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Differential decay kinetics of human cytomegalovirus glycoprotein B genotypes following antiviral chemotherapy.

ABSTRACT: The impact of different cytomegalovirus (HCMV) glycoprotein B (gB) genotypes on pathogenesis remains controversial.To investigate the effect of gB genotypes either as single infections or as part of multiple infections on the early kinetics of response to ganciclovir therapy.Patients (n=239) enrolled in a study of intravenous ganciclovir or valganciclovir for the treatment of HCMV disease were analysed by a gB genotype specific PCR to quantify the amount of each gB genotype present at initiation of therapy (baseline, day 0) and at days 3, 7, 14 and 21 post therapy.In all gB groups (individual gB genotype infections and mixed genotype infections) there was a biphasic decline in viral load after therapy. The first phase half life (days 0-3) was ?1 day and was followed over the next 18 days by a slower second phase decline with half lives ranging from 3.4 to 4.4 days. The 1st phase rapid decline in viral load was dependent upon gB genotype whereas the ultimate viral load reduction at day 21 was relatively insensitive to gB genotype. A strong correlation between 1st phase decline and extent of viral load reduction at day 21 was observed (r=0.37; p=0.002). These data imply that early reductions in HCMV load after therapy may be useful in predicting the duration of drug therapy needed to control HCMV replication.

SUBMITTER: Emery VC

PROVIDER: S-EPMC3328767 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Differential decay kinetics of human cytomegalovirus glycoprotein B genotypes following antiviral chemotherapy.

Emery Vincent C VC Manuel Oriol O Asberg Anders A Pang Xiaoli X Kumar Deepali D Hartmann Anders A Preiksaitis Jutta K JK Pescovitz Mark D MD Rollag Halvor H Jardine Alan G AG Gahlemann Christoph G CG Humar Atul A

Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology 20120310 1

<h4>Background</h4>The impact of different cytomegalovirus (HCMV) glycoprotein B (gB) genotypes on pathogenesis remains controversial.<h4>Objectives</h4>To investigate the effect of gB genotypes either as single infections or as part of multiple infections on the early kinetics of response to ganciclovir therapy.<h4>Methods</h4>Patients (n=239) enrolled in a study of intravenous ganciclovir or valganciclovir for the treatment of HCMV disease were analysed by a gB genotype specific PCR to quantif ...[more]

PMID: 22410132

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Project description:The core, conserved function of the herpesvirus gH/gL is to promote gB-mediated membrane fusion during entry, although the mechanism is poorly understood. The human cytomegalovirus (HCMV) gH/gL can exist as either the gH/gL/gO trimer or the gH/gL/UL128/UL130/UL131 (gH/gL/UL128-131) pentamer. One model suggests that gH/gL/gO provides the core fusion role during entry into all cells within the broad tropism of HCMV, whereas gH/gL/UL128-131 acts at an earlier stage, by a distinct receptor-binding mechanism to enhance infection of select cell types, such as epithelial cells, endothelial cells, and monocytes/macrophages. To further study the distinct functions of these complexes, mutants with individual charged cluster-to-alanine (CCTA) mutations of gH and gL were combined to generate a library of 80 mutant gH/gL heterodimers. The majority of the mutant gH/gL complexes were unable to facilitate gB-mediated membrane fusion in transient-expression cell-cell fusion experiments. In contrast, these mutants supported the formation of gH/gL/UL128-131 complexes that could block HCMV infection in receptor interference experiments. These results suggest that receptor interactions with gH/gL/UL128-131 involve surfaces contained on the UL128-131 proteins but not on gH/gL. gH/gL/UL128-131 receptor interference could be blocked with anti-gH antibodies, suggesting that interference is a cell surface phenomenon and that anti-gH antibodies can block gH/gL/UL128-131 in a manner that is distinct from that for gH/gL/gO.Interest in the gH/gL complexes of HCMV (especially gH/gL/UL128-131) as vaccine targets has far outpaced our understanding of the mechanism by which they facilitate entry and contribute to broad cellular tropism. For Epstein-Barr virus (EBV), gH/gL and gH/gL/gp42 are both capable of promoting gB fusion for entry into epithelial cells and B cells, respectively. In contrast, HCMV gH/gL/gO appears to be the sole fusion cofactor that promotes gB fusion activity, whereas gH/gL/UL128-131 expands cell tropism through a distinct yet unknown mechanism. This study suggests that the surfaces of HCMV gH/gL are critical for promoting gB fusion but are dispensable for gH/gL/UL128-131 receptor interaction. This underscores the importance of gH/gL/gO in HCMV entry into all cell types and reaffirms the complex as a candidate target for vaccine development. The two functionally distinct forms of gH/gL present in HCMV make for a useful model with which to study the fundamental mechanisms by which herpesvirus gH/gL regulates gB fusion.

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Differential decay kinetics of human cytomegalovirus glycoprotein B genotypes following antiviral chemotherapy.

Publications

Differential decay kinetics of human cytomegalovirus glycoprotein B genotypes following antiviral chemotherapy.

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