title: Suppression of HIV replication in vitro by CpG and CpG conjugated to the non toxic B subunit of cholera toxin.
abstract: Administration of oligodeoxynucleotides (ODNs) containing CpG motifs generates a rapid and potent response of CC-chemokines, known as ligands of the HIV-1 co-receptor CCR5, in the murine female genital tract. The present study explored the potential HIV inhibitory activities of different human CpG prototypes either alone or conjugated to the non-toxic subunit of cholera toxin (CTB). Results showed that in vitro replication of both HIV-1 and HIV-2 can be suppressed by different human CpG prototypes. Importantly, the conjugation of CpG ODN to CTB (CTB-CpG) enhanced the antiviral activity of CpG against primary HIV-1 isolates of both R5 and X4 phenotypes in peripheral blood mononuclear cells (PBMC) as well as U87.CD4 co-receptor indicator cells. CTB-CpGs triggered higher amounts of MIP-1alpha, and MIP-1beta in PBMC than the corresponding CpG ODNs, which may explain the superior antiviral effect of CTB-CpG against R5 virus in PBMC. Incubation of PBMC with CpG ODN and CTB-CpG did not alter surface expression of HIV-1 receptors indicating that the observed anti-HIV-1 effect is not mediated through down regulation of HIV-1 receptors on target cells. Further, the enhanced antiviral effect of CTB-CpG was dependent on the presence of phosphorothioate backbone in the ODN, whereas the presence of CpG motif in ODNs was dispensable. These results have implications for the development of novel intervention strategies to prevent HIV infection.
authors.affiliation: Department of Virology, Swedish Institute for Infectious Disease Control, Karolinska Institute, Sweden.
authors.forename: Salma
authors.initials: S
authors.lastname: Nowroozalizadeh
authors.forename: Marianne
authors.initials: M
authors.lastname: Jansson
authors.forename: Jenni
authors.initials: J
authors.lastname: Adamsson
authors.forename: Marianne
authors.initials: M
authors.lastname: Lindblad
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Fenyö
authors.forename: Jan
authors.initials: J
authors.lastname: Holmgren
authors.forename: Ali M
authors.initials: AM
authors.lastname: Harandi
mesh_terms: D054405:Chemokine CCL3 / Q000096:biosynthesis / Q000276:immunology; D054407:Chemokine CCL4 / Q000096:biosynthesis / Q000276:immunology; D002772:Cholera Toxin / Q000494:pharmacology*; D018899:CpG Islands; D016207:Cytokines / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006678:HIV / Q000187:drug effects* / Q000502:physiology; D016655:HIV Core Protein p24 / Q000032:analysis / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D015498:HIV-2 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D018796:Immunoconjugates / Q000276:immunology / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000821:virology; D009841:Oligonucleotides / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: C515429:CCL3 protein, human; C066507:CCL4 protein, human; C527276:CXCR4 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines; D016655:HIV Core Protein p24; D018796:Immunoconjugates; D009841:Oligonucleotides; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D002772:Cholera Toxin