaccine regimen against RSV infection.Respiratory syncytial virus (RSV) is the most important viral pathogen causing serious respiratory tract disease in infants and young children worldwide. RSV is also receiving increasing recognition as an important cause of lower respiratory tract illness in immunocompromised patients and the elderly (13,15,16). Despite the importance of RSV as a respiratory pathogen, there is no licensed vaccine currently available against RSV infection. Thus, developing an effective and safe RSV vaccine remains a worldwide priority.The RSV G glycoprotein was identified as the major RSV attachment protein (24) and is thought to be important for protection against RSV infection (39). G protein lacks any major histocompatibility complex class I-restricted epitope (8,26,36) and has not yet been demonstrated to elicit a cytotoxic T-lymphocyte response in either humans or mice (19,29). It has a single immunodominant I-E d epitope spanning amino acids 183 to 198 and largely induces a specific subset of CD4 T cells restricted to V␤14 expression in the T-cell receptor (40,42). Numerous studies have suggested that immunization with RSV G is associated with the induction of polarized Th2-type responses, which leads to pulmonary eosinophilia upon RSV challenge of G-immunized mice (17,20,30,35,40). In contrast, it was recently suggested that G-specific immune responses are not solely the basis for vaccine-enhanced illness and should not be excluded from potential vaccine strategies (21,22). In addition, int...