The KT Jeang retrovirology prize 2025: Carine Van Lint

Carine Van Lint studied chemistry at the University of Brussels (ULB), Brussels, Belgium. While studying, her interests shifted from chemistry to biochemistry and cell biology. Carine was fortunate to perform her Master thesis work in the laboratory of Professor Arsène Burny at the ULB where she studied transcriptional regulation of the Immunodeficiency Virus type 1 (HIV-1). Most importantly, Arsène Burny’s lab provided a scientifically very stimulating and exciting environment as several teams were studying various aspects of the HIV and Bovine Leukemia Virus (BLV) retroviruses biology with MDs, PhDs, veterinarians, biologists, bio-engineers, chemists, pharmacists, all working and interacting together, sharing their enthusiasm about fundamental research, a fertile ground for applied science, especially in the medical field. There, she met and worked under the supervision of Doctor Eric Verdin who one year later moved to National Institutes of Health (NIH, Bethesda, Maryland, USA) and asked her to follow him to pursue her PhD thesis at NIH. Carine obtained several fellowships and travel awards, including from the prestigious Belgian American Educational Foundation (B.A.E.F.), from the Fund for Scientific Research (FNRS, Belgium) (“Aspirant” - Research fellow), and from the New York branch of the Alumni Organization of the University of Brussels. She then joined the Laboratory of Viral and Molecular Pathogenesis headed by Doctor Monique Dubois-Dalcq (in Doctor Eric Verdin’s section), at the National Institute of Neurological Disorders and Stroke, NIH.

Her experience at NIH as a graduate student was exhilarating, challenging and unforgettable, working for three years in an environment with mostly postdocs. Her project led her to physically and functionally characterize an intragenic enhancer located in the pol gene of HIV-1 and associated with an open chromatin region (a DNase I-hypersensitive site called HS7) [1, 2]. Moreover, she participated in a study demonstrating that chromatin was an integral component of HIV-1 transcriptional regulation [3]. More specifically, she mapped the nucleosome positioning in the viral 5’ Long Terminal Repeat (LTR) promoter region and identified a nucleosome called nuc-1, located just downstream of the transcription start site and which was specifically remodeled following HIV reactivation from latency [3]. Carine Van Lint received several prizes and awards for outstanding PhD thesis research: the Jean STAS Prize of the Royal Academy of Science, Letters and Fine Arts of Belgium in 1994; the Solvay Award in 1995; and the Docteur Paul A. G. Janssen 1995 Award of the Belgium Royal Chemistry Society.

Upon completion of her PhD, Carine Van Lint decided to pursue her studies on HIV, a decision driven by the emerging reality that HIV was rapidly spreading worldwide at the time, with no effective drug or vaccine available. She then worked as a postdoctoral fellow at the Picower Institute for Medical Research in New York headed by Anthony Cerami in the laboratory of Eric Verdin. During her postdoctoral studies, she reported for the first time the role of histone acetylation in HIV-1 gene expression by demonstrating that the repressive nucleosome nuc-1 was specifically remodeled during transcriptional activation of the HIV-1 promoter by inhibitors of histone deacetylases (HDACi) [4]. This study was going to become critical later on, in the context of the future “shock and kill” approaches, after the introduction of antiretroviral therapy (ART) in the late 1990s and the findings that the persistence of the cellular reservoirs of latent HIV was going to constitute the major barrier to HIV-1 eradication and cure. Indeed, at the time, the persistence of these reservoirs was not known yet and the “shock and kill” therapeutic approaches had not yet been proposed. During her postdoc in New York, Carine Van Lint also characterized a new transcriptional cis-regulatory region associated with another proviral open chromatin region (the DNase I-hypersensitive site HS4 located in the leader region of HIV-1) [5]. She demonstrated the presence in the HS4 of functionally important binding sites for the transcription factors AP-1, Sp1, NF-AT and IRF [5]. During her postdoctoral training, she also participated in other research projects [6–10] in Eric Verdin’s laboratory to further understand the transcriptional and epigenetic regulation of HIV-1, in collaboration with Stéphane Emiliani, Melanie Ott, Georges Herbein, Ulrike Mahlknecht and Wolfgang Fischle, all postdocs in Eric Verdin’s lab at the time. These studies showed that distinct mechanisms trigger apoptosis in HIV-1-infected and in uninfected bystander T lymphocytes [8], and reported the characterization of HDAC3, a new human RPD3 ortholog [10] and the immune hyperactivation of HIV-1-infteced T cells mediated by Tat and the CD28 pathway [7]. These studies also showed that the disruption of the Tat-TAR axis was responsible for postintegration latency in the U1 and ACH-2 latently HIV-infected cell lines [6, 9].

In 1996, Carine Van Lint got a permanent position at the FNRS (Fund for Scientific Research, Belgium) and moved back in 1997 to the University of Brussels (ULB, Belgium) to establish her own independent research group. She maintained an interest in the molecular mechanisms involved in the establishment and maintenance of HIV-1 latency and in the viral reactivation from latency. With her under graduates and graduate students, Carine Van Lint further investigated the role of NF-kB activation in HIV transcription and in antiviral immunity. She demonstrated that HDAC inhibitors synergized with TNF-induced NF-kappaB to activate the HIV LTR and other NF-kappaB-dependent cellular promoters and that this potentiation of TNF-induced NF-kappaB activation by deacetylase inhibitors was associated with a delayed cytoplasmic reappearance of the inhibitor IkBalpha and with a prolonged TNF-induced IKK kinase activity [11–13]. Interestingly, HDAC inhibition and CBP also enhanced the transactivation potential of HOXB7 homeodomain-containing protein [14]. These studies were performed in collaboration with the laboratories of Alain Chariot, Vincent Bours, and Jacques Piette (University of Liège, Belgium). In cooperation with the 2016 awardee, Frank Kirchhoff (Ulm University Medical Center, Ulm, Germany), Carine Van Lint reported that HIV-1 and its simian precursors employ Nef to boost NF-κB activation early during the viral life cycle to initiate proviral transcription, while Vpu is used to downmodulate NF-κB-dependent expression of interferon-stimulated genes (ISGs) at later stages [15]. Moreover, Daniel Sauter, Frank Kirchhoff and Carine Van Lint highlighted the key role of NF-κB in antiviral immunity by demonstrating that primate lentiviruses follow distinct evolutionary paths to suppress NF-kB-mediated immune activation [16]. In collaboration with Rosemary Kiernan and Monsef Benkirane (Institut de Génétique Humaine, University of Montpellier, France), Carine showed that the transcriptional activity of the HIV-1 Tat protein itself was regulated by direct acetylation [17] and, in collaboration with Robert Harrod and Genoveffa Franchini (Southern Methodist University, Dallas, Texas, USA), that the Tat/co-activator acetyltransferase interactions inhibit p53Lys-320 acetylation and p53-responsive transcription [18]. Carine Van Lint also reported that binding sites for transcription factors AP-1, Sp1, PU.1 and Oct1 located in the pol gene intragenic cis-regulatory region of HIV-1 were important for viral transcription and replication [19, 20].

Carine Van Lint also studied chromatin-associated regulation of several cellular genes involved in immunity. In collaboration with Yves Collette, Ivan Hirsch and Daniel Olive (Aix Marseille University, France), she showed that active transcription of the human FasL/CD95L/TNFSF6 promoter region in T lymphocytes involved chromatin remodeling [21]. In collaboration with her colleagues Michel Goldman and Stanislas Goriely from the University of Brussels, she demonstrated that human IL-12(p35) gene activation involved selective remodeling of a single nucleosome within the promoter region [22] and that a defect in nucleosome remodeling prevented IL-12(p35) gene transcription in LPS-stimulated neonatal dendritic cells [23]. Together with Guy Haegeman and Wim Vanden Berghe from the University of Ghent (Belgium), she showed that hyperactivated NF-kappaB and AP-1 transcription factors promoted highly accessible chromatin and constitutive transcription across the IL-6 gene promoter in metastatic breast cancer cells [24].

Carine’s work thus largely contributed to the molecular understanding of the transcriptional and epigenetic mechanisms involved in the establishment and maintenance of HIV-1 latency and reactivation from latency [25–29]. Based on the understanding of these viral silencing mechanisms, several classes of latency-reversing agents (LRAs) were proposed to reactivate HIV in latently-infected cells, while maintaining ART in order to prevent de novo infection (a strategy called “the shock and kill” strategy) [30–37]. In this context, Carine Van Lint initiated collaborations with clinical units to have access to blood samples from people living with HIV (PLWH) at the Saint-Pierre Hospital (Brussels, Belgium) in collaboration with Drs Nathan Clumeck and Stéphane De Wit and at the Bicêtre Hospital (Paris Saclay University, Le Kremlin-Bicêtre, Paris, France) in collaboration with Dr Olivier Lambotte. This work on PLWH samples has been possible thanks to a fruitful collaboration with the laboratory of Christine Rouzioux and Véronique Avettand-Fènoël (Hôpital Necker-Enfants-Malades, Université Paris-Descartes, Paris, France) to quantify the HIV reservoirs and viral reactivation. An important discovery of Carine’s team was that targeting a single mechanism might not be efficient enough to activate the majority of latent proviruses and that combinations of LRAs acting on several HIV-1 silencing molecular mechanisms, to reactivate viral transcription simultaneously at different levels, are needed to obtain synergistic viral activation [11, 38–42]. In this regard, Carine showed that the HIV-1 promoter was synergistically activated using HDAC inhibitors (HDACi) in concert with NF-κB inducers [11, 38]. However, in 40% of the cultures, she could not detect any viral outgrowth following treatment with prostratin (an NF-kB inducer) and HDACis individually or in combination. She hypothesized that this could result from a stronger epigenetic control of some integrated proviruses and she investigated the role of histone methylation in HIV-1 transcription regulation in order to identify new compounds capable of reversing the locked transcriptional status of the promoter in those latent proviruses that were resistant to reactivation with a combination NF-κB inducer + HDACi. Carine Van Lint then showed that histone methyltransferase inhibitors (HMTi) (chaetocin and BIX-01294) induced HIV-1 recovery in the majority of the resting CD4⁺ T-cell ex vivo cultures isolated from ART-treated PLWH and acted synergistically with HDACi [39]. These latter results constituted the first demonstration for the reactivation of latent HIV in ART-treated PLWH cells using HMTis.

Carine also found that specific combinations of PKC agonists with compounds that release P-TEFb, a crucial actor in HIV-1 transcriptional elongation, led to an even higher percentage of HIV-1 reactivation. Indeed, combination of the PKC agonist bryostatin-1 with JQ1 induced a recovery of HIV-1 in ex vivo cultures of CD8⁺-depleted PBMCs isolated from ART-treated PLWH similar to the recovery observed with the anti-CD3 + anti-CD28 positive control [40]. These results constituted the first demonstration of LRAs combinations exhibiting such a potent effect. In addition to showing the importance of combining the LRAs, Carine also demonstrated the importance of temporal parameters in efficient HIV-1 latency reversal [41]. Indeed, she showed that a sequential treatment with an inhibitor of DNA methylation (5-aza-2’-deoxycytidine or 5-AzadC) and a HDACi (romidepsin) was more effective both in vitro and ex vivo to induce HIV-1 gene expression than the corresponding simultaneous treatment [41]. This study constituted the first demonstration of the importance of the treatment time schedule for LRAs combinations in HIV-1 reactivation. Based on these proof-of-concept studies highlighting the potency of LRAs combination and the importance of time schedule in LRAs administration for efficient reactivation, Carine has now started a pilot open label phase Ib/II reactivation clinical trial with the financial support of ULB and the ANRS/MIE (ANRS 171 SYNACTHIV clinical trial) and in collaboration with the St-Pierre Hospital (Prof. Stéphane De Wit, ULB, Brussels) and several French teams. The launch of this clinical trial illustrates the physiological relevance of Carine’s basic science studies and their translational therapeutic applications.

HIV-1 latency is highly heterogeneous as illustrated by the effects of LRAs which have been demonstrated to be silencing mechanism-specific, cell model-specific, cell type-specific, patient-specific, integration site-specific, gender-specific and tissue-specific in various in vitro and ex vivo latency models [34, 36]. In this regard, Carine’s basic studies have highlighted patient-specific qualitative and quantitative variations in the ex vivo capacity of the PLWH infected cells to be reactivated in response to different classes of LRAs [43]. In addition to patient-specific variations, she showed the cell type-specific effects of the anti-alcoholism drug disulfiram [42]. This LRA presented exclusive HIV-1 reactivation effects in myeloid but not T-lymphoid cell lines, suggesting that it could be a potential LRA for this neglected reservoir [42]. In this regard, molecular mechanisms of HIV-1 silencing in myeloid infected cells are less understood than in their T-lymphoid counterparts. In the context of a longstanding collaboration with Prof. Olivier Rohr (University of Strasbourg, France), Carine studied the mechanisms of HIV-1 transcriptional silencing in human microglial cells, the resident macrophages of the central nervous system and crucial reservoirs for HIV-1 persistence in the brain [44]. Their work demonstrated that the transcriptional cellular cofactor CTIP2 (COUP-TF interacting Factor 2/Bcl11 B) recruited to the HIV-1 promoter a multi-enzymatic chromatin-modifying complex containing HDAC and HMT activities, resulting in formation of a local heterochromatin environment at the HIV-1 promoter and in viral silencing [45]. Moreover, their collaborative studies showed that CTIP2 was recruited to the p21 promoter and silences p21 gene transcription through interactions with HDAC and the HMT SUV39H1 [46]. Importantly, treatment with the specific SUV39H1 inhibitor, chaetocin, repressed histone H3 lysine 9 trimethylation at the p21 gene promoter, stimulated p21 gene expression and induced cell cycle arrest [46]. The histone demethylase LSD1 cooperates with CTIP2 to promote HIV-1 transcriptional silencing [47]. Furthermore, the groups of Olivier Rohr and Carine Van Lint have reported that CTIP2 interacts with the inactive form of the P-TEFb complex (composed of CDK9 and human cyclin T1) and that CTIP2 is a negative regulator of P-TEFb (by inhibiting the kinase activity of CDK9) in physiological and pathological conditions [48]. Another study from Carine showed that CTIP2 and HMGA1 (High Mobility Group A1) cooperatively repressed HIV-1 gene expression by a HMGA1-mediated recruitment of CTIP2-inactivated P-TEFb to the HIV-1 promoter [49]. This latter work was performed in collaboration with Arndt Benecke (Institut de Biologie Paris-Seine, France) and Olivier Rohr (University of Strasbourg, France). These teams also showed that the transcription factor HIC1 (Hypermethylated In Cancer 1) interacted with CTIP2 and HMGA1 to mediate another repression mode of HIV-1 5’LTR in microglial cells, that involved Tat and the HDAC SIRT1 and that was independent of P-TEFb [50]. The HIV-1 protein Vpr was demonstrated to mediate the depletion of CTIP2 to counteract viral gene silencing [51]. In collaboration with Olivier Rohr and Virginie Gautier (University College Dublin, Ireland), Carine participated in a study unravelling the role of the SUMO E3 ligase KAP1 (KRAB (Krugel-Associated Box) domain-Associated Protein 1) which was shown to be a new CTIP2-interacting factor in the regulation of HIV-1 post-integration latency in microglial cells [52]. Carine also demonstrated the recruitment of the epigenetic integrator Ubiquitin-like with PHD and RING finger domain 1 (UHRF1) to multiple binding sites in the HIV-1 promoter [53], as well as the role of UHRF1 in the epigenetic repression of the latent viral promoter by a concerted control of DNA and histone methylations [53].

More recently, Carine developed a fruitful collaboration with Prof. Petronela Ancuta (CHUM, University of Montreal, Canada) and participated in a study identifying Aryl Hydrocarbon Receptor (AhR) as a barrier to HIV-1 infection and outgrowth in CD4⁺ T cells [54]. This latter study showed that AhR governed a T-cell transcriptional program controlling viral replication/outgrowth and tissue residency/recirculation, supporting the use of AhR inhibitors in “shock and kill” HIV-1 cure strategies [54]. Carine also reported another collaborative study with Prof. Petronela Ancuta demonstrating that retinoic acid enhanced HIV-1 reverse transcription and transcription in macrophages via mTOR-modulated mechanisms [55].

Carine Van Lint also contributed to the molecular understanding of the post-transcriptional blocks to HIV-1 gene expression. Indeed, current LRAs employed in the “shock and kill” strategy primarily focus on relieving epigenetic and transcriptional blocks to reactivate the latent HIV-1. However, the in vivo clinical efficacy of current LRAs has been limited so far, partly due to their inability to fully reverse latency and the lack of LRAs specifically targeting post-transcriptional mechanisms. In this context, in collaboration with Alessandro Marcello (International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy), and Ben Berkhout and Alexander Pasternak (Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands), Carine showed that the cellular factor MATR3, an RNA-binding component of the nuclear matrix that promotes nuclear export of HIV-1 transcripts, is expressed at limiting levels in resting CD4⁺ T cells, correlating with incapacities of some LRAs to fully reactivate HIV [56]. More recently, the same teams in collaboration with Anna Kula-Pacurar (Małopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland) showed that, during infection and reactivation, unspliced HIV-1 RNA was subjected to a complex and dynamic regulation by the Rev cofactor MATR3 and the MTR4 cofactor of the nuclear exosome [57]. They demonstrated, in ex vivo cell cultures from ART-treated PLWH, nuclear retention of unspliced HIV-1 RNA as a reversible post-transcriptional block to HIV-1 latency [57]. Anna Kula-Pacurar, Alexander Pasternak, Alessandro Marcello and Carine Van Lint also reported a proof-of-concept for the modulation of the N6-methyladenosine (m6A) modification pathway (using ALKBH5 inhibitor 3) in enhancing HIV-1 reactivation [58]. This approach represents a promising adjunct to existing reactivation protocols and provides a concept of “dual-kick”, aiming to target both transcriptional and post-transcriptional steps in HIV-1 reactivation from latency [58].

In parallel to her work on HIV-1 latency, Carine Van Lint initiated in 1997 a new direction of research and became interested in studying transcriptional and epigenetic regulation of two oncogenic retroviruses: HTLV-1 (Human T-cell leukemia virus 1) and BLV (Bovine Leukemia Virus). HTLV-1 infects and transforms CD4⁺ T lymphocytes and is the etiologic agent of two major diseases: Adult T-cell Leukemia/Lymphoma (ATLL), an aggressive lymphoproliferative disease and a neurological degenerative syndrome known as tropical spastic paraparesis (TSP) or HTLV-1-associated myelopathy (HAM). BLV, a B-lymphotropic oncogenic deltaretrovirus structurally and biologically closely related to the T-lymphotropic HTLV-1 and -2, causes a B-lymphocytic leukemia/lymphosarcoma in sheep and cattle. As such, BLV is considered as a unique animal system, which has become helpful in understanding some aspects of HTLV-1-induced leukemogenesis. BLV transcription initiates at the U3/R junction in the 5'LTR and is regulated by cellular transcription factors binding to the 5’LTR, by the viral transactivating Tax_BLV protein and by the chromatin organization of the BLV provirus [59]. Transactivation by Tax_BLV requires the presence of three enhancer elements (called TxREs for Tax_BLV Responsive Elements) located in the U3 region of the 5’LTR and composed of an imperfectly conserved cyclic-AMP-responsive element (CRE), which binds the cellular transcription factors CRE-binding protein (CREB), the CRE-modulator (CREM) and the activating transcription factors-1 and -2 (ATF-1 and ATF-2). Although CREB and Tax_BLV synergistically transactivate the BLV promoter, Carine’s team showed that the CREMτau isoform negatively modulates the level of Tax_BLV transactivation [60], which likely represents a viral strategy to reduce the levels of viral transcription. In addition, in collaboration with Jacques Ghysdael (Institut Curie, Paris, France), Carine characterized a PU.1/Spi-B site in the BLV 5’LTR U3 region [61]. Carine’s team showed that BLV expression was also regulated by LTR sequences located downstream of the transcription start site. In this regard, she characterized an upstream stimulatory factor (USF)-binding site in the R region (termed E-box 4) that binds the basic helix-loop-helix factors USF-1 and USF-2 [62], and an interferon regulatory factor (IRF)-binding site in the U5 region, which stimulates BLV expression in the absence of Tax_BLV [63].

In collaborative studies with Richard Kettmann, Arsène Burny, Lucas Willems and Anne Van den Broeke (Faculté de Gembloux Agro-Bio Tech, Gembloux, Belgium), Carine showed that histone acetylation events played a crucial role in Tax_BLV-independent and -dependent BLV expression in vivo in both latently-infected cell lines and primary peripheral blood mononuclear cells (PBMCs) from BLV-infected cows [64, 65]. Indeed, she showed that treatment with HDAC inhibitors induced BLV expression in correlation with an increased in vivo level of histone H4 acetylation in the 5’LTR region [65]. Importantly, the HDAC inhibitor TSA also increased the occupancy of the CRE-like motifs by CREB/ATF, suggesting that the proteins binding to the E boxes overlapping the three CRE-like elements exert their negative effect on BLV transcription by steric hindrance with the activators CREB/ATF and/or the associated histone acetyltransferases (HATs) p300/CBP [66]. This work was performed in collaboration with Yvan de Launoit (Institut Pasteur de Lille, Université de Lille, France) et Arsène Burny (Faculté de Gembloux Agro-Bio Tech, Gembloux, Belgium). Besides the role of histone deacetylation in the epigenetic repression of BLV expression, Carine demonstrated that DNA cytosine hypermethylation in the BLV 5’LTR U3 and R regions is associated with true latency in the lymphoma-derived B-cell line L267, but not with defective latency in YR2 cells [67]. Mechanistically, methylation at the −154 or at the −129 CpG position (relative to the transcription start site) impaired in vitro binding of CREB transcription factors to their respective CRE sites, thereby decreasing BLV transcriptional activity. Moreover, chromatin immunoprecipitation (ChIP) assays revealed the in vivo recruitment of CREB/CREM and to a lesser extent of ATF-1 to the hypomethylated CRE region of the YR2 5’LTR, whereas no CREB/CREM/ATF recruitment was detected to the corresponding hypermethylated region in the L267 cells [67]. Importantly, Tax_BLV was shown to decrease DNA methyltransferases (DNMTs) expression levels, in correlation with the partial loss of DNA methylation observed in the L267 cells 5’LTR consequently to Tax_BLV expression [67]. This latter study was performed with the collaboration of Olivier Rohr (University of Strasbourg) and Ivan Hirsch (Cancer Research Center of Marseille, Institut Paoli-Calmettes, Aix-Marseille University, Marseille, France).

In addition, Carine elucidated the chromatin organization of the BLV provirus in the two latently-infected cell lines YR2 and L267 by the indirect end-labelling technique, and discriminated two types of latency of the BLV provirus: an easily reactivable defective latent state characterized by an open chromatin organization in the BLV promoter and a “locked” latent state maintained by a stronger epigenetic control of the BLV promoter region, respectively [68]. Importantly, Carine also determined the BLV 5’LTR chromatin organization in PBMCs isolated from BLV-infected cows. This study constituted the first example of determination of the nucleosomal organization of a retroviral promoter in vivo in its naturally infected host [68]. Carine Van Lint observed that reactivation of viral expression in YR2 cells by the combination phorbol 12-myristate 13-acetate (PMA) plus ionomycin, one of the most efficient BLV activators, was accompanied by a rapid but transient nucleosomal remodeling in the 5’LTR region. She determined the molecular mechanisms involved in this nucleosome disruption following PMA plus ionomycin-mediated transcriptional reactivation of BLV expression and showed the crucial role of two transcription factor binding sites in the chromatin remodeling : (1) the U3 region PU.1/Spi.B site; and (2) of the USF-1/USF-2 transcription factors binding to the E-box 4 motif located in the BLV 5’LTR U5 region [68].

BLV silencing is not complete since a highly expressed BLV micro-RNA (miRNA) cluster has been reported in primary leukemic B cells and B-cell lymphoma isolated from BLV-infected sheep using bioinformatics prediction tools and high-throughput sequencing of small RNA libraries [69]. Carine’s team characterized the RNA polymerase III (RNA Pol)-dependent promoter responsible for the miRNA cluster transcription and identified a new RNA Pol II promoter responsible for antisense transcription from the BLV 3’LTR [70]. Carine showed that the BLV miRNA cluster and the 3’LTR/host genomic junction were both enriched in positive epigenetic marks related to active promoters. Functionally, she showed that the BLV LTR exhibited a strong antisense RNA Pol II promoter activity and provided evidence for a collision between RNA Pol III and RNA Pol II convergent transcriptions [70]. These results provided new insights into alternative ways used by BLV to express parts of its genome despite silencing of the 5’LTR.

Carine’s lab also studied the complex transcriptional network regulating BLV expression, with a focus on the three-dimensional (3D) chromatin organization changes following BLV infection and on the potential transcriptional interference between the different BLV promoters. In this context, in collaboration with Wouter de Laat (Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands), Carine’s team reported the critical role of the cellular CCCTC-binding factor (CTCF) both in the regulation of BLV transcriptional activities and in the deregulation of the 3D chromatin architecture surrounding the BLV integration site [71]. She demonstrated the co-recruitment of CTCF and cohesin in vivo to three conserved CTCF binding motifs along the BLV provirus (5’LTR, 3’LTR and TAX/REXE2) [71], suggesting the involvement of CTCF in BLV transcriptional and epigenetic regulations. CTCF localized to regions of transitions in the histone modifications profile along the BLV genome and was implicated in the repression of the 5’ LTR promoter activity, thereby contributing to viral latency, while favoring the 3’ LTR promoter activity [71]. 4C-seq assays in BLV latently-infected ovine cell lines demonstrated that BLV integration deregulated the host cellular 3D chromatin organization through the formation of viral/host chromatin loops. These findings highlighted CTCF as a new critical effector of BLV transcriptional regulation and BLV-induced physiopathology [71].

Another research topic studied by Carine Van Lint’s laboratory is the transcriptional regulation of HTLV-1 gene expression. In collaborative studies with Franck Dequiedt, Jean-Claude Twizere and Richard Kettmann (GIGA, University of Liège, Belgium), Carine’s team reported an interaction between the Tax_HTLV−1 oncoprotein and the G-protein β subunit [72]. Interestingly, though the G-protein beta subunit inhibited Tax_HTLV−1-mediated viral transcription, Tax_HTLV−1 perturbed G-protein beta subcellular localization. This study indicated that HTLV-1 developed a strategy based on the activation of the SDF-1/CXCR4 axis in the infected cell and could have implications for new therapeutic strategies [72]. Moreover, the HTLV-1 Tax protein inhibited formation of stress granules by interacting with histone deacetylase HDAC6 [73]. In collaboration with Jean-Claude Twizere and Marc Vidal (Dana-Farber Cancer Institute, Boston, USA), Carine participated to publications reporting the host-pathogen interactome mapping for HTLV-1 and -2 [74] and reporting the identification of small molecule antivirals against HTLV-1 by targeting the protein-protein interaction between Tax-1 and the human homolog of the drosophila discs large tumor suppressor (hDLG1/SAP97), a multi-domain scaffolding protein involved in Tax-1-transformation ability [75]. In collaboration with Robert Harrod (Southern Methodist University, Dallas, USA) and Lee Ratner (Washington University School of Medicine, St. Louis, Missouri, USA), Carine showed that the human T-cell leukemia virus type-1 Tax oncoprotein dissociated NF-κB p65^RelA-Stathmin/oncoprotein-18 complexes and caused mitotic spindle damage and genomic instability [76]. Moreover, Carine characterized physically and functionally two additional binding sites for the cellular ubiquitous transcription factor Sp1 in the HTLV-1 LTRs promoter nucleotide sequence [77]. She showed that these two newly identified Sp1 binding sites exhibited together a repressor effect on the HTLV-1 LTR sense transcriptional activity, but had no effect on the viral LTR antisense transcriptional activity [77]. Together, these studies contribute to better understand the molecular basis of how chromatin modifications influence gene expression of the oncogenic retroviruses HTLV-1 and BLV, and thus leukemogenesis.

Recently, together with her Belgian colleagues Benoît Muylkens and Damien Coupeau (University of Namur, Belgium) and Benjamin Dewals (University of Liège, Belgium), Carine participated in identifying non-canonical virus-derived circular RNAs in a large range of animal and human viruses belonging to Herpesviridae, Retroviridae, Adenoviridae, Flaviridae and Orthomyxoviridae families [78]. This was performed by developing and using a novel bioinformatic tool named vCircTrappist and by subsequent RT-PCR and sequencing validation for a selection of new virus-derived circular RNAs. These circular RNAs may serve as valuable targets for the development of new therapeutic strategies against viral diseases [78].

Since 1997, Carine Van Lint has been teaching courses in Virology, gene expression and epigenetics both at the Faculty of Sciences and the Faculty of Medicine of the ULB. She has trained more than 60 students and postdoctoral fellows, many of whom are now in leading roles in academia and other industries. She is an Associate Editor on the Editorial Board of Retrovirology, EbioMedicine, Clinical Epigenetics and Journal of Virus Eradication. She co-organized several international scientific meetings, including the Joint 2021 Keystone Symposia on HIV Vaccines/HIV Pathogenesis and Cure. She was a member of the ANRS scientific committees (2000–2004), and since 2022, she has been a member of the Sidaction medical and scientific committee (Paris, France). Carine has received several awards and honorary distinctions, including the Pharmacia 2002 Scientific Prize (FNRS and Pharmacia Society), the Biennial 2003 Prize of the Princess Josephine-Charlotte Study Center (FNRS), and the Atomia Prize “Brussels Women for Science” (2014). In 2011, she was given the title of Officer of the Order of Leopold II of the Kingdom of Belgium for services rendered. In 2016, she was elected member of the French Academy of Pharmacy.

Declarations

Competing interests

Carine Van Lint is an Associate Editor for Retrovirology.