Specific targeted binding of herpes simplex virus type 1 to hepatocytes via the human hepatitis B virus preS1 peptide.
To improve the utility of herpes simplex virus type 1 (HSV-1) vectors for gene therapy, the viral envelope needs to be manipulated to achieve cell-specific gene delivery. In this report, we have engineered an HSV-1 mutant virus, KgBpK(-) gC(-), deleted for the glycoprotein C (gC) and the heparan sulfate-binding domain (pK) of gB, in order to express gC:preS1 and gC:preS1 active peptide (preS1ap) fusion molecules. PreS1, and a 27 amino acid active peptide inside preS1 (preS1ap), are supposed to be the molecules that the human hepatitis B virus (HBV) needs to bind specifically to hepatocytes. Biochemical analysis demonstrated that the gC:preS1ap fusion molecule was expressed and incorporated into the envelope of the recombinant HSV-1 virus KgBpK(-)gC:preS1ap. Moreover, KgBpK(-)gC:preS1ap recombinant virus gained a specific binding activity to an hepatoblastoma cell line (HepG2) with a consequent productive infection. In addition, anti-preS1-specific antibodies were shown to neutralize recombinant virus infectivity, and a synthetic preS1ap peptide was able to elute KgBpK(-)gC:preS1ap virus bound on HpeG2 cells. These data provide further evidence that HSV-1 can productively infect cells through a specific binding to a non-HSV-1 receptor. Furthermore, these data strongly support the hypothesis that the HBV preS1ap molecule is an HBV ligand to hepatocytes.
Argnani
Rafaela
R
Department of Experimental and Diagnostic Medicine, Section of Microbiology, University of Ferrara, Ferrara, Italy.
Boccafogli
Luca
L
Marconi
Peggy C
PC
Manservigi
Roberto
R
D000818:Animals; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D017353:Gene Deletion; D005818:Genetic Engineering; D005822:Genetic Vectors / Q000378:metabolism*; D006514:Hepatitis B Surface Antigens / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding; D011498:Protein Precursors / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D014162:Transfection; D014709:Vero Cells; D014759:Viral Envelope Proteins / Q000235:genetics
D006514:Hepatitis B Surface Antigens; D011498:Protein Precursors; D011993:Recombinant Fusion Proteins; D014759:Viral Envelope Proteins; C038535:glycoprotein gC, herpes simplex virus type 1; C050806:presurface protein 1, hepatitis B surface antigen