Reactivation of Latent HIV-1 in Central Memory CD4⁺ T Cells Through TLR-1/2 Stimulation

Retrovirology. 2013 Oct 24;10:119. doi: 10.1186/1742-4690-10-119.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / virology*
  • HIV-1 / physiology*
  • Humans
  • Lipopeptides / immunology
  • Lipopeptides / metabolism*
  • Signal Transduction
  • Toll-Like Receptor 1 / agonists*
  • Toll-Like Receptor 1 / immunology
  • Toll-Like Receptor 2 / agonists*
  • Toll-Like Receptor 2 / immunology
  • Virus Activation*
  • Young Adult

Substances

  • Lipopeptides
  • Pam(3)CSK(4) peptide
  • Toll-Like Receptor 1
  • Toll-Like Receptor 2