Abstract
A better understanding of the mechanisms underlying cell tropisms and the efficiency of viral infection is critical for the development of vaccines and antiviral drugs for viral diseases. In this study, we worked on the entry mechanisms of guinea pig cytomegalovirus and found that endogenous expression of a combination of two components (GP131 and GP133) of the pentameric glycoprotein complex, which is required for non-fibroblast cell tropisms, enhanced viral infection more than 10-fold. In addition, D138A alteration in GP131 increased this enhancement by an additional 10-fold. Although differences in the efficiency of viral infection among various cell types are usually explained by differences in viral entry or traffic processes, our experimental evidences dismissed such possibilities. Instead, our findings that i) endogenous expression of GP131 and GP133 after nuclear delivery of viral DNA still enhanced infection and ii) an HDAC inhibitor overcame the need of the endogenous expression led us to hypothesize a novel mechanism that controls the efficiency of viral infection through the activation of gene expression from viral DNA delivered to the nuclei. Further studies of this unexpected phenomena warrant to understand novel but also general mechanisms for cell tropisms of viral infection and determinants that control infection efficiency.
Highlights
A better understanding of the mechanisms underlying cell tropisms and the efficiency of viral infection is critical for the development of vaccines and antiviral drugs for viral diseases
In the cells transduced with any combination containing both the recombinant adenovirus (rAd) expressing GP131(rAd-131) and GP133, but not in those transduced with rAd-131 or rAd-133 individually, guinea pig CMV (GPCMV) infection resulted in a 6- to 30-fold increase in the number of GFP-positive cells in comparison with those in the cells transduced with the rAd expressing β-galactosidase (Fig. 1a)
We demonstrated that i) GP131/GP133 expression did not increase viral attachment or cellular virion traffic processes, and ii) endogenous co-expression of GP131 and GP133 did not compensate for the lack of GP131 in the GPCMV used for infection, which is different from trans-complementation of the defect in MCMV m131/m129 encoding Mck-2, a homolog of UL130 and GP131, to promote viral entry into macrophages as a glycoprotein H (gH)/gL/MCK-2 complex[26]
Summary
A better understanding of the mechanisms underlying cell tropisms and the efficiency of viral infection is critical for the development of vaccines and antiviral drugs for viral diseases. We worked on the entry mechanisms of guinea pig cytomegalovirus and found that endogenous expression of a combination of two components (GP131 and GP133) of the pentameric glycoprotein complex, which is required for non-fibroblast cell tropisms, enhanced viral infection more than 10-fold. To clarify the precise requirements of Pentamer for GPCMV infection and to identify cellular receptors for Pentamer-dependent infection, we examined whether endogenously expressed Pentamer components inhibit GPCMV infection due to receptor binding competition (so-called “interference”) as shown in HCMV Pentamer[20] During such experiments, we found an unexpected phenomenon in which, instead of interference, co-expression of GP131 and GP133, two components of GPCMV Pentamer, enhanced GPCMV infection of epithelial cells more than 10-fold. As there were no precedents to such a phenomenon, we analyzed its mechanisms to understand how the efficiency of viral infection is controlled
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