Administration of a Toll-Like Receptor 9 Agonist Decreases the Proviral Reservoir in Virologically Suppressed HIV-Infected Patients

• Published in: PloS one Vol. 8; no. 4; p. e62074
• Main Authors: Winckelmann, Anni A., Munk-Petersen, Lærke V., Rasmussen, Thomas A., Melchjorsen, Jesper, Hjelholt, Thomas J., Montefiori, David, Østergaard, Lars, Søgaard, Ole S., Tolstrup, Martin
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26.04.2013; Public Library of Science (PLoS)
• Subjects: Acquired immune deficiency syndrome; Adult; Adults; AIDS; Antibodies; Antiretroviral agents; Antiretroviral drugs; Antiretroviral therapy; Biology; CD4 antigen; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - virology; CD8 antigen; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - virology; Cell Compartmentation - drug effects; CpG islands; Degranulation; Deoxyribonucleic acid; Disease Reservoirs - virology; DNA; HIV; HIV Antibodies - biosynthesis; HIV Infections - drug therapy; HIV Infections - immunology; HIV Infections - virology; Human immunodeficiency virus; Humans; Immune system; Immunity; Immunity - drug effects; Immunization; Immunologic Memory - drug effects; In vivo methods and tests; Inflammation; Latency; Latent infection; Load distribution; Lymphocytes; Lymphocytes T; Macrophage inflammatory protein; Macrophages; Medicine; Middle Aged; Oligodeoxyribonucleotides - administration & dosage; Oligodeoxyribonucleotides - pharmacology; Oligodeoxyribonucleotides - therapeutic use; Patients; Phenotype; Proteins; Proviruses - drug effects; Randomization; Species Specificity; Stress concentration; T cell receptors; TLR9 protein; Toll-Like Receptor 9 - agonists; Toll-Like Receptor 9 - metabolism; Toll-like receptors; Vaccines; Viral Load - drug effects; Denmark; Aarhus Denmark
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0062074

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.