Complement‐Independent neutralising monoclonal antibody with differential reactivity for strains of human cytomegalovirus

Baboonian, C.; Blake, Kim; Booth, J. C.; Wiblin, C.

doi:10.1002/jmv.1890290212

Cited by 22 publications

(19 citation statements)

References 24 publications

(7 reference statements)

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“…One likely possibility, based on the precedence in other viruses such as influenza viruses, may be related to evasion of virus-neutralizing antibodies secondary to sequence variation in envelope glycoproteins. Consistent with this possibility has been the finding of antigenic diversity among HCMV isolates that precludes complete neutralization by a given polyclonal serum or monoclonal antibody, a finding that is wellestablished and documented in numerous studies (Waner & Weller, 1978;Baboonian et al, 1989;Simpson et al, 1993;Klein et al, 1999). Of special interest in this respect are virus envelope glycoproteins, as they represent the targets for neutralizing antibodies.…”

Section: Introductionmentioning

confidence: 48%

Glycoprotein N subtypes of human cytomegalovirus induce a strain-specific antibody response during natural infection

Burkhardt

Himmelein

Britt

et al. 2009

Journal of General Virology

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Human cytomegalovirus (HCMV) encodes several highly polymorphic envelope glycoproteins; however, the biological relevance of this polymorphism is unclear. Glycoprotein N (gN) is one member of this polymorphic protein family. Four major gN genotypes (gN1-4) have been identified. We have tested the hypothesis that the gN polymorphism represents a mechanism to evade a neutralizing antiviral antibody response. Four recombinant viruses that differed only in the expression of the gN genotype were constructed on the genetic background of HCMV strain AD169. Exchange of gN genotypes had a minor detectable influence on virus replication, gN expression and gN-gM complex formation. Randomly selected human sera were analysed for neutralizing activity against the recombinant viruses. Of these, 70 % showed no difference in neutralizing titre between the viruses, whereas 30 % showed strain-specific neutralization. Differences in 50 % neutralization titre reached .8-fold. Viruses expressing the gN4 genotype were neutralized significantly better than those expressing the other gN genotypes. Strain specificity, or lack thereof, could not be attributed to the presence or absence of anti-gN antibodies, as all sera contained antibodies reacting with gN (as determined by ELISA). Thus, polymorphism of gN could contribute to evasion of an efficient neutralizing-antibody response and facilitate reinfection in previously seropositive individuals. INTRODUCTIONHuman cytomegalovirus (HCMV) is a significant cause of morbidity and mortality in immunocompromised individuals, such as transplant recipients, AIDS patients and newborns . A puzzling aspect of HCMV biology is the fact that a large number of genetically distinct HCMV strains circulate in the population (Chandler & McDougall, 1986;Chou, 1990;Rasmussen et al., 2002Rasmussen et al., , 2003Murphy et al., 2003;Pignatelli et al., 2003). The presence of more than one strain has been observed in immunocompetent persons, indicating the possibility of simultaneous coinfection with multiple different virus strains or reinfection in the presence of a functional immune response (Chandler et al., 1987;Bale et al., 1996;Schoppel et al., 1997;Boppana et al., 2001). In immunocompromised patients, reinfection may represent a clinically important problem, as a de novo adaptive immune response against the reinfecting strain is impaired. Clinical studies in transplant patients have supported the importance of HCMV reinfection in these patients (Grundy et al., 1988; Coaquette et al., 2004;Ishibashi et al., 2007). Moreover, in women who are seropositive for HCMV, reinfection with a different strain can lead to intrauterine transmission and symptomatic congenital infection (Boppana et al., 2001). In the closely related murine cytomegalovirus (MCMV), simultaneous or sequential infection with different virus strains results in mixed infections in immunocompetent mice (Farroway et al., 2005;Gorman et al., 2006). Thus, reinfection with different strains of cytomegalovirus is frequent in both immunocompetent and ...

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Section: Introductionmentioning

confidence: 48%

Glycoprotein N subtypes of human cytomegalovirus induce a strain-specific antibody response during natural infection

Burkhardt

Himmelein

Britt

et al. 2009

Journal of General Virology

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“…This is in contrast to the second immunodominant envelope protein, gB, where seropositivity rates for native or denatured protein were identical. The high percentage of conformation-dependent antibodies against gH could also provide an explanation for the findings that gH specific MAbs, if not developed against prokaryotic fusion proteins, recognize conformational epitopes (Baboonian et al, 1989;Cranage et al, 1988;Rasmussen et al, I984;Simpson et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

“…Fixation of insect cells using acetone could potentially alter antigenic structures necessary for binding of certain types of antibodies. In addition, gH specific MAbs show a wide range of neutralizing activity when different HCMV strains are compared (Baboonian et al, 1989;Rasmussen et al, 1984;Simpson et al, 1993). This could indicate that despite the high homology found between gH proteins from various isolates (Chou, 1992), strain specific recognition and neutralization takes place, mediated through minor differences between different gH molecules.…”

Section: Discussionmentioning

confidence: 99%

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Glycoprotein H of human cytomegalovirus is a major antigen for the neutralizing humoral immune response

Urban

Klein

et al. 1996

Journal of General Virology

105

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A recombinant baculovirus expressing glycoprotein H (gpUL75) of human cytomegalovirus was used to examine the humoral immune response in naturally infected individuals. Recombinant baculovirus infected insect cells produced two forms of gH with molecular masses of 78-82 kDa and 94 kDa. The 94 kDa polypeptide was modified by high mannose oligosaccharide side-chains as shown by reduction in molecular mass after treatment with endoglycosidases H and F. The 78-82 kDa protein represented the non-glycosylated precursor which was resistant to the enzymes. In contrast to gH expressed in mammalian cells, the recombinant baculovirus expressed gH was transported to the cell surface. Glycoprotein H produced in insect cells was reactive with human convalescent sera and all tested neutralizing monoclonal antibodies recognizing either linear or conformational epitopes. Antibodies reacting with insect cell derived gH were detected in 96% of HCMV seropositive human sera. Using insect cells infected with the gH expressing recombinant baculovirus as immunoabsorbent, between 0% and 58% of the total virus neutralizing activity was removed from sera of individuals with a past HCMV infection, gH must therefore be considered a major antigen for the induction of neutralizing antibodies during natural infection.

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“…The complement-independent neutralizing gH-specific MAb were : C2 (Baboonian et al, 1989) and HCMV-16 (Cogent Diagnostics ;Cranage et al, 1988). The non-neutralizing MAb were : C13 (specific for ppUL83 ; Baboonian et al, 1989) and HCMV-34 (specific for gB ; Cogent Diagnostics), all in the form of mouse ascitic fluids. Pre-and post-immunization guinea-pig sera with complementindependent neutralizing activity, specific for HCMV gB, were the generous gift of Dirk Gheysen (SmithKline Beecham).…”

Section: Methodsmentioning

confidence: 99%

Human cytomegalovirus glycoprotein H/glycoprotein L complex modulates fusion-from-without.

Milne

Paterson

Booth

1998

Journal of General Virology

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Complement‐Independent neutralising monoclonal antibody with differential reactivity for strains of human cytomegalovirus

Cited by 22 publications

References 24 publications

Glycoprotein N subtypes of human cytomegalovirus induce a strain-specific antibody response during natural infection

Glycoprotein N subtypes of human cytomegalovirus induce a strain-specific antibody response during natural infection

Glycoprotein H of human cytomegalovirus is a major antigen for the neutralizing humoral immune response

Human cytomegalovirus glycoprotein H/glycoprotein L complex modulates fusion-from-without.

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