title: Promising Role of Toll-Like Receptor 8 Agonist in Concert with Prostratin for Activation of Silent HIV.
abstract: The persistence of latently HIV-infected cells in patients under combined antiretroviral treatment (cART) remains the major hurdle for HIV eradication. Thus far, individual compounds have not been sufficiently potent to reactivate latent virus and guarantee its elimination in vivo. Thus, we hypothesized that transcriptional enhancers, in concert with compounds triggering the innate immune system, are more efficient in reversing latency by creating a Th1 supportive milieu that acts against latently HIV-infected cells at various levels. To test our hypothesis, we screened six compounds on a coculture of latently infected cells (J-lat) and monocyte-derived dendritic cells (MDDCs). The protein kinase C (PKC) agonist prostratin, with a Toll-like receptor 8 (TLR8) agonist, resulted in greater reversion of HIV latency than any single compound. This combinatorial approach led to a drastic phenotypic and functional maturation of the MDDCs. Tumor necrosis factor (TNF) and cell-cell interactions were crucial for the greater reversion observed. Similarly, we found a greater potency of the combination of prostratin and TLR8 agonist in reversing HIV latency when applying it to primary cells of HIV-infected patients. Thus, we demonstrate here the synergistic interplay between TLR8-matured MDDCs and compounds acting directly on latently HIV-infected cells, targeting different mechanisms of latency, by triggering various signaling pathways. Moreover, TLR8 triggering may reverse exhaustion of HIV-specific cytotoxic T lymphocytes that might be essential for killing or constraining the latently infected cells.
  
  
  
  Curing HIV is the Holy Grail. The so-called "shock and kill" strategy relies on drug-mediated reversion of HIV latency and the subsequent death of those cells under combined antiretroviral treatment. So far, no compound achieves efficient reversal of latency or eliminates this latent reservoir. The compounds may not target all of the latency mechanisms in all latently infected cells. Moreover, HIV-associated exhaustion of the immune system hinders the efficient elimination of the reactivated cells. In this study, we demonstrated synergistic latency reversion by combining agonists for protein kinase C and Toll-like receptor 8 in a coculture of latently infected cells with myeloid dendritic cells. The drug prostratin stimulates directly the transcriptional machinery of latently infected cells, and the TLR8 agonist acts indirectly by maturing dendritic cells. These findings highlight the importance of the immune system and its activation, in combination with direct-acting compounds, to reverse latency.
authors.affiliation: Department of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland mary-aude.r@hotmail.fr.
authors.forename: M A
authors.initials: MA
authors.lastname: Rochat
authors.affiliation: Department of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Schlaepfer
authors.affiliation: Department of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: R F
authors.identifier: http://orcid.org/0000-0002-8453-1137
authors.initials: RF
authors.lastname: Speck
mesh_terms: D000328:Adult; D000818:Animals; D018791:CD4 Lymphocyte Count; D002450:Cell Communication; D002460:Cell Line; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010703:Phorbol Esters / Q000494:pharmacology*; D064546:Protein Kinase C beta / Q000378:metabolism; D000072377:Syk Kinase / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000378:metabolism / Q000821:virology; D051200:Toll-Like Receptor 8 / Q000819:agonists*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019562:Viral Load; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency
chemical_list: D010703:Phorbol Esters; D051200:Toll-Like Receptor 8; D014409:Tumor Necrosis Factor-alpha; C070999:prostratin; D000072377:Syk Kinase; D064546:Protein Kinase C beta; D020928:Mitogen-Activated Protein Kinases
keywords: HIV cure; HIV-1; J-lat cells; aviremic patients; latency-reversing agents; monocyte-derived dendritic cells