Abstract
Human cytomegalovirus (HCMV) infection can lead to congenital hearing loss and mental retardation. Upon immune suppression, reactivation of latent HCMV or primary infection increases morbidity in cancer, transplantation, and late stage AIDS patients. Current treatments include nucleoside analogues, which have significant toxicities limiting their usefulness. In this study we screened a panel of synthetic heparin-binding peptides for their ability to prevent CMV infection in vitro. A peptide designated, p5+14 exhibited ~ 90% reduction in murine CMV (MCMV) infection. Because negatively charged, cell-surface heparan sulfate proteoglycans (HSPGs), serve as the attachment receptor during the adsorption phase of the CMV infection cycle, we hypothesized that p5+14 effectively competes for CMV adsorption to the cell surface resulting in the reduction in infection. Positively charged Lys residues were required for peptide binding to cell-surface HSPGs and reducing viral infection. We show that this inhibition was not due to a direct neutralizing effect on the virus itself and that the peptide blocked adsorption of the virus. The peptide also inhibited infection of other herpesviruses: HCMV and herpes simplex virus 1 and 2 in vitro, demonstrating it has broad-spectrum antiviral activity. Therefore, this peptide may offer an adjunct therapy for the treatment of herpes viral infections and other viruses that use HSPGs for entry.
Highlights
Human cytomegalovirus (HCMV) is a beta-herpesvirus with nearly 90% prevalence in the adult human population in developing countries [1]
Seven synthetic peptides based on the structure of peptide p5 were screened for their ability to reduce murine CMV (MCMV) infection in vitro (Table 1)
In the initial screening assays all peptides were tested at a single concentration (500 μg/ml) using a plaque-reduction assay, in which mouse embryonic fibroblasts were incubated with the peptides for 30 min prior to the addition of virus
Summary
Human cytomegalovirus (HCMV) is a beta-herpesvirus with nearly 90% prevalence in the adult human population in developing countries [1]. Initial viral infection is generally asymptomatic in immune competent individuals. Severe CMV disease occurs in individuals with a deficient immune system (e.g., transplant patients suppressed to avoid graft rejection, late stage AIDS patients, and the developing fetus). HCMV can cause pneumonitis, multi-organ disease, and death [1,2,3]. Retinitis and blindness are common in HCMV-infected, late-stage AIDS patients in the absence of highly active antiretroviral.
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