BRD proteins in human retroviral infection: emerging evidence from HIV-1 and future perspectives for HTLV-1

Abstract

Human retroviruses, including Human Immunodeficiency Virus Type 1 (HIV-1) and Human T-cell Leukemia Virus Type 1 (HTLV-1), remain major global health challenges because of their ability to establish persistent infections and evade host immune responses. Viral persistence depends on the exploitation of host epigenetic and transcriptional machinery, particularly chromatin-remodeling complexes and bromodomain-containing proteins. Bromodomain-containing protein 9 (BRD9), an epigenetic reader and core component of the non-canonical BRG1 (Brahma-related gene 1)/BRM-associated factor (ncBAF) complex, regulates chromatin accessibility, enhancer activity, transcription, and immune signaling. While the roles of BRD4 and other bromodomain and extra-terminal (BET) proteins in retroviral infection are well established, the contribution of BRD9 has only recently emerged. In HIV-1 infection, bromodomain proteins regulate viral transcription, latency, and reactivation by modulating chromatin organization and transcriptional elongation. Recent studies identify BRD9 as a novel regulator of HIV-1 latency through ncBAF-dependent control of proviral transcription, highlighting its potential as a therapeutic target. In contrast, direct evidence linking BRD9 to HTLV-1 infection is currently unavailable. However, the established roles of BRD4 and other BET proteins in HTLV-1 transcription, oncogenic signaling, and Adult T-cell Leukemia/Lymphoma (ATLL) progression suggest that other BRDs proteins may also participate in similar regulatory pathways. This review synthesizes current evidence on the emerging role of BRDs proteins in retroviral biology, highlights critical knowledge gaps, and proposes future mechanistic and translational research directions to clarify its therapeutic potential in HIV-1 and HTLV-1 infection.

Introduction

Human retroviruses are a unique group of enveloped RNA viruses that replicate through a DNA intermediate generated by reverse transcription and subsequently integrate into the host genome [1, 2]. Among the known human retroviruses, the most clinically significant are the Human Immunodeficiency Virus (HIV) and the Human T-cell Leukemia Virus (HTLV), both of which continue to pose substantial global health challenges [3, 4]. HIV is the causative agent of acquired immunodeficiency syndrome (AIDS), affecting millions of individuals worldwide despite significant advances in antiretroviral therapy [5]. In contrast, HTLV-1 is associated with severe diseases such as adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) [6, 7]. The persistence of these viruses is largely attributed to their ability to exploit host cellular machinery to establish long-term infection, evade immune responses, and regulate viral gene expression.

The successful replication and persistence of retroviruses depend on extensive interactions between viral proteins and host cellular factors [1, 2]. Over the past decades, numerous host proteins involved in chromatin remodeling, transcriptional regulation, and epigenetic control have been identified as critical determinants of retroviral infection [8–10]. These host factors influence multiple stages of the viral life cycle, including viral entry, reverse transcription, integration, transcription, latency, and reactivation [8, 10–12]. Understanding the molecular mechanisms governing host–virus interactions is therefore essential for identifying novel therapeutic targets and developing innovative antiviral strategies.

HIV has served as a major model for studying host epigenetic regulators during retroviral infection [3]. Following integration into the host genome, HIV transcription is tightly controlled by the chromatin environment surrounding the provirus [13, 14]. Various chromatin-modifying complexes and bromodomain-containing proteins have been shown to regulate HIV transcriptional activity, latency establishment, and viral reactivation [15, 16]. Similarly, HTLV-1 relies on host transcriptional and epigenetic machinery to sustain viral gene expression and promote cellular transformation [4]. Viral regulatory proteins such as Tax (trans-activator protein x) and HBZ (HTLV-1 basic leucine zipper factor) interact with multiple host chromatin regulators, thereby influencing cellular signaling pathways, immune responses, and oncogenic processes [10, 17, 18]. These findings highlight the importance of epigenetic mechanisms in the pathogenesis of human retroviral infections.

Bromodomain-containing proteins have emerged as important regulators of chromatin accessibility, transcriptional elongation, enhancer activity, and immune signaling. Among these proteins, the bromodomain and extra-terminal (BET) family, particularly BRD4, has been extensively investigated in human retroviral infections because of its established roles in regulating viral transcription, latency, and host transcriptional machinery [15, 19–21]. BRD4 has become a central epigenetic regulator in both HIV-1 and HTLV-1 research through its interactions with positive transcription elongation factor b (P-TEFb), RNA polymerase II, and multiple chromatin-remodeling complexes [16, 22, 23].

BRD9 belongs to a distinct non-BET bromodomain family and functions as a defining component of the non-canonical BRG1/BRM-associated factor (ncBAF) chromatin-remodeling complex [24]. Unlike BRD4, BRD9 has only recently attracted attention in retroviral biology following evidence implicating ncBAF-mediated chromatin remodeling in HIV-1 latency regulation [16]. At present, only one study has directly investigated BRD9 in HIV-1 infection, while no direct experimental evidence has yet linked BRD9 to HTLV-1 infection [16].

Accordingly, this review is organized around the broader landscape of bromodomain proteins in human retroviral infection, using the extensive BRD4/BET literature as the established biological framework for understanding chromatin-dependent regulation of HIV-1 and HTLV-1. Within this framework, BRD9 is presented as an emerging and currently underexplored bromodomain-containing protein. Throughout the manuscript, experimentally validated BRD9 findings are clearly distinguished from hypotheses derived from BET protein biology, and major knowledge gaps are highlighted to define future research priorities rather than established biological functions [16, 24–26].

Bromodomain proteins: structure, classification, and biological functions

Bromodomain-containing proteins as epigenetic readers

Bromodomain-containing proteins (BRDs) constitute a highly conserved family of epigenetic reader proteins that recognize acetylated lysine residues on histone tails and numerous non-histone proteins, thereby linking histone acetylation to transcriptional regulation, chromatin remodeling, DNA repair, and immune signaling [27, 28] (Fig. 1A). Bromodomains were originally identified in the Drosophila melanogaster Brahma protein, a component of the SWI/SNF chromatin-remodeling complex, and have since been recognized as one of the principal protein modules responsible for interpreting the histone acetylation code [27, 29]. Rather than modifying chromatin directly, bromodomain proteins function as molecular adaptors that recruit transcriptional regulators and chromatin-remodeling complexes to acetylated genomic regions, thereby coordinating gene expression in response to developmental, environmental, and inflammatory signals [25, 28] (Fig. 1A). Recent comprehensive analyses have further emphasized that bromodomain proteins integrate epigenetic information with transcriptional and signaling networks, making them central regulators of cell identity, differentiation, and disease pathogenesis.

Fig. 1.

Bromodomain proteins: structure, classification, and biological functions. (A) Bromodomain-containing proteins function primarily as epigenetic reader modules that recognize acetylated lysine residues on histone tails and facilitate the recruitment of transcriptional regulators and chromatin-associated proteins. Recognition of acetylated chromatin can influence transcriptional regulation, chromatin remodeling, DNA repair and genome stability, and immune or inflammatory signaling. (B) Bromodomain-containing proteins can be broadly divided into the bromodomain and extra-terminal (BET) family, comprising BRD2, BRD3, BRD4, and BRDT, and the more structurally and functionally diverse non-BET group. Selected non-BET proteins shown include BRD7, BRD9, SMARCA2, SMARCA4, PBRM1, EP300/CBP, GCN5/PCAF, TAF1, and ASH1L/MLL. (C) Representative domain architectures illustrate the structural distinction between BET and selected non-BET proteins. BET proteins contain two tandem bromodomains (BD1 and BD2) followed by an extra-terminal (ET) domain, while BRD4 and BRDT additionally contain a C-terminal domain (CTD). Non-BET proteins display greater diversity in bromodomain number and in the additional functional domains associated with chromatin remodeling and transcriptional regulation. (D) The conserved bromodomain adopts a four-α-helix fold composed of the αZ, αA, αB, and αC helices, with the ZA and BC loops forming the acetyl-lysine-binding pocket. A conserved asparagine residue mediates recognition of the acetylated lysine through hydrogen bonding, whereas structural variation in the ZA and BC loops contributes to ligand and substrate specificity. (E) Functional specialization of BET and non-BET proteins is illustrated schematically. BET proteins, particularly BRD4, recognize acetylated chromatin and facilitate recruitment of transcriptional cofactors, positive transcription elongation factor b (P-TEFb), and Mediator to support RNA polymerase II-dependent transcription, enhancer activity, cell-cycle regulation, and inflammatory gene expression. In contrast, non-BET proteins participate in diverse processes, including ATP-dependent chromatin remodeling, nucleosome repositioning, DNA damage repair, lineage-specific transcription, and innate immune signaling. BRD7 is represented as a component of the polybromo-associated BAF (PBAF) complex, whereas BRD9 is represented as a defining component of the non-canonical BAF (ncBAF) complex. Overall, the figure emphasizes that bromodomain proteins constitute a structurally and functionally diverse family of epigenetic readers whose biological activities are determined by bromodomain specificity, domain architecture, interacting partners, and incorporation into distinct chromatin-regulatory complexes. Abbreviations: ASH1L, absent, small, or homeotic 1-like; ATP, adenosine triphosphate; BAF, BRG1/BRM-associated factor; BD, bromodomain; BD1, bromodomain 1; BD2, bromodomain 2; BET, bromodomain and extra-terminal; BRD, bromodomain-containing protein; CBP, CREB-binding protein; CTD, C-terminal domain; DNA, deoxyribonucleic acid; DUF3512, domain of unknown function 3512; EP300, E1A binding protein p300; ET, extra-terminal domain; GCN5, general control of amino acid synthesis 5; Kac, acetylated lysine; MLL, mixed-lineage leukemia; ncBAF, non-canonical BRG1/BRM-associated factor; P-TEFb, positive transcription elongation factor b; PBAF, polybromo-associated BRG1/BRM-associated factor; PCAF, p300/CBP-associated factor; PBRM1, polybromo 1; PHD, plant homeodomain; Pol II, RNA polymerase II; SMARCA2, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2; SMARCA4, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4; TAF1, TATA-box binding protein-associated factor 1; WD, tryptophan-aspartic acid repeat. This figure was created by the authors using BioRender.com

The human genome contains 61 bromodomains distributed among 46 proteins, illustrating the remarkable structural and functional diversity of this protein family [27, 28]. Although all bromodomains recognize acetylated lysine residues, individual proteins differ substantially in domain organization, interacting partners, cellular localization, and biological function. Consequently, bromodomain-containing proteins participate in diverse molecular processes, including transcriptional activation, transcriptional repression, enhancer regulation, DNA replication, chromatin remodeling, RNA processing, and maintenance of genome stability [25, 27]. Genome-wide studies have demonstrated that bromodomain proteins occupy promoters, enhancers, super-enhancers, and other regulatory elements where they coordinate recruitment of transcription factors, mediator complexes, and RNA polymerase II [30, 31] (Fig. 1).

Among bromodomain proteins, the bromodomain and extra-terminal (BET) family has been the most extensively studied because of its essential role in transcriptional elongation and enhancer biology [32, 33]. In contrast, several non-BET bromodomain proteins, including BRD7 and BRD9, primarily function within ATP-dependent chromatin-remodeling complexes such as SWI/SNF, where they regulate chromatin accessibility rather than directly controlling transcriptional elongation [24, 26]. This distinction is particularly important for retroviral biology because most experimental evidence currently concerns BET proteins, especially BRD4, whereas BRD9 has only recently emerged as a candidate regulator through its association with the non-canonical BAF (ncBAF) complex [16] (Fig. 1B).

Bromodomain proteins have attracted increasing attention as therapeutic targets because dysregulated acetylation-dependent transcription contributes to cancer, inflammatory diseases, viral infections, cardiovascular disorders, and developmental syndromes [34–36]. The development of selective bromodomain inhibitors, degraders, and proteolysis-targeting chimeras (PROTACs) has expanded the therapeutic landscape beyond BET proteins to include non-BET bromodomain proteins such as BRD9, SMARCA2/4 (SWI/SNF Related), CBP (CREB-binding protein)/p300, and TAF1 (TATA-box binding protein-associated factor 1 ) [37–39].

Classification and structural diversity of bromodomain proteins

Bromodomain-containing proteins are classified according to their evolutionary relationships, bromodomain sequence homology, domain architecture, and biological function [27, 28]. Phylogenetic analyses divide the human bromodomain family into eight major evolutionary families, encompassing proteins involved in chromatin remodeling, histone acetylation, histone methylation, transcriptional activation, transcriptional repression, DNA repair, ubiquitination, and nuclear organization [28]. More recent functional classifications group these proteins into approximately nine biological categories according to their predominant cellular functions, emphasizing the extensive functional diversification that has occurred during evolution [40].

A broader and widely adopted classification separates bromodomain proteins into BET and non-BET families based on domain organization and molecular function. The BET family consists of BRD2, BRD3, BRD4, and BRDT, each containing two tandem bromodomains (BD1 and BD2) followed by an extraterminal (ET) domain that mediates recruitment of transcriptional cofactors. BRD4 and BRDT additionally contain a unique C-terminal domain (CTD), which interacts with positive transcription elongation factor b (P-TEFb) and plays a central role in RNA polymerase II-dependent transcriptional elongation [32, 33]. Because of this specialized architecture, BET proteins function primarily as transcriptional coactivators that regulate enhancer activity, super-enhancer formation, inflammatory gene expression, and cell-cycle progression(Fig. 1C).

In contrast, the non-BET bromodomain family comprises more than forty proteins containing one to six bromodomains combined with diverse functional domains, including ATPase motifs, helicase domains, histone acetyltransferase domains, PHD fingers, WD repeats, and DNA-binding motifs [27, 28]. This group includes chromatin remodelers (SMARCA2, SMARCA4, BRD7, BRD9, PBRM1), histone acetyltransferases (EP300, CBP, GCN5, PCAF), histone methyltransferases (ASH1L, MLL), scaffold proteins (TAF1), and multiple transcriptional regulators [27, 40, 41]. Their biological activities extend beyond transcriptional elongation to encompass nucleosome repositioning, enhancer selection, DNA damage repair, replication-coupled chromatin assembly, and regulation of innate immune signaling [28, 42] (Fig. 1C).

Despite their diversity, bromodomains share a highly conserved structural fold composed of four α-helices (αZ, αA, αB, and αC) connected by the ZA and BC loops, which together form a hydrophobic acetyl-lysine-binding pocket [29, 43]. A conserved asparagine residue within this pocket forms a hydrogen bond with the acetyl group of lysine, providing the molecular basis for acetyl-lysine recognition [27, 29]. Structural differences within the ZA and BC loops generate ligand specificity among bromodomain proteins and explain why different bromodomains recognize distinct acetylation patterns on histones and transcriptional regulators [40, 44, 45] (Fig. 1D).

BET bromodomains exhibit functional specialization between BD1 and BD2 [40]. BD1 preferentially maintains constitutive chromatin occupancy, whereas BD2 is more responsive to stimulus-dependent transcriptional activation and inflammatory signaling [32]. This functional distinction has motivated the development of domain-selective inhibitors targeting either BD1 or BD2 to reduce toxicity associated with pan-BET inhibition.

Conversely, BRD7 and BRD9 each contain a single bromodomain with unique structural features, including a tyrosine gatekeeper residue within the acetyl-lysine-binding pocket, distinguishing them from BET proteins and enabling selective pharmacological targeting [27, 29]. These structural differences reinforce that BRD9 belongs to a mechanistically distinct branch of the bromodomain family despite sharing the conserved acetyl-lysine recognition fold (Fig. 1E).

The structural diversity of bromodomain proteins is reflected in their biological specialization. BET proteins primarily regulate transcriptional elongation through recruitment of P-TEFb and mediator complexes, whereas many non-BET proteins participate directly in ATP-dependent chromatin remodeling, enhancer accessibility, DNA repair, and lineage-specific transcriptional programs [40, 46].

The functional separation between BET proteins and BRD7/BRD9 provides an important conceptual framework for this review. BET proteins, especially BRD4, predominantly act as acetyl-lysine readers and transcriptional scaffolds that regulate transcription initiation and elongation. In contrast, BRD7 and BRD9 are integrated into ATP-dependent SWI/SNF chromatin-remodeling complexes, where their biological effects depend strongly on complex composition and chromatin context [26, 47]. Thus, although all of these proteins contain bromodomains, their contributions to gene regulation are mechanistically distinct (Fig. 1E).

This distinction provides the conceptual framework for interpreting bromodomain biology in retroviral infection: BRD4 represents the best-established bromodomain regulator of HIV-1 and HTLV-1 transcription, whereas BRD9 is currently being investigated as an emerging chromatin-remodeling factor with potentially distinct biological functions.

SWI/SNF chromatin-remodeling complexes and the biological context of BRDs

The switch/sucrose non-fermentable (SWI/SNF) family comprises ATP-dependent chromatin-remodeling complexes that regulate chromatin accessibility by altering nucleosome positioning and histone-DNA interactions [42]. Mammalian SWI/SNF complexes, also referred to as BAF complexes, are assembled from a common set of core and accessory subunits but exist as compositionally distinct assemblies with different genomic targets and biological functions. Three major forms have been recognized: canonical BAF (cBAF), polybromo-associated BAF (PBAF), and non-canonical BAF (ncBAF or GBAF) [24, 30].

The three complexes share an ATPase subunit, either SMARCA4 (BRG1) or SMARCA2 (BRM), together with several conserved structural components [48–50]. Their functional specificity is generated largely through incorporation of distinct accessory subunits. cBAF contains ARID1A or ARID1B as characteristic targeting subunits and is broadly involved in enhancer accessibility, lineage-specific transcription, and cell-state regulation. PBAF contains distinctive subunits including PBRM1 (BAF180), ARID2 (BAF200), PHF10, and BRD7, and is frequently associated with promoter regulation and specialized transcriptional programs [48–50]. ncBAF differs more substantially from these canonical assemblies and contains BRD9 together with GLTSCR1 (BICRA) or GLTSCR1L (BICRAL) as characteristic components [24, 26].

BRD9 therefore occupies a fundamentally different position within chromatin regulation from BRD4. Rather than functioning primarily as a transcriptional elongation factor or P-TEFb-associated scaffold, BRD9 is integrated into an ATP-dependent chromatin-remodeling complex whose activity can alter the physical accessibility of regulatory DNA. The BRD9 bromodomain contributes to recognition of acetylated chromatin, while the C-terminal DUF3512 region is important for ncBAF assembly and stability [26, 51]. Consequently, pharmacological inhibition of the BRD9 bromodomain and depletion or degradation of BRD9 can produce overlapping but not necessarily identical phenotypes, because the latter approaches can affect the structural integrity of the ncBAF complex in addition to bromodomain-dependent chromatin recognition [26, 49].

The distinction between cBAF, PBAF, and ncBAF is particularly relevant to interpretation of viral chromatin regulation. SWI/SNF complexes regulate nucleosome organization at promoters and enhancers and can influence transcriptional responses to cellular stimulation, differentiation, DNA damage, and immune signaling [42]. Because integrated retroviral genomes are embedded within host chromatin, these complexes have the potential to influence viral transcription by altering the accessibility of proviral regulatory elements. However, the existence of this mechanistic possibility should not be interpreted as evidence that every SWI/SNF subunit regulates every retrovirus (Fig. 2).

Fig. 2.

Bromodomain-containing protein-mediated signaling in chromatin remodeling and transcriptional regulation. Bromodomain-containing proteins (BRDs), including bromodomain-containing protein 2 (BRD2), bromodomain-containing protein 3 (BRD3), bromodomain-containing protein 4 (BRD4), and bromodomain-containing protein 9 (BRD9), function as epigenetic readers that recognize acetylated lysine residues on histones through their bromodomains. This interaction facilitates the recruitment of transcriptional regulators and chromatin-remodeling complexes to promoters and enhancers, thereby modulating chromatin accessibility, transcription factor binding, and RNA polymerase II (RNA Pol II)-dependent transcription. BRD9 represents a distinct BRD family member that functions as an integral component of the non-canonical BRG1/BRM-associated factor (ncBAF) chromatin-remodeling complex. Through its bromodomain, BRD9 recognizes acetylated chromatin and facilitates the recruitment and activity of the ncBAF complex, which includes SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4 (SMARCA4, also known as BRG1), SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily C member 1 (SMARCC1, also known as BAF155), actin-like protein 6 A (ACTL6A), glioma tumor suppressor candidate region gene 1 (GLTSCR1), and glioma tumor suppressor candidate region gene 1-like (GLTSCR1L). ATP-dependent chromatin remodeling promotes nucleosome repositioning and increases accessibility of regulatory DNA elements, facilitating transcriptional activation. BRD- and BRD9-dependent chromatin regulation influences several signaling and transcriptional programs, including MYC-dependent transcription, interferon (IFN) signaling, Wnt/β-catenin signaling, inflammatory signaling, DNA damage responses and repair, and immune-related gene expression. BRD9 also contributes to homologous recombination through regulation of the RAD51–RAD54 complex, linking chromatin remodeling to genome stability. In addition, BRD9 participates in enhancer–promoter looping and higher-order chromatin organization, thereby facilitating communication between distal regulatory elements and target promoters. The right panel illustrates the consequences of BRD9 inhibition, in which pharmacological disruption of bromodomain-mediated chromatin recognition reduces BRD9 binding to acetylated chromatin and interferes with ncBAF-dependent chromatin remodeling. This results in reduced chromatin accessibility, impaired enhancer activity, decreased transcription factor and RNA Pol II recruitment, and altered expression of downstream genes involved in MYC, IFN, inflammatory, DNA repair, and immune-associated pathways. Overall, the figure illustrates how BRDs connect histone acetylation with chromatin remodeling and signal-dependent transcription, while highlighting BRD9 as a specialized regulator of ncBAF-mediated chromatin organization and downstream cellular signaling. The abbreviation Ac denotes an acetyl group, ATP denotes adenosine triphosphate, ADP denotes adenosine diphosphate, DNA denotes deoxyribonucleic acid, and TF denotes transcription factor. This figure was created by the authors using BioRender.com

Taken together, the organization of the SWI/SNF family provides a mechanistic framework for understanding why ncBAF is relevant to retroviral biology without implying that BRD9 has already been established as a universal retroviral regulator. cBAF, PBAF, and ncBAF are compositionally distinct chromatin-remodeling assemblies with different targeting properties and biological functions [52, 53]. BRD7 is associated primarily with PBAF, whereas BRD9 defines ncBAF [26].

Molecular mechanisms and signaling pathways regulated by bromodomain-containing proteins

Bromodomain-containing proteins (BRDs) are important epigenetic regulators that translate changes in chromatin acetylation into transcriptional and signaling responses [54]. Their biological functions are largely mediated through bromodomains, which recognize acetylated lysine residues on histones and, in some cases, acetylated non-histone proteins, thereby facilitating the recruitment of transcriptional and chromatin-remodeling complexes to specific genomic regions [25, 28]. Through these interactions, BRDs regulate chromatin accessibility, enhancer and promoter activity, transcription factor recruitment, and RNA polymerase II-dependent transcription, allowing extracellular and intracellular signals to be integrated with cell-specific transcriptional programs [55, 56]. Consequently, BRD proteins participate in multiple signaling pathways associated with cell proliferation, differentiation, stem-cell maintenance, DNA repair, inflammation, and immune responses [30].

A major mechanism through which BRDs regulate cellular signaling is their association with ATP-dependent chromatin-remodeling complexes [14, 57]. Within this context, BRD9 represents a distinct and well-characterized BRD family member that functions as an integral component of the non-canonical BAF (ncBAF) chromatin-remodeling complex [24, 28, 57]. BRD9 recognizes acetylated chromatin and facilitates the recruitment and positioning of the ncBAF complex at regulatory genomic regions [24, 57]. This activity promotes nucleosome repositioning and increases the accessibility of transcriptional regulatory elements, thereby enabling transcription factors and RNA polymerase II to engage their target genes [28, 30]. Thus, BRD9 provides an important mechanistic link between chromatin acetylation, chromatin remodeling, and signal-dependent transcription.

The ability of BRD proteins to regulate chromatin accessibility has important consequences for oncogenic and developmental signaling networks. In particular, BRD4 and SWI/SNF complexes has been implicated in the regulation of MYC (myelocytomatosis)–dependent transcriptional programs, in which its chromatin-remodeling activity contributes to the maintenance of transcriptional states associated with cellular proliferation and malignant transformation [53, 58, 59]. Beyond MYC-associated signaling, BATF3 and BRD9 influences interferon-responsive genes, Wnt/β-catenin signaling, inflammatory pathways, and DNA damage-response mechanisms [60–62]. These findings illustrate how BRDs family can function not simply as a structural component of a chromatin-remodeling complex but also as an important regulator of signaling-dependent transcriptional outputs.

BRD-mediated regulation of DNA damage responses further demonstrates the functional connection between epigenetic signaling and genome maintenance. BRD9 has been shown to contribute to homologous recombination by regulating the assembly and/or function of the RAD51–RAD54 complex, thereby linking ncBAF-dependent chromatin remodeling to the repair of DNA double-strand breaks and maintenance of genome stability [63]. More broadly, SMARCA can regulate the accessibility of DNA repair factors to damaged chromatin, providing a mechanism through which chromatin state influences cellular responses to genotoxic stress [48]. The involvement of BRD proteins in these processes is particularly relevant because disruption of its chromatin-remodeling function may simultaneously alter transcriptional regulation and DNA repair capacity.

BRDs also participate in higher-order chromatin organization and long-range regulatory interactions. Emerging evidence indicates that BRD9 contributes to enhancer–promoter looping and three-dimensional chromatin architecture, thereby facilitating communication between distal regulatory elements and their target genes [31, 64]. Such activities provide an additional mechanism through which BRD proteins can coordinate signaling pathways at the level of genome organization. By integrating histone acetylation recognition with chromatin remodeling, enhancer activity, and three-dimensional genome architecture, BRD9 can influence the transcriptional output of multiple signaling networks simultaneously [30, 41, 65].

Other members of the bromodomain-containing protein family, particularly the BET proteins BRD2, BRD3, BRD4, and BRDT, can regulate transcriptional responses by recognizing acetylated chromatin and recruiting transcriptional regulatory machinery to active promoters and enhancers [46, 66, 67]. Among these proteins, BRD4 is particularly important for the regulation of enhancer-dependent transcription and signaling programs associated with MYC, inflammatory responses, and cellular proliferation [20, 55]. Therefore, BRD proteins collectively represent an important interface between chromatin state and intracellular signaling, whereas BRD9 provides a distinct example in which bromodomain-mediated chromatin recognition is integrated with ncBAF-dependent chromatin remodeling.

The functional importance of BRD-mediated signaling is further highlighted by pharmacological and genetic inhibition studies. Disruption of bromodomain–acetyl-lysine interactions can interfere with the recruitment of BRD-containing regulatory complexes, alter enhancer activity, reduce transcription factor occupancy, and consequently modify downstream signaling pathways [68, 69]. Collectively, these observations establish BRD proteins as critical molecular regulators that connect epigenetic information with signaling-dependent transcription and cellular phenotype (Fig. 2).

Bromodomain proteins in HTLV-1 infection: established evidence and emerging perspectives for BRD9

Current knowledge regarding bromodomain proteins in HTLV-1 infection is derived almost entirely from studies of BET family members, particularly BRD4. These proteins regulate viral transcription, Tax-mediated transactivation, oncogenic signaling, and therapeutic responses in Adult T-cell Leukemia/Lymphoma (ATLL) [22, 23, 62, 70, 71]. In contrast, no direct experimental study has investigated BRD9 during HTLV-1 infection. Therefore, this section first summarizes the established evidence for BET proteins in HTLV-1 biology and subsequently discusses BRD9 only as a biologically plausible but currently unvalidated candidate based on its role in ncBAF-mediated chromatin remodeling [16, 24, 26].

BRD4 and P-TEFb in HTLV-1 transcriptional regulation

The first evidence linking bromodomain proteins to HTLV-1 transcriptional regulation was provided by Cho et al. (2007), who investigated interactions between the viral transactivator Tax and the host transcription elongation machinery [22]. The authors demonstrated that Tax modulates the interaction between BRD4 and positive transcription elongation factor b (P-TEFb), a key regulator of RNA polymerase II-dependent transcription. Mechanistically, Tax competed with BRD4 for binding to P-TEFb, thereby increasing the availability of active P-TEFb for recruitment to the HTLV-1 promoter and enhancing viral transcription [22]. These findings identified BRD4 as an important host factor involved in Tax-mediated transactivation and established a direct connection between bromodomain proteins and HTLV-1 gene expression.

Further mechanistic insights were reported by Cho et al. (2010), who demonstrated that Tax forms transcriptionally active complexes with P-TEFb and competes not only with BRD4 but also with the inhibitory 7SK snRNP/HEXIM1 complex for binding to P-TEFb [23]. This competition increased the pool of active P-TEFb available for transcriptional elongation and enhanced expression from the HTLV-1 long terminal repeat (LTR) promoter [23]. The study revealed a sophisticated mechanism through which HTLV-1 hijacks host transcriptional machinery and highlighted bromodomain-associated transcriptional regulators as critical components of viral gene expression. Although BRD9 was not examined, these findings suggest that other bromodomain-containing proteins involved in chromatin remodeling may also influence HTLV-1 transcriptional activity.

Collectively, these studies established that HTLV-1 Tax manipulates the BRD4–P-TEFb axis to promote viral transcription and demonstrated the central role of bromodomain-associated transcriptional machinery in HTLV-1 gene expression [22, 23].

Bromodomain proteins in HTLV-1-Induced oncogenic signaling

In addition to regulating viral transcription, bromodomain proteins contribute to HTLV-1-mediated oncogenic transformation. Wu et al. (2013) investigated the role of BET proteins in Tax-driven tumorigenesis using the BET bromodomain inhibitor JQ1 [70]. The authors demonstrated that BET inhibition suppressed Tax-mediated cellular transformation and significantly reduced NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling, a pathway constitutively activated in HTLV-1-transformed cells. Treatment with JQ1 reduced the expression of NF-κB-responsive genes and impaired the tumorigenic capacity of Tax-expressing cells [70]. These findings identified BET proteins as essential mediators of HTLV-1-induced oncogenic signaling and provided the first evidence that bromodomain proteins may represent therapeutic targets in HTLV-1-associated malignancies.

Further support for the importance of bromodomain-associated transcriptional regulation in ATLL was provided by Nakagawa et al. (2018) [62]. Through comprehensive genomic, transcriptomic, and functional analyses, the authors identified a BATF3/IRF4 (Basic Leucine Zipper Transcription Factor ATF-Like 3/ Interferon Regulatory Factor 4)-dependent transcriptional network that is essential for ATLL cell survival. Pharmacological BET inhibition disrupted this oncogenic transcriptional circuitry, leading to suppression of ATLL cell growth and survival [62]. The study demonstrated that HTLV-1-transformed cells are highly dependent on epigenetic transcriptional regulators and highlighted bromodomain proteins as critical components of the transcriptional networks sustaining malignant transformation.

Together, these findings demonstrate that bromodomain proteins regulate key oncogenic pathways downstream of HTLV-1 infection, including NF-κB signaling and BATF3/IRF4-mediated transcriptional programs, both of which are crucial for ATLL development and maintenance [62, 70].

Therapeutic targeting of bromodomain proteins in ATLL

The discovery that bromodomain proteins regulate both HTLV-1 transcription and oncogenic signaling has stimulated interest in their therapeutic targeting (Table 1). The first proof-of-concept study was reported by Wu et al. (2013), who demonstrated that BET inhibition using JQ1 suppressed Tax-mediated transformation and reduced NF-κB activation [70]. These findings suggested that bromodomain inhibition may represent a viable therapeutic strategy for HTLV-1-associated malignancies.

Table 1.

Preclinical studies evaluating BET bromodomain inhibition in HTLV-1-associated adult T-cell leukemia/lymphoma (ATLL)

Study	BET inhibitor(s)	Experimental model	Dose/Concentration examined	Major findings	Clinical implication
Wu et al., 2013	JQ1	Tax-transformed Rat-1 fibroblasts, HTLV-1-positive cell lines (MT4, C8166, SLB1), mouse xenografts	In vitro: 0.1–2 µM JQ1 (0.5 µM markedly inhibited proliferation); In vivo: 50 mg/kg/day intraperitoneally for 19 days	Disrupted BRD4–RelA interaction, inhibited Tax-mediated NF-κB activation, reduced proliferation, suppressed xenograft tumor growth.	First proof-of-concept demonstrating BET proteins as therapeutic targets in HTLV-1-associated malignancy.
Nakagawa et al., 2018	JQ1; CPI-203	ATLL cell lines, primary ATLL samples, xenograft mouse models	JQ1: dose-response experiments (multiple concentrations); CPI-203: 5 mg/kg twice daily (intraperitoneally) for 12–14 days	Disrupted HBZ/BATF3/IRF4 network, reduced BATF3 and MYC, impaired ATLL growth.	Supported BET-targeted epigenetic therapy in ATLL.
Yeh et al., 2020	JQ1; OTX015 (MK-8628)	ATL cell lines, FBXW7-mutant models, mouse xenografts	In vitro: dose-response studies; In vivo: JQ1 50 mg/kg intraperitoneally every 3 days	FBXW7-mediated BRAF stabilization caused BET inhibitor resistance; combination with MAPK inhibition restored sensitivity.	Highlighted resistance mechanisms and rationale for combination therapy.

The therapeutic relevance of bromodomain proteins was further strengthened by Nakagawa et al. (2018), who showed that BET inhibition disrupted the BATF3/IRF4 oncogenic transcriptional network and impaired ATLL cell growth [62]. Their findings suggested that ATLL cells exhibit transcriptional addiction to bromodomain-regulated pathways and may therefore be particularly susceptible to epigenetic therapies.

However, therapeutic resistance represents a major challenge. Yeh et al. (2020) demonstrated that loss of FBXW7 (F-box/WD repeat-containing protein 7)-mediated degradation of BRAF promotes resistance to BET inhibitors in ATLL cells through sustained activation of MAPK signaling [71]. The study revealed that activation of compensatory oncogenic pathways can reduce the efficacy of BET-targeted therapies and identified BRAF stabilization as a potential mechanism of drug resistance [71]. These findings underscore the need for combination therapies targeting both bromodomain proteins and alternative oncogenic pathways in HTLV-1-associated malignancies.

Collectively, the available evidence supports bromodomain proteins as promising therapeutic targets in ATLL and highlights the importance of understanding resistance mechanisms that may limit the long-term effectiveness of BET-directed therapies [62, 70, 71].

It should be noted that the therapeutic studies performed in HTLV-1 have almost exclusively employed pan-BET inhibitors, including JQ1, CPI-203, and OTX015, which target multiple BET family proteins (BRD2, BRD3, BRD4, and BRDT) rather than BRD9 [62, 70, 71]. Therefore, the reported inhibition of Tax-mediated transcription, NF-κB signaling, and ATLL cell proliferation cannot currently be attributed specifically to BRD9 inhibition. Since BRD9 belongs to the non-BET bromodomain family and functions as a core component of the ncBAF chromatin-remodeling complex, its contribution to HTLV-1 biology remains to be established experimentally. Future studies using selective BRD9 inhibitors or targeted BRD9 degradation strategies will be necessary to determine whether BRD9 independently regulates HTLV-1 transcription, viral persistence, or leukemogenesis [16, 26].

BRD9 as an emerging candidate in HTLV-1 chromatin regulation

Despite the extensive evidence supporting BRD4 and other BET proteins in HTLV-1 transcription and leukemogenesis, no direct experimental evidence currently demonstrates that BRD9 regulates HTLV-1 infection, viral persistence, Tax-mediated transcription, HBZ function, or ATLL progression. Consequently, BRD9 should not presently be considered an established regulator of HTLV-1 biology. Future studies are required to determine whether BRD9 participates in HTLV-1 pathogenesis.

The interest in BRD9 arises because it functions as a core component of the ncBAF chromatin-remodeling complex, which regulates enhancer accessibility, transcription-factor recruitment, chromatin architecture, and gene expression programs associated with proliferation, differentiation, and immune signaling [24–26]. Since HTLV-1 relies heavily on host chromatin remodeling and transcriptional regulation, it is reasonable to investigate whether BRD9-containing ncBAF complexes participate in these processes. However, this hypothesis remains untested experimentally.

At present, whether BRD9 influences HTLV-1 transcription, proviral chromatin organization, viral persistence, or ATLL progression remains unknown. Future investigations examining BRD9 expression patterns, genomic occupancy, protein interaction networks, and functional significance in HTLV-1-infected and ATLL cells will be essential to determine whether BRD9 serves as a novel host factor involved in HTLV-1 pathogenesis and whether it represents a potential therapeutic target for HTLV-1-associated diseases.

Bromodomain proteins in HIV-1 infection: established mechanisms and emerging evidence for BRD9

HIV-1 infection provides the strongest evidence linking bromodomain proteins to retroviral transcription and latency. Over the past two decades, numerous studies have established that BRD4 regulates HIV transcription through interactions with positive transcription elongation factor b (P-TEFb), Tat, RNA polymerase II, and chromatin-remodeling complexes [19, 20, 55, 56, 72–79].

In contrast, BRD9 has only recently entered the field through evidence identifying ncBAF-dependent chromatin remodeling as a regulator of HIV-1 latency [16]. Accordingly, this section first summarizes the established BRD4/BET mechanisms that define the current understanding of bromodomain biology in HIV-1 infection before discussing the currently limited experimental evidence specifically involving BRD9.

Over the past two decades, extensive investigations have demonstrated that BRD4 regulates HIV transcription through interactions with P-TEFb, Tat, chromatin-remodeling complexes, and transcription elongation machinery [19, 20, 55, 56, 72–79]. These studies established the conceptual foundation for understanding bromodomain-mediated regulation of HIV transcription and ultimately led to investigations of non-BET bromodomain proteins such as BRD9 (Fig. 3). Therefore, the following sections summarize key BRD4 discoveries only insofar as they provide the biological context necessary to interpret the recent findings implicating BRD9 in HIV-1 latency regulation [16, 21, 66, 80–86].

Fig. 3.

Schematic representation of the established BRD4-dependent transcriptional pathway and the experimentally validated BRD9-dependent chromatin remodeling pathway regulating HIV-1 transcription and latency. Step 1: HIV-1 integrates into the host genome, where nucleosome positioning at the 5′ long terminal repeat (LTR), particularly nucleosomes Nuc-0 and Nuc-1, influences chromatin accessibility and transcriptional competence. Step 2: In the established BRD4 pathway, the viral transactivator Tat recruits positive transcription elongation factor b (P-TEFb), composed of cyclin-dependent kinase 9 (CDK9) and Cyclin T1, together with RNA polymerase II (RNA Pol II) and the super elongation complex (SEC), to promote efficient transcriptional elongation and viral RNA synthesis. Step 3: In the experimentally validated BRD9 pathway, BRD9 functions as a component of the non-canonical BRG1/BRM-associated factor (ncBAF) chromatin-remodeling complex. Recognition of acetylated histones facilitates ncBAF recruitment, ATP-dependent chromatin remodeling, and increased chromatin accessibility at the HIV-1 L, thereby contributing to transcriptional regulation. Step 4: Pharmacological inhibition of BRD9 decreases ncBAF activity, reduces chromatin accessibility, maintains a closed chromatin configuration, suppresses HIV-1 reactivation, and promotes viral latency. Step 5: Reduced chromatin accessibility favors maintenance of stable latent reservoirs in infected CD4⁺ T cells by limiting viral reactivation following cellular stimulation. Step 6: Potential therapeutic strategies include selective BRD9 inhibition to support a block-and-lock approach aimed at durable proviral silencing and reservoir stabilization, whereas BRD9 inhibition may reduce the efficiency of shock-and-kill strategies that rely on latency reversal. The navy-blue pathway represents the established BRD4-mediated transcriptional mechanism, whereas the green pathway represents the experimentally validated BRD9-mediated regulation of chromatin accessibility and HIV-1 latency. Abbreviations: ATP, adenosine triphosphate; BRD4, bromodomain-containing protein 4; BRD9, bromodomain-containing protein 9; CDK9, cyclin-dependent kinase 9; HIV-1, human immunodeficiency virus type 1; LTR, long terminal repeat; ncBAF, non-canonical BRG1/BRM-associated factor chromatin-remodeling complex; Nuc-0, nucleosome 0; Nuc-1, nucleosome 1; P-TEFb, positive transcription elongation factor b; RNA Pol II, RNA polymerase II; SEC, super elongation complex; AFF4, AF4/FMR2 family member 4; ELL2, elongation factor for RNA polymerase II 2; ENL, eleven-nineteen leukemia protein; TAR RNA, transactivation response RNA; Tat, HIV-1 transactivator of transcription protein

BRD4, P-TEFb, and the regulation of HIV transcription

The transcriptional activity of HIV-1 is critically dependent on the recruitment and activation of positive transcription elongation factor b (P-TEFb), a complex consisting of cyclin-dependent kinase 9 (CDK9) and Cyclin T1. Early studies established the molecular foundation for understanding the role of bromodomain-containing proteins in HIV transcription. Zeng and Zhou (2002) characterized bromodomains as acetyl-lysine recognition modules that facilitate chromatin-dependent transcriptional regulation [69]. Subsequently, Pumfery et al. (2003) demonstrated that HIV-1 Tat-mediated transcription requires extensive chromatin remodeling and histone modifications, highlighting the importance of epigenetic regulators in viral gene expression [57].

A major advance came when Yang et al. (2005) identified BRD4 as a key recruiter of P-TEFb to cellular promoters, promoting transcriptional elongation through activation of CDK9 [19]. Marshall and Grana (2006) further summarized the mechanisms regulating CDK9 activity and emphasized the central role of P-TEFb in transcriptional control [72]. Likewise, Zhou and Yik (2006) proposed that competition among cellular and viral factors for P-TEFb recruitment is a critical determinant of HIV transcriptional activity [73].

Subsequent studies demonstrated that BRD4 acts as a negative regulator of HIV transcription. Bisgrove et al. (2007) identified a conserved P-TEFb-binding domain within BRD4 that inhibits HIV transcription by competing with Tat for access to P-TEFb [20]. Urano et al. (2008) further showed that this BRD4 domain suppresses HIV replication, providing direct evidence that BRD4 functions as an endogenous restriction factor [74]. Zhou et al. (2009) subsequently demonstrated that BRD4 regulates HIV transcription by phosphorylating CDK9 at threonine 29, thereby modulating Tat-dependent transcriptional elongation [75].

Additional mechanistic studies revealed how P-TEFb is mobilized during HIV transcription. Krueger et al. (2010) showed that activation of HIV transcription requires release of P-TEFb from the inhibitory 7SK snRNP complex through conformational changes in 7SK RNA [76]. Ai et al. (2011) reported that signal-induced release of BRD4 from chromatin is necessary for its transition from chromatin targeting to transcriptional regulation [77]. Schroder et al. (2012) demonstrated that BRD4 liberates P-TEFb from inactive ribonucleoprotein complexes through a dual-binding mechanism [78], while Devaiah et al. (2012) identified BRD4 as an atypical kinase capable of phosphorylating serine-2 residues within the RNA polymerase II C-terminal domain [55]. Itzen et al. (2014) further demonstrated that BRD4 directly activates P-TEFb and promotes RNA polymerase II CTD phosphorylation [56]. In parallel, Lu et al. (2014) revealed that AFF1 facilitates Tat-mediated extraction of P-TEFb from 7SK snRNP and promotes assembly of the super elongation complex (SEC), which is essential for efficient HIV transactivation [79].

Collectively, these studies established BRD4 as a central regulator of HIV transcription by modulating the Tat–P-TEFb axis. Reviews by Wu and Chiang (2007), Zhou and Yik (2006), Jeng and Ott (2015), and Alamer et al. (2021) summarized the pivotal role of BRD4 in coordinating transcriptional elongation, chromatin remodeling, and HIV gene expression [73, 87–89] (Fig. 3).

Bromodomain proteins in HIV latency and chromatin regulation

Beyond active transcription, bromodomain proteins play crucial roles in maintaining HIV latency. Bartholomeeusen et al. (2012) demonstrated that inhibition of BET bromodomains transiently releases P-TEFb from the 7SK complex, thereby enhancing transcriptional elongation [80]. In the same year, Zhu et al. (2012) showed that BRD4 inhibition reactivates latent HIV-1, providing one of the earliest demonstrations that bromodomain proteins regulate proviral latency [81].

Li et al. (2013) further demonstrated that the BET inhibitor JQ1 reactivates latent HIV by antagonizing BRD4-mediated inhibition of Tat transactivation [82]. Similarly, Boehm et al. (2013) reported that BET inhibitors reactivate latent HIV through Tat-independent mechanisms, indicating that multiple pathways contribute to latency reversal [66].

Conrad et al. (2017) provided important mechanistic insight by demonstrating that the short isoform of BRD4 promotes HIV latency by recruiting repressive SWI/SNF chromatin-remodeling complexes to the proviral promoter [21]. This study was particularly significant because it established a direct connection between bromodomain proteins and the chromatin-remodeling machinery involved in latency maintenance. Since BRD9 is a defining component of the non-canonical BAF (ncBAF) complex, these findings provided an important rationale for exploring BRD9 in HIV latency regulation.

Additional studies highlighted the complexity of latency-associated chromatin regulation. Li et al. (2018) identified the KAT5 (Lysine Acetyltransferase 5)-acetyl-Histone H4-BRD4 axis as a mechanism promoting HIV latency through transcriptional silencing [83]. Lindqvist et al. (2022) demonstrated that T-cell stimulation remodels proviral chromatin and alters the composition of latently infected cell populations [84]. Genome-wide CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) screens performed by Dai et al. (2022) and Hsieh et al. (2023) further revealed that HIV latency is maintained by interconnected epigenetic and transcriptional pathways rather than single host factors [85, 86].

Overall, these studies established that HIV latency is strongly influenced by bromodomain-dependent chromatin remodeling and transcriptional control. Reviews by Karn (2013), Rice (2013), Salahong et al. (2021), and Tolomeo and Cascio (2026) emphasized the importance of bromodomain proteins as regulators of HIV persistence and latency maintenance [90–93].

Emerging BRD9-specific evidence in HIV-1 latency regulation

Compared with BRD4, direct evidence linking BRD9 to HIV-1 infection is currently very limited. For many years, BRD9 was discussed only indirectly because of its role within the ncBAF chromatin-remodeling complex and the recognized importance of SWI/SNF family complexes in HIV latency [21]. The availability of selective non-BET bromodomain chemical probes subsequently enabled direct investigation of BRD9 function [94].

Luk et al. (2025) provided the first direct experimental evidence implicating BRD9 in HIV-1 latency [16]. Using complementary genetic and pharmacological approaches, the study demonstrated that BRD9-containing ncBAF complexes regulate chromatin accessibility at the HIV-1 provirus and influence proviral transcriptional competence, latency maintenance, and viral reactivation [16]. This work established BRD9 as a bona fide host factor involved in HIV persistence.

Importantly, this single study should be interpreted as the beginning rather than the culmination of BRD9 research in retrovirology. Independent validation, mechanistic studies across multiple HIV reservoir cell types, and investigation of BRD9 interaction partners remain necessary before broader conclusions regarding BRD9 function in HIV-1 infection can be drawn [16, 21, 84–86].

Before discussing therapeutic strategies, it is important to distinguish therapies directed against BET proteins from those specifically targeting BRD9. Nearly all bromodomain-targeted compounds evaluated in HIV-1 cure research were developed to inhibit BET family members, particularly BRD4, because BRD4 has well-established roles in HIV transcription and latency [66, 82]. Consequently, the therapeutic literature summarized below represents evidence for BET protein modulation rather than BRD9-directed antiviral therapy, except where explicitly stated.

Therapeutic targeting of bromodomain proteins in HIV infection

The therapeutic potential of bromodomain proteins in HIV cure strategies has been extensively investigated (Table 2). Early studies demonstrated that BET inhibitors, including JQ1, reactivate latent HIV through disruption of BRD4-mediated repression [66, 82]. Walker-Sperling et al. (2016) subsequently reported that bromodomain inhibitors influence immune cell function, an important consideration for latency-reversal strategies [95].

Table 2.

Bromodomain-targeted therapeutic strategies for HIV cure research

Study	Therapeutic strategy	Bromodomain inhibitor(s)	Experimental model	Dose/Concentration reported	Principal findings	Clinical significance
Li et al., 2013; Boehm et al., 2013	Shock-and-kill	JQ1	Latent HIV cell models	Dose-response studies. 0.1–1 µM	BET inhibition disrupted BRD4-mediated repression and reactivated latent HIV.	Provided proof-of-concept for BET inhibitors as latency-reversing agents.
Walker-Sperling et al., 2016	Immune modulation	BET inhibitors	Primary immune cells	Not primary focus	BET inhibitors altered immune cell function relevant to HIV eradication.	Highlighted immunological consequences of latency reversal.
Abner et al., 2018	Shock-and-kill	Novel quinoline-based BRD4 inhibitor	Latent HIV models	Dose-response studies, Variable µM,	Reactivated HIV from reservoirs resistant to conventional LRAs.	Identified next-generation BRD4 inhibitors.
Zheng et al., 2021	Shock-and-kill	CPI-637 (BRD4/TIP60 inhibitor)	Latent HIV models	Dose-response studies. Up to 20 µM	Dual BRD4/TIP60 inhibition efficiently reactivated latent HIV.	Suggested dual epigenetic targeting improves latency reversal.
Wang et al., 2024	Shock-and-kill	Triazolopyridine-based BRD4 inhibitors	Latent HIV models	Dose-response studies, Low µM	Developed potent novel BRD4 latency-reversing compounds.	Expanded the BET inhibitor drug pipeline.
Niu et al., 2019	Block-and-lock	BRD4-selective small molecule	HIV infection models	Dose-response studies	Suppressed HIV transcription and replication.	Supported long-term proviral silencing.
Alamer et al., 2020	Block-and-lock	ZL0580	Myeloid HIV latency models	Dose-response studies	Epigenetically suppressed HIV transcription.	Demonstrated durable transcriptional repression.
Pellaers et al., 2025	Block-and-lock	ZL0580 + LEDGINs	Cellular HIV latency models	Dose-response combination studies	Additive suppression of HIV transcription.	Supported combination block-and-lock therapy.
Kumar et al., 2026	Block-and-lock	ZL0580	In vitro and in vivo HIV models	Dose-response studies	Confirmed durable HIV suppression and mechanism.	Strengthened translational potential of block-and-lock.
Campbell et al., 2018	Autophagy modulation	BET inhibitors	Cell culture	Dose-response studies	Induced autophagy and suppressed HIV replication.	Identified additional antiviral mechanisms.
Li et al., 2019	Shock-and-kill	BET inhibitor	Humanized mice receiving ART	In vivo dosing reported in original article	Selective activation of latent HIV during ART.	Validated latency reversal in vivo.
Kisaka et al., 2024	Macrophage latency	BET pathway modulation	Macrophage latency models	Mechanistic study	Identified BRD4 axis in macrophage HIV latency.	Expanded cellular targets for cure strategies.
Turner et al., 2025	Mechanistic latency reversal	BRD4 inhibition	Primary CD4 + T cells	Mechanistic study	Disruption of the 7SK/P-TEFb complex was required for efficient latency reversal.	Clarified molecular basis of BET-mediated latency reversal.
Geanes et al., 2026	Immune modulation	BET inhibitors	Natural killer cells	Mechanistic study	BET inhibition altered NK-cell differentiation and function.	Suggested improved immune-mediated clearance of infected cells.

Abner et al. (2018) identified a novel quinoline-based BRD4 inhibitor capable of reactivating HIV from latent reservoirs resistant to other latency-reversing agents [96]. Zheng et al. (2021) demonstrated that the dual BRD4/TIP60 (Tat-interactive protein) inhibitor CPI-637 effectively reactivates latent HIV, suggesting that simultaneous targeting of multiple epigenetic regulators may improve latency reversal [97]. Wang et al. (2024) further developed triazolopyridine-based BRD4 inhibitors with potent latency-reversing activity [51].

In contrast to latency-reversal approaches, several studies have pursued a “block-and-lock” strategy to achieve durable proviral silencing. Niu et al. (2019) developed a BRD4-selective small molecule that suppresses HIV replication [98]. Alamer et al. (2020) demonstrated that ZL0580 epigenetically suppresses HIV transcription in myeloid cells [99]. Pellaers et al. (2025) showed that ZL0580 and LEDGINs cooperatively suppress HIV transcription through additive block-and-lock mechanisms [100], while Kumar et al. (2026) provided mechanistic and in vivo evidence supporting durable HIV suppression by ZL0580 [101].

Additional studies revealed broader biological effects of bromodomain-targeted therapies. Campbell et al. (2018) demonstrated that BRD4 inhibition induces autophagy and suppresses HIV replication [67]. Li et al. (2019) showed selective activation of latent HIV in humanized mice during antiretroviral therapy [102]. Kisaka et al. (2024) revealed an unexpectedly important role for the bromodomain axis in macrophage HIV latency [103]. Turner et al. (2025) further demonstrated that BRD4-mediated disruption of the 7SK (7SK small nuclear ribonucleoprotein)/P-TEFb complex is essential for efficient latency reversal in primary CD4⁺ T cells [104]. Moreover, Geanes et al. (2026) showed that BET inhibitors modulate natural killer cell differentiation and function, suggesting that bromodomain-targeted therapies may influence immune-mediated clearance of infected cells [105].

Reviews by Liang et al. (2020), Alamer et al. (2021), Salahong et al. (2021), and Tolomeo and Cascio (2026) concluded that bromodomain-targeted interventions are among the most promising epigenetic strategies for HIV cure research. However, they also emphasized the need to balance latency reversal, long-term silencing, immune modulation, and toxicity when designing future therapeutic approaches [89, 92, 93, 106].

An important consideration when interpreting these studies is the target specificity of the bromodomain inhibitors used. Most compounds investigated in HIV-1 and HTLV-1 research, including JQ1, CPI-203, and OTX015 (MK-8628), are bromodomain and extra-terminal (BET) inhibitors that simultaneously target multiple BET family members, particularly BRD2, BRD3, BRD4, and BRDT, rather than BRD9 [62, 66, 71, 82]. Likewise, CPI-637 was developed as a dual BRD4/TIP60 inhibitor, whereas ZL0580 selectively modulates BRD4-dependent transcriptional regulation in block-and-lock strategies [97, 99–101]. Consequently, the antiviral, latency-reversing, and antitumor activities reported in these studies primarily reflect inhibition of BET proteins, particularly BRD4, and should not be interpreted as direct evidence for BRD9 function. In contrast, the contribution of BRD9 to retroviral infection has only recently been investigated through genetic and pharmacological approaches, with the study by Luk et al. providing the first direct evidence that BRD9-containing ncBAF complexes regulate HIV-1 latency [16]. Therefore, future studies employing selective BRD9 inhibitors or degraders will be required to distinguish BRD9-specific mechanisms from the broader effects produced by pan-BET inhibition.

Conclusion

Research on bromodomain proteins has established chromatin remodeling and transcriptional regulation as central mechanisms governing human retroviral infection. Among bromodomain proteins, BRD4 and other BET family members have been extensively characterized as regulators of HIV-1 transcription, viral latency, HTLV-1 transactivation, oncogenic signaling, and therapeutic response [15, 19, 21–23, 70].

Overall, bromodomain proteins should therefore be viewed as a functionally diverse group of chromatin readers rather than as a single mechanistic class. The strongest evidence in retroviral infection concerns the BET family, with BRD4 playing particularly prominent roles in P-TEFb regulation, HIV-1 transcription and latency, and Tax-dependent HTLV-1 signaling [19, 21, 22, 70, 81]. BRD2 has also been implicated in HIV-1 latency, whereas evidence for BRD3 and BRDT in retroviral systems remains comparatively limited [66].

Within this broader field, BRD9 has recently emerged as a potentially important but currently underexplored epigenetic regulator. At present, direct experimental evidence is limited to HIV-1 latency regulation through ncBAF-dependent chromatin remodeling, while no direct studies have demonstrated a role for BRD9 in HTLV-1 infection or ATLL [16]. BRD9 should consequently be discussed as a developing area rather than as the dominant bromodomain regulator. This evidence-based distinction avoids overinterpretation while providing an appropriate rationale for continued investigation of BRD9-containing ncBAF complexes in retroviral chromatin biology.

Although the role of BRD9 in retroviral infection has remained largely unexplored for many years, recent evidence has begun to reveal its significance in HIV-1 latency regulation. The identification of BRD9 as a host factor that regulates proviral transcription provides the first direct evidence that non-BET bromodomain proteins contribute to HIV persistence.

Key Knowledge Gaps

The available evidence supporting BRD9 in retroviral infection remains substantially less developed than the evidence for BRD4 and other BET proteins. Whereas BRD4 has been extensively characterized in HIV-1 transcription, latency regulation, HTLV-1 transactivation, and ATLL biology [22, 23, 62, 70, 71], BRD9 has been directly investigated only in one HIV-1 latency study and has not yet been experimentally examined in HTLV-1 infection [16]. Therefore, BRD9 represents an emerging research direction rather than a mature field within retrovirology.

This review identifies several critical knowledge gaps that should guide future investigations. First, the molecular mechanisms governing BRD9 recruitment to retroviral chromatin remain unknown. Second, it is unclear whether BRD9 cooperates with or functions independently of BRD4 during regulation of viral transcription. Third, the genomic occupancy of BRD9 at HIV-1 proviral loci and its potential interactions with viral proteins have not been comprehensively characterized. Finally, no studies have yet examined whether BRD9 regulates HTLV-1 transcription, viral persistence, Tax- or HBZ-mediated chromatin remodeling, or Adult T-cell Leukemia/Lymphoma (ATLL) development [16, 22, 23, 71].

By integrating recent discoveries in BRD9 biology with established knowledge of bromodomain-mediated chromatin regulation in retroviral infection, this review provides a conceptual framework for addressing these unanswered questions. We anticipate that this framework will facilitate future mechanistic studies investigating ncBAF-dependent chromatin remodeling as a previously underexplored component of retroviral persistence and pathogenesis.

Future perspectives

Despite substantial advances in understanding bromodomain proteins during retroviral infection, the contribution of BRD9 remains incompletely defined. The recent discovery that BRD9 functions as a regulator of HIV-1 latency has opened a new area of investigation and raised numerous questions regarding its broader role in retroviral pathogenesis. Future studies should therefore focus on elucidating the molecular mechanisms through which BRD9-containing ncBAF complexes regulate proviral chromatin structure, transcriptional accessibility, and viral gene expression.

One major priority is to define the genomic occupancy and interaction networks of BRD9 in retrovirus-infected cells. Genome-wide approaches, including chromatin immunoprecipitation sequencing (ChIP-seq), CUT&RUN, CUT&Tag, and single-cell multi-omics technologies, may reveal how BRD9 is recruited to viral and host genomic loci and how it influences chromatin organization during infection. Furthermore, proteomic analyses are needed to identify viral and cellular proteins that interact with BRD9 and to determine whether retroviral regulatory proteins directly manipulate BRD9-containing chromatin-remodeling complexes.

For HIV-1, future investigations should examine how BRD9 contributes to the establishment, maintenance, and reversal of viral latency across different cellular reservoirs, including resting CD4⁺ T cells, macrophages, and tissue-resident immune cells. Determining whether BRD9 functions independently of, cooperatively with, or antagonistically to BRD4 will be particularly important for understanding bromodomain-mediated regulation of proviral transcription. Such studies may also identify novel therapeutic strategies that combine BRD9 modulation with existing latency-reversing agents or block-and-lock approaches.

The role of BRD9 in HTLV-1 infection remains completely unexplored, representing a major knowledge gap. Future studies should investigate BRD9 expression and function in HTLV-1-infected cells and ATLL tumors, evaluate its contribution to Tax-mediated transcriptional regulation, and determine whether BRD9 participates in the oncogenic signaling pathways that drive leukemogenesis. Given the demonstrated importance of bromodomain proteins in NF-κB activation and BATF3/IRF4-dependent transcriptional programs, Whether BRD9 functions as a regulator of HTLV-1 infection remains unknown. Future mechanistic studies will be necessary to determine whether BRD9 contributes to viral transcription, chromatin organization, or leukemogenic signaling in HTLV-1-infected cells.

From a translational perspective, the development of highly selective BRD9 inhibitors, degraders, and proteolysis-targeting chimeras (PROTACs) offers new opportunities for therapeutic intervention. Future preclinical studies should evaluate the efficacy, specificity, and safety of BRD9-targeted compounds in retroviral infection models and determine whether they can be integrated into HIV cure strategies or novel treatments for HTLV-1-associated malignancies. Moreover, combining BRD9-targeted therapies with immunomodulatory approaches may enhance viral control while minimizing off-target effects associated with broader bromodomain inhibition.

In summary, BRD9 represents an emerging frontier in retrovirology and epigenetic research. Expanding our understanding of BRD9-mediated chromatin regulation in HIV-1 and HTLV-1 infection will not only advance fundamental knowledge of host–virus interactions. However, it may also facilitate the development of innovative therapeutic strategies to control viral persistence, reverse latency, or prevent retrovirus-associated disease progression.

Author contributions

All authors contributed to the conception of the study, and MMA and HRA designed it. MMA, ZF, and HRA performed data collection and analysis. MMA and ZF wrote the initial draft of the manuscript, and all authors provided comments on subsequent versions. MMA and HRA edited the final draft. All authors read and approved the final manuscript.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Consent for publication

Not Applicable.

Competing interests

The authors declare no competing interests.

Ethical Approval and Consent to Participate

This is an observational study. The UNAM Research Ethics Committee has confirmed that no ethical approval is required for this research.

Conflict of interest

Mohammad Mehdi Akbarin, Zahra Farjami, and Hugo Ramírez Álvarez declare that they have no conflict of interest.