Synergistic activation of HIV-1 expression by deacetylase inhibitors and prostratin: implications for treatment of latent infection
; ; et al
in PLoS ONE (2009), 4(6), 6093
The persistence of transcriptionally silent but replication-competent HIV-1 reservoirs in Highly Active Anti-Retroviral Therapy (HAART)-treated infected individuals, represents a major hurdle to virus ... [more ▼]
The persistence of transcriptionally silent but replication-competent HIV-1 reservoirs in Highly Active Anti-Retroviral Therapy (HAART)-treated infected individuals, represents a major hurdle to virus eradication. Activation of HIV-1 gene expression in these cells together with an efficient HAART has been proposed as an adjuvant therapy aimed at decreasing the pool of latent viral reservoirs. Using the latently-infected U1 monocytic cell line and latently-infected J-Lat T-cell clones, we here demonstrated a strong synergistic activation of HIV-1 production by clinically used histone deacetylase inhibitors (HDACIs) combined with prostratin, a non-tumor-promoting nuclear factor (NF)- kappaB inducer. In J-Lat cells, we showed that this synergism was due, at least partially, to the synergistic recruitment of unresponsive cells into the expressing cell population. A combination of prostratin+HDACI synergistically activated the 5' Long Terminal Repeat (5'LTR) from HIV-1 Major group subtypes representing the most prevalent viral genetic forms, as shown by transient transfection reporter assays. Mechanistically, HDACIs increased prostratin-induced DNA-binding activity of nuclear NF-kappaB and degradation of cytoplasmic NF-kappaB inhibitor, IkappaBalpha . Moreover, the combined treatment prostratin+HDACI caused a more pronounced nucleosomal remodeling in the U1 viral promoter region than the treatments with the compounds alone. This more pronounced remodeling correlated with a synergistic reactivation of HIV-1 transcription following the combined treatment prostratin+HDACI, as demonstrated by measuring recruitment of RNA polymerase II to the 5'LTR and both initiated and elongated transcripts. The physiological relevance of the prostratin+HDACI synergism was shown in CD8(+)-depleted peripheral blood mononuclear cells from HAART-treated patients with undetectable viral load. Moreover, this combined treatment reactivated viral replication in resting CD4(+) T cells isolated from similar patients. Our results suggest that combinations of different kinds of proviral activators may have important implications for reducing the size of latent HIV-1 reservoirs in HAART-treated patients. [less ▲]Detailed reference viewed: 64 (8 ULg)
Are the IKKs and IKK-related kinases TBK1 and IKK-ε similarly activated ?
Chau, Tieu-Lan ; Gioia, Romain ; et al
in Trends in Biochemical Sciences - Regular Edition (2008), 33
The IKKs, IKKa and IKKb, and the IKK-related kinases TBK1 and IKKe, play essential roles in innate immunity through signal-induced activation of NF-κB and IRF3/7, respectively. Although the signaling ... [more ▼]
The IKKs, IKKa and IKKb, and the IKK-related kinases TBK1 and IKKe, play essential roles in innate immunity through signal-induced activation of NF-κB and IRF3/7, respectively. Although the signaling events within these pathways have been extensively studied, the mechanisms of IKK and IKK-related complex assembly and activation remain poorly defined. Recent data provide insight into the requirement for scaffold proteins in complex assembly; NEMO coordinates some IKK complexes, whereas TANK, NAP1 or SINTBAD assemble TBK1 and IKKe complexes. The different scaffold proteins undergo similar post-translational modifications, including phosphorylation and non-degradative polyubiquitylation. Moreover, increasing evidence suggests that distinct scaffold proteins assemble IKK and potentially TBK1 and IKKε sub-complexes in a stimulus-specific manner, which might be a mechanism to achieve specificity. [less ▲]Detailed reference viewed: 100 (9 ULg)
Lipopolysaccharide-mediated interferon regulatory factor activation involves TBK1-IKK epsilon-dependent lys(63)-linked polyubiquitination and phosphorylation of TANK/I-TRAF
; Gioia, Romain ; Chau, Tieu-Lan et al
in Journal of Biological Chemistry (2007), 282(43), 31131-31146
Type I interferon gene induction relies on IKK-related kinase TBK1 and IKK epsilon-mediated phosphorylations of IRF3/7 through the Toll-like receptor-dependent signaling pathways. The scaffold proteins ... [more ▼]
Type I interferon gene induction relies on IKK-related kinase TBK1 and IKK epsilon-mediated phosphorylations of IRF3/7 through the Toll-like receptor-dependent signaling pathways. The scaffold proteins that assemble these kinase complexes are poorly characterized. We show here that TANK/ITRAF is required for the TBK1- and IKK epsilon-mediated IRF3/7 phosphorylations through some Toll-like receptor-dependent pathways and is part of a TRAF3-containing complex. Moreover, TANK is dispensable for the early phase of double-stranded RNA-mediated IRF3 phosphorylation. Interestingly, TANK is heavily phosphorylated by TBK1-IKK epsilon upon lipopolysaccharide stimulation and is also subject to lipopolysaccharide- and TBK1-IKK epsilon-mediated Lys(63)-linked polyubiquitination, a mechanism that does not require TBK1-IKK epsilon kinase activity. Thus, we have identified TANK as a scaffold protein that assembles some but not all IRF3/7-phosphorylating TBK1-IKK epsilon complexes and demonstrated that these kinases possess two functions, namely the phosphorylation of both IRF3/7 and TANK as well as the recruitment of an E3 ligase for Lys63-linked polyubiquitination of their scaffold protein, TANK. [less ▲]Detailed reference viewed: 67 (17 ULg)
Interacting surface of the receptor-binding domain.
; ; et al
in Société Belge de Biochimie et de Biologie moléculaire. (2002, February 22)Detailed reference viewed: 6 (0 ULg)
A critical cysteine residue of bovine leukemia virus SU protein interacts with zinc and plays a role in viral infectivity.
; ; et al
in The 2001 meeting on Retroviruses. (2001, May)Detailed reference viewed: 12 (0 ULg)
Implication de la protéine transmembranaire d’enveloppe du virus de la leucémie bovine dans la fusion cellulaire et l’infectivité virale.
; ; et al
in Séminaire de la Recherche Télévie (1999, March 16)Detailed reference viewed: 13 (1 ULg)
Mutations in the immunosuppressive peptide of bovine leukema virus affect fusion and infectivity in vivo
; Kettmann, Richard ; et al
in Virus Research (1997), 47(2-Special Issue), 103Detailed reference viewed: 6 (0 ULg)