Abstract
The guinea pig is the only small animal model for congenital cytomegalovirus (cCMV) but requires guinea pig cytomegalovirus (GPCMV). Current GPCMV research utilizes prototype strain 22122, which limits the translational impact of GPCMV as numerous human CMV strains exist and cCMV is possible in the setting of re-infection. A novel strain of GPCMV (TAMYC) exhibited differences to 22122 in various glycoproteins with GP74 (gO homolog) the most variable (25% difference). Antibody ELISAs for TAMYC-convalescent animals evoked similar immune response to viral glycoprotein complexes (gB, gH/gL, gM/gN, pentamer) and cell-mediated response to pp65 homolog (GP83). Convalescent sera from TAMYC-infected animals neutralized GPCMV infection on fibroblasts but was less effective on epithelial cells. TAMYC-convalescent animals were not protected from dissemination of heterogenous virus challenge (22122). However, in a cCMV protection study, TAMYC-convalescent animals challenged mid-pregnancy (22122) exhibited high-level protection against cCMV compared to seronegative animals with pup transmission reduced from 80% (control) to 12%. Overall, pre-existing immunity in guinea pigs provides limited ability to prevent GPCMV re-infection by a different viral strain but provides a high level of protection against cCMV in heterogenous strain challenge. This level of cross protection against cCMV should be a prerequisite of any CMV vaccine.
Highlights
Human cytomegalovirus (HCMV), a betaherpesvirus, is a leading cause of congenital disease in newborns [1]
The correlates of protection against Congenital CMV (cCMV) are poorly defined, it is generally thought that neutralizing antibodies to viral glycoprotein complexes significantly contribute to protection, but immunity can be enhanced by response to T cell target antigens in convalescent individuals [9]
Viral DNA was isolated from pass 1 virus stock from renal epithelial (REPI) cells in culture and used to PCR clone various virus glycoprotein genes: GP55; GP73; GP74; GP75; GP100; GP115; GP129 (HCMV UL128 homolog); GP131 (UL129 homolog); GP133 (UL131 homolog) as described in materials and methods using specific primer sets (Table S1) or previously described primers for GP100, GP115, GP129, GP131 and GP133 [15,16]
Summary
Human cytomegalovirus (HCMV), a betaherpesvirus, is a leading cause of congenital disease in newborns [1]. Congenital CMV (cCMV) can lead to serious symptomatic disease including cognitive and vision impairment as well as sensorineural hearing loss (SNHL) in newborns [1,2,3]. The viral gB glycoprotein which is essential for virus entry into all cell types, and an immunodominant neutralizing antibody target, remains a significant focus in various vaccine approaches. Vaccine strategies that include the viral pentamer complex (PC), which is important for infection of non-fibroblast cells are being evaluated [8]. The correlates of protection against cCMV are poorly defined, it is generally thought that neutralizing antibodies to viral glycoprotein complexes significantly contribute to protection, but immunity can be enhanced by response to T cell target antigens (e.g., pp65) in convalescent individuals [9]
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