Stress granules at the crossroads of retroviral replication and antiviral immunity: mechanisms and therapeutic opportunities

Abstract

Stress granules (SGs) are dynamic cytoplasmic ribonucleoprotein aggregates that form in response to cellular stress and function as key regulators of mRNA translation, stability, and antiviral defense. Increasing evidence demonstrates that retroviruses, including HIV-1, HTLV-1, and other oncogenic retroviruses, interact extensively with stress granule pathways to promote viral replication, persistence, and immune evasion. This review summarizes current knowledge of the molecular mechanisms governing stress granule assembly and highlights how retroviruses manipulate SG components, such as G3BP1, TIA-1, TIAR, and eIF2α signaling, to control host translational arrest and innate immune responses. In HIV-1 infection, viral proteins, including Gag, Tat, and Vpr, interfere with SG formation to support viral RNA translation and replication. Similarly, HTLV-1 modulates stress-response pathways to favor viral persistence and transformation. We also discuss the dual role of stress granules as both antiviral platforms and viral replication facilitators, depending on the stage of infection and cellular context. Importantly, emerging data suggest that dysregulated stress granule dynamics may contribute to chronic inflammation, neurodegeneration, and virus-associated malignancies. Understanding the interplay between retroviruses and stress granule biology provides insight into host–virus coevolution and identifies potential therapeutic targets to restore antiviral stress responses. Targeting SG-associated pathways may represent a novel strategy to limit retroviral replication and virus-induced pathogenesis.

Introduction

Retroviruses establish persistent infections by integrating their genomes into host chromatin and exploiting cellular transcriptional and post-transcriptional regulatory pathways to ensure viral gene expression [1]. This obligate reliance on host RNA metabolism places viral replication at the intersection of mRNA synthesis, processing, transport, translation, and decay [1]. Consequently, host mechanisms that govern mRNA fate represent both critical vulnerabilities and regulatory checkpoints during retroviral infection. Among human retroviruses, human immunodeficiency virus (HIV) and human T-cell lymphotropic viruses (HTLVs) exemplify distinct yet convergent strategies of host exploitation, shaped by their evolutionary divergence and pathogenic profiles [2].

HTLVs are members of the genus Deltaretrovirus and are characterized by clonal expansion of infected cells, low levels of viral gene expression, and long-term persistence in the host [2, 3]. Their pathogenicity arises primarily from chronic dysregulation of cellular signaling and transcriptional programs rather than from direct cytopathic effects [2]. In contrast, HIV, a member of the genus Lentivirus, displays high replication rates, extensive genetic variability, and progressive immune dysfunction [4]. Despite these differences, both viruses require precise control over viral and host mRNA expression to balance productive replication, immune evasion, and persistence. Viral regulatory proteins, together with host RNA-binding factors, collectively shape the post-transcriptional environment that governs viral gene expression [4].

Post-transcriptional regulation of mRNA is a dynamic and highly coordinated process that allows cells to rapidly adapt protein synthesis in response to environmental and physiological stress [5]. Central to this regulation is the reversible partitioning of mRNAs between translationally active polysomes and cytoplasmic ribonucleoprotein complexes [5]. These processes are mediated by RNA-binding proteins that sense changes in cellular signaling, stress responses, and metabolic states, thereby integrating external cues into global and transcript-specific translational outcomes [6]. Viruses must therefore interface with, and frequently subvert, these regulatory networks to ensure efficient expression of their genomes.

Stress granules are cytoplasmic, non-membranous ribonucleoprotein assemblies that form when translation initiation is inhibited, leading to the accumulation of stalled pre-initiation complexes [7]. They are composed of untranslated mRNAs, translation initiation factors, and RNA-binding proteins involved in mRNA silencing and triage [8]. Stress granules function as dynamic regulators of mRNA fate, influencing transcript stability, translational repression, and re-entry into active translation [8]. In addition to their role in cellular stress adaptation, stress granules are increasingly recognized as platforms that intersect with innate immune signaling and RNA surveillance pathways, positioning them as key modulators of host defense [8].

The involvement of stress granules in viral infection has emerged as a general principle of virus–host interaction [9]. Across diverse viral families, stress granules can act as antiviral structures by sequestering viral RNAs or limiting access to the translational machinery, while viruses have evolved countermeasures to inhibit granule assembly, redirect granule components, or functionally repurpose these structures [9, 10]. However, how stress granule–mediated mRNA regulation influences chronic retroviral infections, particularly those characterized by long-term persistence and immune modulation, remains poorly defined at the molecular level [9, 10].

Despite substantial advances in understanding HIV and HTLV biology, the integration of stress granule dynamics into models of retroviral mRNA regulation remains incomplete. Comparative analyses of how lentiviruses and deltaretroviruses engage host RNA granule pathways are limited, and the consequences of these interactions for viral persistence, latency, and pathogenesis remain poorly understood. The aim of this study is to provide a molecular framework for understanding stress granule function in the context of HIV and HTLV infection, highlighting shared and divergent regulatory principles and identifying key gaps that warrant further investigation.

General properties of stress granules

Stress granules (SGs) are dynamic cytoplasmic ribonucleoprotein (RNP) condensates that assemble in response to diverse cellular stresses that impair translation initiation and disrupt proteostasis [7]. They represent archetypal examples of biomolecular condensates formed through liquid–liquid phase separation (LLPS), a biophysical process driven by multivalent, low-affinity interactions among untranslated messenger RNAs (mRNAs), RNA-binding proteins (RBPs), and translation factors [11]. Unlike membrane-bound organelles, SGs lack delimiting lipid bilayers and instead exhibit liquid-like properties characterized by rapid internal molecular exchange, fusion events, spherical morphology, and reversibility in response to changes in cellular conditions [7]. Their formation reflects a coordinated and highly regulated reprogramming of mRNA metabolism that transiently suppresses bulk protein synthesis while preserving cellular viability under stress.

Molecular triggers of stress granule assembly

At the core of SG biogenesis is inhibition of translation initiation. The most extensively characterized pathway involves phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α) at Ser51 by stress-responsive kinases, including protein kinase R (PKR), PKR-like endoplasmic reticulum kinase (PERK), general control non-derepressible 2 (GCN2), and heme-regulated inhibitor kinase (HRI) [12] (Fig. 1). Phosphorylated eIF2α acts as a competitive inhibitor of its guanine nucleotide exchange factor eIF2B, thereby reducing regeneration of eIF2-GTP and limiting formation of the ternary complex (eIF2-GTP–Met-tRNAi^Met) required for start codon recognition. This depletion leads to stalled translation initiation, ribosome runoff from polysomes, and accumulation of untranslated 48 S pre-initiation complexes [13].

Fig. 1.

Mechanisms of cap-dependent translation initiation through eIF2-dependent and eIF2α-independent pathways. (A) eIF2-dependent pathway. Under normal conditions, the heterotrimeric eukaryotic initiation factor 2 (eIF2), composed of α (alpha), β (beta), and γ (gamma) subunits, binds guanosine triphosphate (GTP) to form the active eIF2–GTP complex. This complex associates with the initiator methionyl–transfer RNA (Met-tRNAi^Met) to generate the ternary complex, which delivers Met-tRNAi^Met to the 40 S small ribosomal subunit (represented here as 48 S pre-initiation complex after mRNA recruitment). Recruitment of messenger RNA (mRNA) to the ribosome requires the eIF4F cap-binding complex, consisting of eukaryotic initiation factor 4E (eIF4E; cap-binding protein), eukaryotic initiation factor 4G (eIF4G; scaffolding protein), and eukaryotic initiation factor 4 A (eIF4A; ATP-dependent RNA helicase). The 5′-methylguanosine cap structure (CAP) at the 5′ end of mRNA is recognized by eIF4E, while eIF4G bridges interactions with other initiation factors and the ribosome. The 48 S pre-initiation complex scans the mRNA from the 5′ to 3′ direction to identify the start codon.During cellular stress, specific kinases including Protein Kinase R (PKR; double-stranded RNA-activated protein kinase), General Control Nonderepressible 2 (GCN2; eukaryotic translation initiation factor 2 alpha kinase 4, EIF2AK4), Heme-Regulated Inhibitor kinase (HRI; eukaryotic translation initiation factor 2 alpha kinase 1, EIF2AK1), and PKR-like Endoplasmic Reticulum Kinase (PERK; eukaryotic translation initiation factor 2 alpha kinase 3, EIF2AK3) phosphorylate the α subunit of eIF2 at serine 51 (Ser51). Phosphorylated eIF2α (eIF2α-P) inhibits guanine nucleotide exchange on eIF2, thereby preventing regeneration of eIF2–GTP and blocking ternary complex formation. As a result, global cap-dependent translation initiation is suppressed. (B) eIF2α-independent pathway. Under conditions where eIF2α is phosphorylated and canonical ternary complex formation is inhibited, alternative translation initiation mechanisms can operate. In this pathway, mRNA recruitment still involves the eIF4F complex (eIF4E, eIF4G, and eIF4A) binding to the 5′ cap structure. However, initiation occurs independently of functional eIF2α, allowing assembly of the 48 S pre-initiation complex through alternative factor usage. Eukaryotic initiation factor 3 (eIF3), a multi-subunit complex, facilitates ribosomal recruitment and assembly. This alternative pathway enables selective translation of specific mRNAs during stress conditions when global protein synthesis is attenuated. eIF2, eukaryotic initiation factor 2; eIF2α, alpha subunit of eukaryotic initiation factor 2; eIF2α-P, phosphorylated eukaryotic initiation factor 2 alpha; eIF4E, eukaryotic initiation factor 4E; eIF4G, eukaryotic initiation factor 4G; eIF4A, eukaryotic initiation factor 4 A; eIF3, eukaryotic initiation factor 3; PKR, Protein Kinase R; GCN2, General Control Nonderepressible 2; HRI, Heme-Regulated Inhibitor kinase; PERK, PKR-like Endoplasmic Reticulum Kinase; GTP, guanosine triphosphate; CAP, 7-methylguanosine cap; mRNA, messenger RNA; Met-tRNAi^Met, initiator methionyl transfer RNA; Ser51, serine residue at position 51

These stalled 48 S complexes, composed of small ribosomal subunits, mRNA, and initiation factors such as eIF3 and eIF4G, accumulate in the cytoplasm and serve as nucleation substrates for SG assembly. Importantly, untranslated mRNAs are not passive cargo; rather, they function as multivalent scaffolds that promote intermolecular RNP interactions and phase separation. SG assembly can also occur independently of eIF2α phosphorylation by disrupting the eIF4F cap-binding complex [13]. In this alternative pathway, inhibition of eIF4A helicase activity, sequestration of eIF4E, or interference with eIF4G–eIF3 interactions prevents recruitment of capped mRNAs to ribosomes (Fig. 1). This results in the accumulation of non-translating mRNPs capable of undergoing phase separation. Thus, SG formation can be triggered by either ternary complex depletion or impaired cap-dependent initiation, converging mechanistically on the buildup of untranslated mRNA–protein complexes.

Phase separation and structural organization

The nucleation and maturation of SGs are governed by RBPs containing intrinsically disordered regions (IDRs) and low-complexity domains (LCDs), which enable weak, transient, multivalent interactions essential for LLPS [14]. These IDRs often contain prion-like domains enriched in glycine, glutamine, asparagine, tyrosine, and serine residues, facilitating π–π interactions, electrostatic contacts, and reversible crosslinking [14]. RNA itself further enhances phase separation by providing a multivalent binding platform that increases the local concentration of RBPs. Core SG nucleators bind RNA and self-associate to establish a dense interaction network that recruits additional factors, including translation initiation components (eIF3, eIF4E, eIF4G), RNA helicases, poly(A)-binding protein (PABP), and signaling intermediates [11, 15].

As assembly proceeds, SGs undergo structural maturation characterized by internal compartmentalization. High-resolution imaging and biochemical analyses reveal a biphasic architecture consisting of a relatively stable, less dynamic core surrounded by a more fluid and rapidly exchanging shell [11, 16]. The core likely forms through higher-order crosslinking and slower molecular exchange, whereas the shell maintains liquid-like properties that permit dynamic recruitment and release of components. This hierarchical organization allows SGs to function both as sequestration sites and as platforms for signaling integration.

mRNA Triage and Post-Transcriptional Regulation

Functionally, SGs serve as hubs of post-transcriptional regulation by transiently withdrawing mRNAs from active translation. This sequestration is not equivalent to indiscriminate storage but rather a selective, regulated triage process that determines transcript fate [11]. Specific mRNAs are differentially recruited into SGs based on sequence features, length, translation efficiency, and associated RBPs. Once localized to SGs, transcripts may follow one of several trajectories: (i) re-entry into polysomes upon stress resolution, (ii) stabilization during prolonged stress, or (iii) transfer to processing bodies (P-bodies) for degradation.

The functional coupling between SGs and P-bodies underscores their coordinated role in mRNA quality control. While SGs are enriched stalling translation initiation complexes, P-bodies contain decapping enzymes (DCP1/2), exonucleases (XRN1), and components of the microRNA machinery. Physical interactions between SGs and P-bodies facilitate exchange of mRNPs, allowing dynamic redistribution between translation repression and decay pathways [11, 15]. In this manner, SGs act as decision-making centers that integrate stress signaling with mRNA triage, ensuring preferential preservation of transcripts encoding stress-response proteins while repressing energetically costly housekeeping translation.

Integration with stress signaling pathways

Beyond RNA metabolism, SGs intersect extensively with cellular signaling networks. They interact with pathways governing innate immunity, apoptosis, redox balance, and proteostasis [17, 18]. By spatially concentrating or excluding signaling molecules, SGs modulate kinase cascades and stress adaptation. For example, SGs can sequester pro-apoptotic factors under transient stress, thereby delaying commitment to cell death while repair mechanisms are engaged. Conversely, persistent stress may alter SG composition, facilitating activation of apoptotic pathways.

SGs also influence proteostasis by limiting the synthesis of misfolded proteins during oxidative or ER stress, thereby reducing proteotoxic burden [19]. Their interaction with molecular chaperones and ubiquitin–proteasome components further links translational control with protein quality control systems. In innate immunity, SGs have been shown to concentrate viral RNAs and pattern-recognition receptors, positioning them as potential antiviral signaling hubs [17]. These multifaceted interactions position SGs as adaptive organelles that coordinate translational repression with broader cellular defense programs.

Stress granule disassembly and homeostatic restoration

Stress granule dissolution is an active, ATP-dependent process that occurs upon restoration of translational competence. Reactivation of eIF2B and dephosphorylation of eIF2α permit reassembly of ternary complexes and re-engagement of mRNAs with ribosomes [20, 21]. Concurrently, RNA helicases and ATP-dependent remodeling enzymes resolve protein–RNA and protein–protein interactions within SGs [22, 23]. Molecular chaperones facilitate refolding or release of aggregated proteins, preventing irreversible solidification of condensates. They are formed following inhibition of translation initiation, most commonly through phosphorylation of eukaryotic initiation factor 2α (eIF2α), leading to accumulation of stalled pre-initiation complexes. SGs contain untranslated mRNAs, translation initiation factors (eIF3, eIF4E, eIF4G), the poly(A)-binding protein (PABP), and RNA-binding proteins such as TIA-1 and G3BP1 [21].

Failure to properly disassemble SGs can result in aberrant transition from liquid-like droplets to more stable, less dynamic assemblies. Such transitions are associated with pathological aggregation in neurodegenerative and stress-related disorders [11, 24]. Therefore, precise temporal regulation of SG assembly and disassembly is essential to maintain cellular homeostasis. Collectively, the molecular architecture, dynamic assembly mechanisms, and regulatory functions of stress granules underscore their central role as reversible modulators of RNA metabolism, signaling integration, and cellular adaptation to stress.

Stress granules and rna quality control pathways in HTLV-1 infection

Beyond their canonical role in transiently repressing translation during stress, SGs serve as hubs for antiviral signaling and RNA triage, interacting functionally with processing bodies (P-bodies) and RNA surveillance pathways [25]. Increasing evidence indicates that many viruses actively antagonize SG assembly to preserve viral protein synthesis and evade host antiviral responses. Human T-cell leukemia virus type 1 (HTLV-1) represents a clear example of this strategy.

The first direct evidence that HTLV-1 interferes with stress granule formation was provided by Legros et al. (2009) [26]. In this study, the authors demonstrated that the viral oncoprotein Tax inhibits SG assembly by interacting with histone deacetylase 6 (HDAC6), a cytoplasmic deacetylase essential for SG formation [26]. HDAC6 regulates microtubule dynamics and facilitates the transport of ubiquitinated proteins to aggresomes, processes that are mechanistically linked to SG nucleation [26] (Fig. 2). Under oxidative stress conditions (e.g., sodium arsenite treatment), control cells formed canonical SGs containing TIA-1, G3BP, eIF3, and PABP [26]. In contrast, Tax-expressing cells exhibited a marked impairment in SG formation. The study showed that Tax directly associates with HDAC6 and that HDAC6 knockdown phenocopied the inhibitory effect of Tax on SG assembly. These findings established that HTLV-1 actively suppresses SG formation rather than passively avoiding it [26].

Fig. 2.

Mechanisms by Which HTLV-1 Tax Modulates Stress Granule Assembly in T Cells

This mechanistic model was further refined by Legros et al. (2011), who confirmed and expanded on the functional interaction between Tax and HDAC6 [27]. The authors demonstrated that Tax not only binds HDAC6 but also inhibits its deacetylase activity, thereby disrupting HDAC6-dependent SG assembly [27]. Tax expression prevented the recruitment of core SG nucleators, including G3BP1 and TIA-1, and altered microtubule acetylation dynamics [27]. Importantly, the study identified specific Tax domains required for SG inhibition and showed that disruption of SG formation correlated with enhanced viral gene expression and increased NF-κB activation [27]. These findings suggest that SG suppression contributes directly to HTLV-1–driven cellular transformation by sustaining translation and promoting oncogenic signaling pathways. Collectively, the studies by Legros et al. (2009; 2011) establish that Tax-mediated inhibition of HDAC6-dependent SG formation is a central strategy employed by HTLV-1 to counteract host translational control mechanisms.

Beyond direct SG inhibition, HTLV-1 also modulates RNA surveillance pathways that functionally intersect with stress granule biology. Mocquet et al. (2012) demonstrated that Tax inhibits nonsense-mediated mRNA decay (NMD), a critical RNA quality control pathway that eliminates aberrant transcripts [28] (Fig. 2). Tax was shown to interact with INT6/EIF3E, a component of the eIF3 translation initiation complex, and with UPF1, the central effector of NMD [28]. Tax expression impaired UPF1 phosphorylation and disrupted normal NMD activity, resulting in the stabilization of transcripts that would otherwise be degraded [28]. Although the study did not directly examine stress granules, NMD components, including UPF1, dynamically shuttle between translating ribosomes, stress granules, and processing bodies [28]. Thus, inhibition of NMD by Tax likely alters the equilibrium between cytoplasmic RNA granules, further reshaping post-transcriptional regulation in infected cells. By simultaneously blocking SG formation and suppressing NMD, HTLV-1 preserves and efficiently translates viral RNAs while globally reprogramming host RNA metabolism.

Additional evidence linking HTLV-1 to stress-associated RNA regulatory networks comes from the work of Takahashi et al. (2013), who investigated the interaction between Tax and ubiquitin-specific protease 10 (USP10) [29] (Fig. 2). USP10 is a deubiquitinating enzyme implicated in oxidative stress responses and is known to localize to stress granules under certain stress conditions. The authors demonstrated that Tax interacts with USP10, leading to increased reactive oxygen species (ROS) production and enhanced apoptosis in T cells [29]. Silencing USP10 reduced ROS accumulation and apoptosis in the presence of Tax, indicating a functional interaction. Although stress granule formation was not directly analyzed in this study, USP10 is recognized as a stress granule-associated factor that regulates p53 stability and stress responses [29]. Therefore, Tax-mediated sequestration or modulation of USP10 may represent an additional layer of interference with stress granule–related pathways and redox homeostasis, contributing to genomic instability and leukemogenic progression.

Taken together, the available evidence indicates that stress granules constitute an important host defense mechanism targeted by HTLV-1. The viral Tax protein plays a central role in this process by interacting with HDAC6 to prevent SG assembly [26, 27], inhibiting nonsense-mediated decay through interactions with INT6/EIF3E and UPF1 [28], and modulating stress-associated factors such as USP10 [29]. These coordinated actions collectively suppress translational repression, preserve viral mRNA stability, alter RNA quality control, and enhance oncogenic signaling. Thus, interference with stress granule dynamics represents a deliberate and multifaceted strategy by which HTLV-1 promotes viral persistence and contributes to leukemogenesis.

Schematic representation of the molecular interactions between HTLV-1 and host stress granule (SG) machinery in the cytoplasm of infected T cells. The viral transactivator protein Tax interferes with stress granule formation through multiple mechanisms. Tax interacts with stress granule nucleating proteins such as TIA-1 and G3BP1, impairing their ability to promote SG assembly. Additionally, Tax associates with HDAC6, a histone deacetylase involved in cytoplasmic stress responses, thereby modulating stress granule dynamics. Tax also enhances the activity of the deubiquitinating enzyme USP10, which negatively regulates stress granule formation. These interactions collectively suppress canonical SG assembly.In parallel, Tax promotes activation of the NF-κB signaling pathway by stimulating phosphorylation and degradation of IκB, leading to nuclear translocation of NF-κB subunits (p50 and p65), thereby enhancing viral transcription and persistence. The combined inhibition of stress granule formation and activation of pro-survival signaling pathways facilitates efficient viral replication, immune evasion, and HTLV-1–associated pathogenesis. HTLV-1 refers to Human T-cell leukemia virus type 1. Tax denotes the HTLV-1 transactivator protein. SG indicates stress granule. TIA-1 stands for T-cell intracellular antigen-1. G3BP1 refers to Ras GTPase-activating protein SH3 domain-binding protein 1. HDAC6 denotes histone deacetylase 6. USP10 represents ubiquitin-specific protease 10. NF-κB refers to nuclear factor kappa-light-chain-enhancer of activated B cells. IκB indicates inhibitor of kappa B. p50 corresponds to nuclear factor kappa B subunit 1, and p65 (RelA) refers to v-Rel avian reticuloendotheliosis viral oncogene homolog A.

HIV, RNA granules, and cellular stress

HIV-Induced cellular stress as a driver of stress granule formation

HIV infection induces profound cellular stress responses that create a permissive environment for stress granule (SG) assembly. Early mechanistic work demonstrated that HIV-1 Tat triggers neuronal apoptosis through oxidative stress, calcium dysregulation, and caspase activation pathways, processes that converge on eIF2α phosphorylation and translational arrest [30]. Importantly, because mature neurons are not productively infected by HIV-1, these neurotoxic effects are thought to occur largely through indirect mechanisms [30]. Tat is released from infected macrophages and microglia and can be taken up by neurons via receptor-mediated endocytosis or other uptake pathways. In addition, Tat can alter the local neuroinflammatory microenvironment by stimulating glial cells to produce pro-inflammatory cytokines, excitotoxic mediators, and reactive oxygen species, which further contribute to neuronal dysfunction [30]. Subsequent in vivo studies reinforced these findings, showing that viral proteins such as gp120 and Tat contribute to hippocampal injury and neurobehavioral alterations [31]. Neuropathological analyses further revealed amyloid-β accumulation in HIV-infected brains, suggesting chronic proteotoxic stress and impaired protein homeostasis [32].

Additional studies demonstrated that Tat disrupts microtubule dynamics under oxidative conditions [33], while mitochondrial dysfunction has been implicated as a central mechanism in HIV-associated neurodegeneration [34]. Antiretroviral therapy itself may exacerbate cellular stress, as protease inhibitors increase neuronal susceptibility to oxidative injury [35]. Mechanistically, apoptosis-inducing factor has been linked to the regulation of cytoplasmic stress granules, further connecting stress signaling with RNA granule dynamics [36]. Collectively, these findings establish that both HIV proteins and therapeutic agents generate cellular stress conditions that favor SG assembly.

APOBEC3 Proteins, Vif Antagonism, and RNA Granule Localization

APOBEC3 proteins represent a central axis linking innate antiviral restriction to RNA granule biology. APOBEC3G was shown to associate with HIV RNA and localize to cytoplasmic RNA granules, suggesting functional integration with stress-responsive RNP complexes [37]. Structured ribonucleoprotein assembly of APOBEC3F and APOBEC3G further supported this model [38], while cytoplasmic retention mechanisms regulating APOBEC3G localization were characterized [39]. Dynamic trafficking of Vif and APOBEC3 proteins between mRNA metabolic compartments highlighted the spatial complexity of this interaction [40], and host cofactors such as Pin1 were shown to regulate APOBEC3G activity [41].

Detailed molecular studies demonstrated that Vif antagonizes APOBEC3 proteins through mechanisms extending beyond proteasomal degradation [42–44]. Spatial targeting within cytoplasmic compartments was shown to be essential for APOBEC-mediated restriction [45], and broader conceptual integration was provided in subsequent syntheses [46]. The importance of specific Vif motifs in regulating APOBEC antagonism was later defined [47], and screening platforms were developed to dissect APOBEC3G–Vif interactions [48].

Importantly, antiviral restriction by APOBEC3G is not exclusively dependent on cytidine deaminase activity. Deaminase-independent restriction mechanisms were demonstrated [49], and RNA binding was shown to regulate enzymatic and antiviral functions [50, 51]. Specific RNA-binding residues influencing restriction potency were identified [52], and integration with microRNA machinery via Argonaute-2 and MOV10 further linked APOBEC3G to RNA granule pathways [53]. More recently, translational control of APOBEC3G was shown to involve a conserved upstream open reading frame, which HIV-1 Vif exploits to repress antiviral protein production [54]. Together, these studies position APOBEC3 proteins at the crossroads of translational regulation, RNA granule localization, and viral antagonism.

Staufen proteins and proviral remodeling of stress granules

Staufen family RNA-binding proteins have emerged as key modulators of viral RNA fate and stress granule dynamics. Staufen1 was shown to prevent stress granule assembly while simultaneously promoting HIV RNA encapsidation [55]. Direct interactions between Gag and Staufen1 were visualized, providing structural insight into this proviral function [56]. Subsequent work demonstrated that HIV replication requires Staufen1-mediated disassembly of stress granules for efficient particle production [57].

The proviral role of Staufen proteins was further supported by studies showing enhanced viral production and infectivity in their presence [58, 59]. Beyond canonical translation, Staufen1 was identified as an IRES-transacting factor regulating cap-independent HIV-1 translation, particularly under stress conditions [60]. In retroelement biology, Staufen proteins were shown to enhance nuclear export of HERV-K and HIV RNAs, indicating broader roles across retroelements [61, 62]. These findings underscore the importance of Staufen-mediated remodeling of RNA granules in sustaining viral replication.

Processing bodies, MOV10, and RNA decay pathways

Processing bodies (P-bodies) function as sites of mRNA decay and translational repression, yet HIV interacts with these compartments in multifaceted ways. MOV10 was shown to restrict HIV and other retroviruses [63–65], and determinants governing MOV10 incorporation into viral particles were subsequently defined [66]. Interestingly, P-body localization was shown not to be strictly required for MOV10 antiviral activity, indicating functional flexibility [67]. HIV Gag was found to co-opt DDX6, a core P-body helicase, to facilitate capsid assembly [68], and DDX6 was further shown to be required for retroviral genome encapsidation [69]. Interactions between HIV and mRNA decay machinery were characterized in detail [70]. Beyond HIV, P-bodies were shown to restrict retrotransposition [71, 72], and ZAP-mediated suppression of retroelements provided additional insight into antiviral RNA surveillance within these compartments [73, 74].

Translational control, stress granule modulation, and RNA condensates in HIV infection

A growing body of evidence indicates that HIV replication is closely linked to host pathways controlling RNA metabolism, translational regulation, and cytoplasmic RNA granule dynamics. These processes involve RNA helicases, RNA-binding proteins, and epitranscriptomic modifications that collectively influence viral RNA stability, localization, and translation.

Among the host factors implicated in these processes, DEAD-box helicases play a central role in coordinating viral gene expression with host stress responses. In particular, the RNA helicase DDX3 functions as an important regulator of HIV replication by integrating transcriptional and translational control mechanisms. DDX3 facilitates Tat-mediated transcriptional activation and can promote viral translation by functionally substituting for the canonical cap-binding factor eIF4E under certain conditions [75–77]. In addition to these proviral activities, DDX3 has also been described as a component of innate antiviral signaling pathways, highlighting its dual role as both an antiviral sensor and a host factor that supports viral gene expression [23, 78]. Further connections between helicase activity and stress signaling have been demonstrated through the coordinated trafficking of HIV RNA with APOBEC3F and the stress-responsive kinase PKR, linking RNA helicase function to eIF2α-mediated translational arrest and RNA granule dynamics [79].

Because active viral protein synthesis is required for productive infection, HIV must also counteract cellular stress responses that would otherwise inhibit translation through stress granule (SG) formation. Several studies have demonstrated that HIV actively suppresses or remodels SG assembly to maintain viral RNA translation. For example, the RNA-binding protein Sam68 relocalizes to stress granules under oxidative stress conditions [80], and mutant forms of Sam68 can promote SG assembly while simultaneously repressing translation of the viral Nef mRNA through sequestration mechanisms [80]. Additional work has shown that HIV-2 RNA accumulates within stress granules during translational inhibition [81], highlighting the close relationship between viral RNA fate and SG dynamics.

Host translational regulators such as eEF2, together with the stress granule nucleating protein G3BP1, further influence granule assembly and RNA metabolism during infection [82]. Importantly, HIV-1 has evolved mechanisms to actively antagonize SG formation: the viral Gag protein can block selenite-induced stress granule assembly by modifying cap-binding complexes and activating mTORC1-dependent signaling pathways, thereby maintaining conditions favorable for viral protein synthesis [83, 84]. These findings collectively demonstrate that suppression or remodeling of stress granule formation is an important strategy by which HIV preserves efficient viral translation.

In addition to protein-mediated regulation, epitranscriptomic modifications of RNA provide another layer of control over viral RNA fate. For example, cytosine methylation mediated by DNMT2 has been shown to enhance the stability of HIV RNA, suggesting that RNA modification can directly influence viral gene expression [85]. More broadly, recent studies have highlighted the potential roles of diverse non-m⁶A RNA modifications in shaping antiviral innate immune responses and viral RNA recognition pathways [86]. Post-translational modification pathways may also intersect with RNA surveillance mechanisms. For instance, poly(ADP-ribose) modification has been shown to enhance the antiviral activity of the zinc-finger antiviral protein (ZAP), linking ADP-ribosylation to the regulation of RNA stability and antiviral restriction [87].

Beyond biochemical regulation, recent studies have emphasized the importance of biophysical organization of viral RNA within cytoplasmic condensates. Retroviral nucleocapsid proteins can undergo liquid–liquid phase separation, forming dynamic condensates that facilitate the spatial organization of viral genomic RNA within the cytoplasm [88, 89]. These RNA–protein condensates are thought to contribute to viral genome packaging and the coordination of RNA-protein interactions required for virion assembly. Consistent with this view, analyses of viral RNA structural elements have shown that RNA architecture can influence the recruitment of host RNA-binding proteins, further supporting a role for RNA structure in directing the formation of functional ribonucleoprotein condensates during infection [90].

Taken together, these findings highlight the complex interplay between HIV replication and host pathways governing RNA helicase activity, stress granule dynamics, RNA modification, and phase-separated RNA condensates. By manipulating these interconnected processes, HIV is able to balance host antiviral defenses with the maintenance of efficient viral RNA translation and genome packaging.

Innate immune integration and neuropathological implications

Innate immune restriction factors intersect directly with RNA granule dynamics. Shiftless was shown to restrict viral gene expression and modulate RNA granule formation [91], and its broader role in innate immunity was subsequently reviewed [91]. Viral strategies to antagonize host antiviral immunity frequently converge on RNA regulatory pathways [92]. APOBEC3G-mediated restriction extends beyond retroviruses to diverse RNA viruses [93], and viral microRNA interactions further illustrate the complexity of post-transcriptional regulation [94].

Persistent dysregulation of RNA granules may contribute to neuropathology. HIV transgenic models exhibit impaired neurogenesis [95], and viral infection has been linked to FUS-associated neurodegeneration [96]. Pharmacological modulation of stress granules may hold therapeutic potential, as quercetin promotes disassembly of insoluble stress granules in gp120-induced astrocyte toxicity [97]. Antiretroviral drugs themselves can activate PERK-dependent integrated stress responses and trigger stress granule formation in oligodendrocytes [98, 99], highlighting the complex interplay between viral infection, therapy, and RNA condensate biology.

Overall, these studies collectively demonstrate that RNA granules are not merely stress byproducts but central regulatory platforms governing viral replication, innate immunity, and neuropathology (Table 1). HIV actively remodels, suppresses, or co-opts these dynamic condensates to sustain replication while host cells deploy RNA-binding restriction factors to counteract infection. Understanding this bidirectional regulation of RNA granule biology provides critical mechanistic insight into retroviral pathogenesis.

Table 1.

Comprehensive Summary of HIV, RNA Granules, and Stress Granule-Related Studies

Study (First Author, Year)	Model/System	Granule or Pathway Type	Key Findings	Relevance to HIV/SG Biology
Kruman, 1998 #193	HIV-1 Tat in hippocampal neurons	Oxidative stress; eIF2α-linked stress pathways	Tat induces apoptosis via caspase activation, Ca2 + overload, oxidative stress	Indirect trigger of SG assembly through stress kinase activation
Fitting, 2008 #173	gp120/Tat in neonatal hippocampus	Neurotoxic stress pathways	Behavioral deficits and hippocampal alterations	Supports chronic stress environment conducive to SG formation
Achim, 2009 #168	HIV patient brain tissue	Proteotoxic stress	Increased intraneuronal amyloid-β accumulation	Links proteotoxic stress to persistent RNP aggregation
Kozak, 2006 #187	Cell culture; APOBEC3G	Stress granules; polysome shuttling	A3G binds HIV RNA and localizes to cytoplasmic RNA granules	Direct link between innate restriction and SG compartments
Gallois-Montbrun, 2008 #175	Cell culture; APOBEC3F/G	RNP complexes	Distinct RNP complexes for APOBEC3F and A3G	Structured antiviral RNP assemblies
Bennett, 2008 #177	Cell culture	Cytoplasmic retention signals	A3G nuclear exclusion independent of RNA binding	Regulated trafficking to RNA granules
Marin, 2008 #178	Cell culture	mRNA metabolic sites; PB/SG trafficking	Vif and APOBEC3 traffic between RNA metabolic sites	HIV modulates granule-associated restriction
Watashi, 2008 #172	Cell culture	Pin1-mediated regulation	Pin1 regulates A3G during replication	Post-translational control of RNP incorporation
Kao, 2007 #179	Cell culture	Vif-mediated degradation pathways	Infectivity and A3G degradation are separable	Multiple Vif antagonism mechanisms
Mehle, 2007 #180	Cell culture	Vif–A3G binding interface	Identified binding sites and inhibitors	Structural basis of antiviral neutralization
Opi, 2007 #184	Cell culture	Vif antagonism	Vif blocks packaging of degradation-resistant A3G	Neutralization beyond proteasomal degradation
Goila-Gaur, 2007 #183	Cell culture	Viral nucleoprotein targeting	Targeting A3A to nucleoprotein complex enhances restriction	Spatial localization critical for antiviral function
Huang, 2007 #181	Cell culture	miRNA repression pathways	A3G derepresses miRNA-mediated inhibition	Integration with RNA silencing machinery
Chable-Bessia, 2009 #169	Cell culture	miRNA effectors	miRNAs suppress HIV replication	RNA silencing intersects with SG/PB biology
Lemay, 2008 #174	Cell culture	HuR-mediated RNP remodeling	HuR interacts with reverse transcriptase	Stress-responsive RNP influence on replication
Candé, 2004 #188	Cell biology	Stress granules; apoptosis signaling	AIF regulates cytoplasmic SG assembly	Mitochondrial-apoptotic link to SG condensation
Kelly, 2004 #189	Human intestine	Secretory granules (Paneth)	Paneth cell granule depletion	Not SG-related
Sugiura, 2007 #186	Keratinocytes	Keratohyalin granules	LEDGF/DFS70 component of keratohyalin granules	Not SG-related
McClure, 2007 #185	Macrophages	GM-CSF replication effects	GM-CSF upregulates HIV replication	Granulocyte term unrelated to RNP granules
Henao-Mejia, 2009 #167	Cell culture	Stress granules (Sam68/TIA-1)	Sam68 relocalizes into SG under oxidative stress	Links HIV-associated stress to SG dynamics
Henao-Mejia, 2009 #171	Cell culture	Stress granules; mRNA sequestration	Sam68 mutant induces SG and suppresses Nef translation	Direct SG-mediated repression of HIV protein
Pery, 2009 #170	Cell culture	Vif YXXL motif regulation	YXXL motif regulates APOBEC antagonism	Fine-tuning of cytoplasmic restriction pathways
Abrahamyan, 2010 #165	Cell culture	Staufen1 RNP complexes; SG suppression	Staufen1 prevents SG assembly and promotes RNA packaging	HIV suppresses SG to preserve translation
Milev, 2010 #161	Live-cell imaging	Gag–Staufen1 RNP complexes	Visualization of Gag–Staufen1 interactions	Dynamic viral RNA trafficking
Burdick, 2010 #160	Cell culture	Processing bodies; MOV10	MOV10 inhibits HIV replication	PB-associated antiviral helicase
Furtak, 2010 #164	Cell culture	MOV10 function	MOV10 perturbation reduces infectivity	Confirms antiviral PB component
Wang, 2010 #162	Retrovirus models	MOV10 restriction	MOV10 inhibits MLV replication	Broad retroviral PB-linked restriction
Abudu, 2012 #150	Cell culture	MOV10 determinants	Defined packaging determinants for anti-HIV activity	Helicase incorporation into virions
Martin, 2011 #154	Cell culture	APOBEC3G RNP complexes	A3G reduces HIV production independent of deaminase	Non-catalytic granule-based restriction
McDougall, 2011 #153	Biochemical assays	RNA-binding regulation	RNA binding inhibits A3G deaminase activity	Granule-associated modulation
Liu, 2012 #147	Cell culture	Argonaute-2/MOV10 complexes	A3G disrupts miRNA repression machinery	Integration with RNA granule networks
Dutko, 2010 #163	Yeast retrotransposon	mRNA decay factors	Decay factors colocalize with Ty1 Gag and A3G	RNA decay intersects retroelement control
Lu, 2011 #155	Retrotransposon model	Processing bodies	PBs inhibit retrotransposition	Granules as surveillance hubs
Yu, 2011 #152	Retroviral model	DDX6 helicase; PB	DDX6 required for genome encapsidation	Granule helicase required for assembly
Butler, 2011 #157	Neuronal model	Oxidative stress; cytoskeleton	Tat inhibits microtubule formation	Indirect influence on SG dynamics
White, 2011 #156	Neuronal model	Mitochondrial stress	Uncoupling of mitochondrial loss and damage	Stress environment for SG activation
Carnero, 2011 #151	Review; adenovirus	miRNA pathways	Viruses modulate RNA silencing	Comparative RNA regulation
Fehrholz, 2012 #149	RNA virus models	APOBEC3G restriction	A3G restricts measles, mumps, RSV	Broad antiviral granule-linked role
Reed, 2012 #148	Cell culture	DDX6; PB complexes	Gag co-opts DDX6 for capsid assembly	HIV exploits PB machinery
Clemens, 2013 #146	Ty3 retroelement	RNA targeting signals	Defined cis-elements for RNA localization	Granule-directed RNA trafficking
Goodier, 2013 #140	LINE-1 model	RNA-binding interactome	ORF1 interactome includes restriction factors	Granule-associated retroelement surveillance
Goodier, 2015 #131	Retrotransposition model	ZAP antiviral pathway	ZAP restricts human retrotransposition	RNA-targeting restriction
Hu, 2015 #130	LINE-1 model	Stress granules; SAMHD1	SAMHD1 promotes SG formation to inhibit LINE-1	SGs as active antiviral compartments
Hanke, 2013 #138	HERV-K model	Staufen-1 RNP complexes	Staufen-1 enhances virion production	Proviral RNA-binding protein
Banerjee, 2014 #136	Cell culture	Staufen-2; RNA export	Staufen-2 enhances Rev-mediated RNA export	Proviral RNA granule modulation
Izumi, 2013 #139	Cell culture	MOV10/APOBEC3G PB localization	PB localization not required for restriction	Granule-independent antiviral function
Bélanger, 2015 #129	Cell culture	RNA-binding residues of A3G	RNA-binding affects restriction efficiency	Structural control of antiviral activity
Polevoda, 2015 #127	Biochemical assays	RNA-induced complex disassembly	RNA displaces ssDNA from A3G complexes	RNA controls enzymatic restriction
Marin, 2016 #126	Live-cell imaging	PKR; antiviral granule pathways	RNA–A3F complexes coordinate with PKR	PKR-linked translational arrest modulation
Lai, 2013 #142	Cell culture	DDX3 helicase	DDX3 interacts with Tat to enhance translation	Helicase links translation and immunity
Soto-Rifo, 2013 #143	Cell culture	DDX3 cap-independent translation	DDX3 substitutes for eIF4E	Maintains translation during stress
Yasuda-Inoue, 2013 #137	Cell culture	DDX3 requirement	DDX3 required for Tat function	Central translational regulator
Soto-Rifo, 2014 #133	Cell culture	Stress granules; HIV-2 RNA	HIV-2 RNA accumulates in SG when translation inhibited	Active translation prevents SG sequestration
Valiente-Echeverría, 2014 #134	Cell culture	G3BP1; eEF2; SG assembly	HIV modulates SG assembly via eEF2/G3BP1	Active SG antagonism
Cinti, 2016 #125	Cell culture	Gag; cap-binding complex; SG inhibition	Gag blocks stress-induced SG assembly	Prevents translational arrest
Manghera, 2016 #123	Neuro model	TDP-43; HERV-K regulation	TDP-43 regulates HERV-K proteins	SG protein influences retroelements
Brandmann, 2014 #135	Neuronal culture	Oxidative stress; redox balance	Protease inhibitors increase glutathione export	Indirect SG activation via oxidative stress
Poblete-Durán, 2016 #124	Review	RNA granule regulation	Viruses regulate granule composition and signaling	Conceptual framework
Toro-Ascuy, 2016 #122	Cell culture	mRNA decay machinery	HIV RNA interfaces with decay pathways	Granule-linked RNA stability control
Cinti, 2017 #119	Cell culture	mTORC1 signaling	HIV activates mTORC1 to suppress SG assembly	Prevents translational repression
Dev, 2017 #120	Cell culture	DNMT2-mediated RNA methylation	Cytosine methylation stabilizes HIV RNA	Epitranscriptomic protection from decay
Knoener, 2017 #118	Proteomics	HIV RNA interactome	Identified granule-associated RBPs	Complex RNP architecture
Barajas, 2018 #116	Cell culture	Genome packaging intermediates	Defined Gag–RNA assembly stage	RNP remodeling precedes assembly
Putatunda, 2018 #114	Tg26 mice	Neurogenic deficits	Chronic viral expression impairs neurogenesis	Stress-linked neuroinflammation
Bellmann, 2019 #110	iPSC neurons	FUS-associated granules	Viral infection exacerbates FUS-ALS phenotypes	SG dysregulation in neurodegeneration
Rao, 2019 #111	Cell culture	Staufen1; SG disassembly	Staufen1 required for SG dissociation and infectivity	Active granule remodeling required
Kukhanova, 2020 #108	Review	DDX3 helicase	DDX3 as antiviral/anticancer target	Helicase at immunity–replication interface
Taschuk, 2020 #109	Review	DEAD-box helicases	Helicases as sensors and effectors	Granule-linked innate defense
Monette, 2020 #105	Biophysical assays	Phase separation; nucleocapsid	Metal ions regulate condensate dynamics	Retroviral condensates resemble SG
Monette, 2020 #107	Cell biology	Nucleocapsid-mediated phase separation	NC-driven condensates regulate RNA positioning	Biomolecular condensates in assembly
Vandelli, 2020 #104	Computational interactome	Viral RNA–RBP interactions	RNA structure predicts host interactions	RNA recruits granule components
Balakrishnan, 2021 #98	Cell culture	Staufen-2 encapsidation	Encapsidation enhances infectivity	RNA-binding protein promotes assembly
Park, 2021 #99	Cell culture	Staufen1 overexpression	Modulates HIV production	Granule remodeling influences replication
Gao, 2021 #100	Mouse model	Stress granule signaling	Darunavir alters SG-associated pathways	Therapy affects stress responses
Reed, 2021 #103	Drug discovery	Host-targeting assembly inhibitor	Identified small molecule blocking assembly	Targeting host RNP interactions
Libre, 2022 #96	Cell culture	uORF-mediated translational control	Vif represses A3G via uORF targeting	Manipulation of translational checkpoints
Ramos, 2022 #97	Cell culture	IRES; Staufen1	Staufen1 acts as IRES trans-acting factor	Maintains translation during stress
Rodriguez, 2022 #93	KSHV model	Shiftless; RNA granules	Shiftless restricts gene expression and alters granules	Innate immunity intersects SG
Xue, 2022 #95	Cell culture	ZAP; PARylation	PAR enhances ZAP antiviral activity	Post-translational regulation of RNA restriction
Shen, 2023 #92	Review	RNA modifications	Non-m6A modifications regulate immunity	Epitranscriptomic control of RNA fate
Chen, 2024 #90	Review	Innate immune antagonism	Viruses target RNA sensing and translation	Granule manipulation as immune evasion
Huang, 2024 #91	Astrocyte model	Stress granule disassembly	Quercetin promotes SG disassembly; reduces toxicity	Granule modulation mitigates neurotoxicity
von Krusenstiern, 2025 #88	Oligodendrocytes	PERK-ISR; SG formation	ART drugs activate PERK and induce SG	Therapy-linked SG activation

Conclusion

Stress granules represent a central hub at the intersection of cellular stress responses, translational regulation, and innate antiviral immunity. Retroviruses have evolved sophisticated mechanisms to modulate stress granule assembly and function, thereby maintaining efficient viral RNA translation, evading host immune responses, and supporting viral persistence. Evidence from studies on HIV-1 and HTLV-1 demonstrates that viral proteins actively interfere with SG nucleating factors and signaling pathways such as eIF2α phosphorylation. These interactions underscore the complexity of host–virus dynamics and highlight stress granules as both antiviral effectors and potential viral exploitation platforms. A comprehensive understanding of stress granule regulation in retroviral infections is essential for elucidating the mechanisms underlying chronic infection, inflammation, and virus-associated oncogenesis.

Future Perspectives

Future research should focus on dissecting the stage-specific regulation of stress granules during retroviral life cycles using high-resolution imaging and single-cell transcriptomic approaches. The identification of key SG-associated proteins that selectively influence viral replication without compromising normal cellular stress responses remains a critical priority. Moreover, the development of small molecules or targeted inhibitors that modulate stress granule assembly may provide innovative therapeutic strategies against HIV-1, HTLV-1, and related retroviruses. Investigating the relationship between chronic stress granule dysregulation and retrovirus-associated neurodegeneration or malignancy could further expand our understanding of long-term disease progression. Integrative studies combining virology, RNA biology, and systems biology will be instrumental in translating mechanistic insights into clinical applications.

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

Competing interests

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

Consent for publication

Not Applicable.

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.