COUP-TF interacting protein 2 represses the initial phase of HIV-1 gene transcription in human microglial cells

Human immunodeficiency virus type 1 (HIV-1) gene transcription is characterized by two temporally distinct phases. While the initial phase relies solely on cellular transcription factors, the subsequent phase is activated by the viral Tat transactivator. We have previously reported that the subsequent phase of viral gene transcription can be repressed by the chicken ovalbumin upstream promoter transcription factor (COUP-TF)-interacting protein 2 (CTIP2) in human microglial cells [O. Rohr, D. Lecestre, S. Chasserot-Golaz, C. Marban, D. Avram, D. Aunis, M. Leid and E. Schaeffer (2003), J. Virol., 77, 5415–5427]. Here, we demonstrate that CTIP proteins also repress the initial phase of HIV-1 gene transcription, mainly supported by the cellular transcription factors Sp1 and COUP-TF in microglial cells. We report that CTIP2 represses Sp1- and COUP-TF-mediated activation of HIV-1 gene transcription and viral replication as a result of physical interactions with COUP-TF and Sp1 in microglial nuclei. Using laser confocal microscopy CTIP2 was found to colocalize with Sp1, COUP-TF and the heterochromatin-associated protein Hp1α, which is mainly detected in transcriptionally repressed heterochromatic region. Moreover, we describe that CTIP2 can be recruited to the HIV-1 promoter via its association with Sp1 bound to the GC-box sequences of the long terminal repeat (LTR). Since our findings demonstrate that CTIP2 interacts with the HIV-1 proximal promoter, it is likely that CTIP2 promotes HIV-1 gene silencing by forcing transcriptionally repressed heterochromatic environment to the viral LTR region

Genome-Wide Binding Map of the HIV-1 Tat Protein to the Human Genome

The HIV-1 Trans-Activator of Transcription (Tat) protein binds to multiple host cellular factors and greatly enhances the level of transcription of the HIV genome. While Tat's control of viral transcription is well-studied, much less is known about the interaction of Tat with the human genome. Here, we report the genome-wide binding map of Tat to the human genome in Jurkat T cells using chromatin immunoprecipitation combined with next-generation sequencing. Surprisingly, we found that ∼53% of the Tat target regions are within DNA repeat elements, greater than half of which are Alu sequences. The remaining target regions are located in introns and distal intergenic regions; only ∼7% of Tat-bound regions are near transcription start sites (TSS) at gene promoters. Interestingly, Tat binds to promoters of genes that, in Jurkat cells, are bound by the ETS1 transcription factor, the CBP histone acetyltransferase and/or are enriched for histone H3 lysine 4 tri-methylation (H3K4me3) and H3K27me3. Tat binding is associated with genes enriched with functions in T cell biology and immune response. Our data reveal that Tat's interaction with the host genome is more extensive than previously thought, with potentially important implications for the viral life cycle

CTIP2, a repressor of HIV-1 gene transcription in microglial cells

Le virus de l'immunodéficience humaine (HIV) est l'agent pathogène responsable du SIDA (Syndrome de l'ImmunoDéficience Acquise). Le HIV infecte de façon privilégiée les cellules du système immunitaire, mais le système nerveux central (SNC) constitue sa deThe Human Immunodeficiency Virus (HIV) is the etiological agent causing AIDS (Acquired ImmunoDeficiency Syndrome). The central nervous system (CNS) is the second important target of HIV after the immune system. About 10% of the patients with AIDS presen

CTIP2, a repressor of HIV-1 gene transcription in microglial cells

Le virus de l'immunodéficience humaine (HIV) est l'agent pathogène responsable du SIDA (Syndrome de l'ImmunoDéficience Acquise). Le HIV infecte de façon privilégiée les cellules du système immunitaire, mais le système nerveux central (SNC) constitue sa deuxième grande cible. En effet, au moins 10% des personnes infectées présentent des atteintes neurologiques associées au SIDA. Les cellules microgliales constituent les principales cibles cellulaires d'une infection virale productive dans le SNC.La transcription des gènes du HIV-1 peut-être subdivisée en deux phases, une phase initiale régulée par des facteurs de transcription cellulaires et une phase tardive principalement régulée par le puissant transactivateur viral Tat. Mon travail de thèse a consisté en l'étude de CTIP2 (COUP-TF Interacting Protein 2), un cofacteur du facteur de transcription cellulaire COUP-TF, sur la transcription des gènes du HIV-1 dans les cellules microgliales.Nos travaux nous ont permis de montrer qu en intervenant au niveau de la transcription des gènes viraux, CTIP2 réprime la réplication du HIV-1 dans les cellules microgliales en induisant la formation de structures hétérochromatiniennes le long du provirus. En effet, CTIP2 est recruté sur le promoteur du HIV-1 par l'intermédiaire des facteurs de transcription Sp1 et COUP-TF fixés sur les boîtes GC du promoteur minimal. Une fois ancré, CTIP2 va recruter des activités histones déacétylases qui vont provoquer une déacétylation locale de l'histone H3. Le domaine central de CTIP2 va également permettre le recrutement de l'histone méthyltransférase SUV39H1 qui va méthyler de manière spécifique le résidu lysine en position neuf de l'histone H3 et ainsi créer un site de fixation pour HP1a, une protéine associée à l'hétérochromatine. La polymérisation de HP1a le long du provirus va ainsi générer un domaine hétérochromatinien inaccessible pour les facteurs cellulaires et viraux impliqués dans la régulation de la transcription des gènes du HIV-1.The Human Immunodeficiency Virus (HIV) is the etiological agent causing AIDS (Acquired ImmunoDeficiency Syndrome). The central nervous system (CNS) is the second important target of HIV after the immune system. About 10% of the patients with AIDS present neurological symptoms. The macroglial cells are the major site of HIV production in the brain.HIV-1 gene transcription can be divided in two phases, an initial phase controlled by cellular transcription factors and a late phase mainly controlled by the powerful viral transcription factor Tat. My thesis work was focused on the study of CTIP2 (COUP-TF Interacting Protein 2), a cofactor of the cellular transcription factor COUP-TF, on HIV gene transcription in microglial cells.Our findings reveal the ability of CTIP2 to specifically act as a potent inhibitor of both initial and late transcriptional phases, leading to repression of viral replication in microglial cells. Indeed, CTIP2 is recruited by the cellular transcription factors Sp1 and COUP-TF fixed on the GC boxes of the minimal HIV-1 promoter. Once anchored, CTIP2 will recruit histone deacetylase activities (HDAC) leading to a local deacetylation of histone H3. The central domain of CTIP2 will also allow the recruitment of the histone methyltransferase (HMT) SUV39H1 which specifically methylate the lysine residue in position nine of histone H3 therefore creating a binding site for the heterochromatin associated protein HP1a. HP1a polymerization along the provirus will then generate a heterochromatic environment making the viral promoter inaccessible for the cellular and viral factors implicated in the regulation of HIV-1 gene transcription

Interplay between the HTLV-2 Tax and APH-2 proteins in the regulation of the AP-1 pathway.

International audienceBACKGROUND: In contrast with human T-cell leukemia virus type 1 (HTLV-1) that causes ATL (adult T-cell leukemia), HTLV-2 has not been causally linked to malignant disease. The minus strand of the HTLV genomes encode the regulatory proteins HTLV-1 bZIP factor (HBZ) for HTLV-1 and antisense protein of HTLV-2 (APH-2) for HTLV-2. Unlike the viral proteins Tax1 and Tax2, both HBZ and APH-2 are constitutively expressed in infected cells suggesting that they may play important roles in the pathogenesis of these viruses. To date, very little is known about the function of APH-2 except that it inhibits Tax2-mediated transcription of HTLV-2 genes. In the present study, we investigated the role of APH-2 in basal and Tax2B-mediated activation of the AP-1 pathway. RESULTS: We demonstrate that, unlike HBZ, APH-2 stimulates basal AP-1 transcription by interacting with c-Jun and JunB through its non-conventional bZIP domain. In addition, when Tax2 and APH-2 are co-expressed, they physically interact in vivo and in vitro and APH-2 acts as an inhibitor of Tax2-mediated activation of AP-1 transcription. CONCLUSIONS: This report is the first to document that HTLV-2 can modulate the AP-1 pathway. Altogether our results reveal that, in contrast with HBZ, APH-2 regulates AP-1 activity in a Tax2-dependant manner. As the AP-1 pathway is involved in numerous cellular functions susceptible to affect the life cycle of the virus, these distinct biological properties between HBZ and APH-2 may contribute to the differential pathogenic potential of HTLV-1 and HTLV-2

Inhibition of HIV-1 expression by CTIP2-mediated recruitment of HDAC activities to the Long Terminal Repeat.

info:eu-repo/semantics/publishe