Hit-and-run stimulation: a novel concept to reactivate latent HIV-1 infection without cytokine gene induction.

Academic Article

Abstract

  • Current antiretroviral therapy (ART) efficiently controls HIV-1 replication but fails to eradicate the virus. Even after years of successful ART, HIV-1 can conceal itself in a latent state in long-lived CD4(+) memory T cells. From this latent reservoir, HIV-1 rebounds during treatment interruptions. Attempts to therapeutically eradicate this viral reservoir have yielded disappointing results. A major problem with previously utilized activating agents is that at the concentrations required for efficient HIV-1 reactivation, these stimuli trigger high-level cytokine gene expression (hypercytokinemia). Therapeutically relevant HIV-1-reactivating agents will have to trigger HIV-1 reactivation without the induction of cytokine expression. We present here a proof-of-principle study showing that this is a possibility. In a high-throughput screening effort, we identified an HIV-1-reactivating protein factor (HRF) secreted by the nonpathogenic bacterium Massilia timonae. In primary T cells and T-cell lines, HRF triggered a high but nonsustained peak of nuclear factor kappa B (NF-kappaB) activity. While this short NF-kappaB peak potently reactivated latent HIV-1 infection, it failed to induce gene expression of several proinflammatory NF-kappaB-dependent cellular genes, such as those for tumor necrosis factor alpha (TNF-alpha), interleukin-8 (IL-8), and gamma interferon (IFN-gamma). Dissociation of cellular and viral gene induction was achievable, as minimum amounts of Tat protein, synthesized following application of a short NF-kappaB pulse, triggered HIV-1 transactivation and subsequent self-perpetuated HIV-1 expression. In the absence of such a positive feedback mechanism, cellular gene expression was not sustained, suggesting that strategies modulating the NF-kappaB activity profile could be used to selectively trigger HIV-1 reactivation.
  • Published In

    Keywords

  • Bacterial Proteins, Cell Line, Cells, Cultured, Gene Expression Regulation, Viral, HIV Infections, HIV-1, Humans, NF-kappa B, Oxalobacteraceae, T-Lymphocytes, Transcriptional Activation, Virus Activation, Virus Latency
  • Digital Object Identifier (doi)

    Pubmed Id

  • 23637325
  • Author List

  • Wolschendorf F; Duverger A; Jones J; Wagner FH; Huff J; Benjamin WH; Saag MS; Niederweis M; Kutsch O
  • Start Page

  • 8712
  • End Page

  • 8720
  • Volume

  • 84
  • Issue

  • 17