title: Administration of a Toll-like receptor 9 agonist decreases the proviral reservoir in virologically suppressed HIV-infected patients.
abstract: Toll-like receptor (TLR) agonists can reactivate HIV from latently infected cells in vitro. We aimed to investigate the TLR-9 agonist, CPG 7909's in vivo effect on the proviral HIV reservoir and HIV-specific immunity. This was a post-hoc analysis of a double-blind randomized controlled vaccine trial. HIV-infected adults were randomized 1:1 to receive pneumococcal vaccines with or without 1 mg CPG 7909 as adjuvant at 0, 3 and 9 months. In patients on suppressive antiretroviral therapy we quantified proviral DNA at 0, 3, 4, 9, and 10 months (31 subjects in the CPG group and 37 in the placebo-adjuvant group). Furthermore, we measured HIV-specific antibodies, characterized T cell phenotypes and HIV-specific T cell immunity. We observed a mean reduction in proviral DNA in the CPG group of 12.6% (95% CI: -23.6-0.0) following each immunization whereas proviral DNA in the placebo-adjuvant group remained largely unchanged (6.7% increase; 95% CI: -4.2-19.0 after each immunization, p = 0.02). Among participants with additional cryo-preserved PBMCs, HIV-specific CD8+ T cell immunity as indicated by increased expression of degranulation marker CD107a and macrophage inflammatory protein 1β (MIP1β) tended to be up-regulated following immunization with CPG 7909 compared with placebo as adjuvant. Further, increasing proportion of HIV-specific CD107a and MIP1β-expressing CD8+ T cells were strongly correlated with decreasing proviral load. No changes were observed in T cell phenotype distribution, HIV-specific CD4+ T cell immunity, or HIV-specific antibodies. TLR9-adjuvanted pneumococcal vaccination decreased proviral load. Reductions in proviral load correlated with increasing levels of HIV specific CD8+ T cells. Further investigation into the potential effect of TLR9 agonists on HIV latency is warranted.
authors: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark. anniw@studmed.au.dk
authors: Anni A
authors: AA
authors: Winckelmann
authors: Lærke V
authors: LV
authors: Munk-Petersen
authors: Thomas A
authors: TA
authors: Rasmussen
authors: Jesper
authors: J
authors: Melchjorsen
authors: Thomas J
authors: TJ
authors: Hjelholt
authors: David
authors: D
authors: Montefiori
authors: Lars
authors: L
authors: Østergaard
authors: Ole S
authors: OS
authors: Søgaard
authors: Martin
authors: M
authors: Tolstrup
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000821:virology; D002451:Cell Compartmentation / Q000187:drug effects; D004197:Disease Reservoirs / Q000821:virology*; D015483:HIV Antibodies / Q000096:biosynthesis; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology*; D006801:Humans; D007109:Immunity / Q000187:drug effects; D007156:Immunologic Memory / Q000187:drug effects; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D010641:Phenotype; D011533:Proviruses / Q000187:drug effects*; D013045:Species Specificity; D051217:Toll-Like Receptor 9 / Q000819:agonists* / Q000378:metabolism; D019562:Viral Load / Q000187:drug effects
chemical_list: D015483:HIV Antibodies; D009838:Oligodeoxyribonucleotides; C483020:ProMune; D051217:Toll-Like Receptor 9
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