title: Reactivation of latent HIV-1 in central memory CD4⁺ T cells through TLR-1/2 stimulation.
abstract: BACKGROUND
  Toll-like receptors (TLRs) are crucial for recognition of pathogen-associated molecular patterns by cells of the innate immune system. TLRs are present and functional in CD4⁺ T cells. Memory CD4⁺ T cells, predominantly central memory cells (TCM), constitute the main reservoir of latent HIV-1. However, how TLR ligands affect the quiescence of latent HIV within central memory CD4⁺ T cells has not been studied.
  
  
  RESULTS
  We evaluated the ability of a broad panel of TLR agonists to reactivate latent HIV-1. The TLR-1/2 agonist Pam3CSK4 leads to viral reactivation of quiescent HIV in a model of latency based on cultured TCM and in resting CD4⁺ T cells isolated from aviremic patients. In addition, we investigated the signaling pathway associated with Pam3CSK4 involved in HIV-1 reactivation. We show that the transcription factors NFκB, NFAT and AP-1 cooperate to induce viral reactivation downstream of TLR-1/2 stimulation. Furthermore, increasing levels of cyclin T1 is not required for TLR-mediated viral reactivation, but induction of viral expression requires activated pTEFb. Finally, Pam3CSK4 reactivates latent HIV-1 in the absence of T cell activation or proliferation, in contrast to antigen stimulation.
  
  
  CONCLUSIONS
  Our findings suggest that the signaling through TLR-1/2 pathway via Pam3CSK4 or other reagents should be explored as an anti-latency strategy either alone or in combination with other anti-latency drugs.
authors.forename: Camille L
authors.initials: CL
authors.lastname: Novis
authors.forename: Nancie M
authors.initials: NM
authors.lastname: Archin
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Buzon
authors.forename: Eric
authors.initials: E
authors.lastname: Verdin
authors.forename: June L
authors.initials: JL
authors.lastname: Round
authors.forename: Mathias
authors.initials: M
authors.lastname: Lichterfeld
authors.forename: David M
authors.initials: DM
authors.lastname: Margolis
authors.forename: Vicente
authors.initials: V
authors.lastname: Planelles
authors.affiliation: Division of Microbiology and Immunology, Department of Pathology, University Of Utah School of Medicine, Emma Eccles Jones Medical Research Building, Salt Lake City, UT 84112, USA. alberto.bosque@path.utah.edu.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bosque
mesh_terms: D000293:Adolescent; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D055666:Lipopeptides / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D051194:Toll-Like Receptor 1 / Q000819:agonists* / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000276:immunology; D014775:Virus Activation; D055815:Young Adult
chemical_list: D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2