TLR7/8 triggering exerts opposing effects in acute versus latent HIV infection.
TLRs trigger innate immunity by recognizing conserved motifs of microorganisms. Recently, ssRNAs from HIV and influenza virus were shown to trigger TLR7 and 8. Thus, we hypothesized that HIV ssRNA, by triggering TLR7/8, affects HIV pathogenesis. Indeed, HIV ssRNA rendered human lymphoid tissue of tonsillar origin or PBMC barely permissive to HIV replication. The synthetic compound R-848, which also triggers TLR7/8, showed similar anti-HIV activity. Loss of R-848's activity in lymphoid tissue depleted of B cells suggested a role for B cells in innate immunity. TLR7/8 triggering appears to exert antiviral effects through soluble factors: conditioned medium reduced HIV replication in indicator cells. Although a number of cytokines and chemokines were increased upon adding R-848 to lymphoid tissue, blocking those cytokines/chemokines (i.e., IFN-alpha receptor, IFN-gamma, MIP-1alpha, -1beta, RANTES, and stromal cell-derived factor-1) did not result in the reversal of R-848's anti-HIV activity. Thus, the nature of this soluble factor(s) remains unknown. Unlike lymphoid tissue acutely infected with HIV, triggering latently infected promonocytic cells induced the release of HIV virions. The anti-HIV effects of triggering TLR7/8 may inhibit rapid killing, while pro-HIV effects may guarantee a certain replication level. Compounds triggering TLR7/8 may be attractive drug candidates to purge latent HIV while preventing new infections.
Division of Infectious Diseases and Hospital Epidemiology, Department of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland.
Erika
E
Schlaepfer
Annette
A
Audigé
Helene
H
Joller
Roberto F
RF
Speck
D000208:Acute Disease; D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000276:immunology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000276:immunology; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008214:Lymphocytes / Q000378:metabolism / Q000821:virology; D019402:Macrophage Inflammatory Proteins / Q000276:immunology; D014066:Palatine Tonsil / Q000166:cytology / Q000378:metabolism / Q000821:virology; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000378:metabolism / Q000502:physiology*; D051200:Toll-Like Receptor 8 / Q000378:metabolism / Q000502:physiology*; D017735:Virus Latency / Q000276:immunology*; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology
D019380:Anti-HIV Agents; C515255:CXCL12 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D007093:Imidazoles; D019402:Macrophage Inflammatory Proteins; D017471:Receptors, Interferon; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D053633:Receptor, Interferon alpha-beta; C402365:resiquimod