title: CpG oligodeoxynucleotides block human immunodeficiency virus type 1 replication in human lymphoid tissue infected ex vivo.
abstract: Oligodeoxynucleotides (ODNs) with immunomodulatory motifs control a number of microbial infections in animal models, presumably by acting through toll-like receptor 9 (TLR9) to induce a number of cytokines (e.g., alpha interferon and tumor necrosis factor alpha). The immunomodulatory motif consists of unmethylated sequences of cytosine and guanosine (CpG motif). ODNs without CpG motifs do not trigger TLR9. We hypothesized that triggering of TLR9 generates a cellular environment unfavorable for human immunodeficiency virus (HIV) replication. We tested this hypothesis in human lymphocyte cultures and found that phosphorothioate-modified ODN CpG2006 (type B ODNs) inhibited HIV replication nearly completely and prevented the loss of CD4(+) T cells. ODNs CpG2216 and CpG10 (type A ODNs) were less effective. CpG2006 blocked HIV replication in purified CD4(+) T cells and T-cell lines; CpG10 was ineffective in this setting, indicating that type A ODNs may inhibit HIV replication in CD4(+) T-cell lines indirectly through a separate cell subset. However, control ODNs without CpG motifs also showed anti-HIV effects, indicating that these effects are nonspecific and not due to TLR9 triggering. The mechanism of action is not clear. CpG2006 and its control ODN blocked syncytium formation in a cell fusion-based assay, but CpG10, CpG2216, and their control ODNs did not. The latter types interfered with the HIV replication cycle during disassembly or reverse transcription. In contrast, CpG2006 and CpG2216 specifically induced cytokines critical to initiation of the innate immune response. In summary, the nonspecific anti-HIV activity of CpG ODNs, their ability to stimulate HIV replication in latently infected cells, potentially resulting in their elimination, and their documented ability to link the innate and adaptive immune responses make them attractive candidates for further study as anti-HIV drugs.
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, Department of Internal Medicine, University Hospital of Zurich, Raemistrasse 100, 8091 Zurich, Switzerland.
authors.forename: Erika
authors.initials: E
authors.lastname: Schlaepfer
authors.forename: Annette
authors.initials: A
authors.lastname: Audigé
authors.forename: Barbara
authors.initials: B
authors.lastname: von Beust
authors.forename: Vania
authors.initials: V
authors.lastname: Manolova
authors.forename: Markus
authors.initials: M
authors.lastname: Weber
authors.forename: Helene
authors.initials: H
authors.lastname: Joller
authors.forename: Martin F
authors.initials: MF
authors.lastname: Bachmann
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Kundig
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Speck
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D015704:CD4 Antigens / Q000032:analysis; D018791:CD4 Lymphocyte Count; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008221:Lymphoid Tissue / Q000821:virology*; D008562:Membrane Glycoproteins / Q000502:physiology; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000032:analysis; D011956:Receptors, Cell Surface / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000032:analysis; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000276:Adjuvants, Immunologic; D015704:CD4 Antigens; C408982:CPG-oligonucleotide; D016207:Cytokines; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D019718:Receptors, CXCR4; D011956:Receptors, Cell Surface; D015375:Receptors, Interleukin-2; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors