Biomedicine & Pharmacotherapy 170 (2024) 115978

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Biomedicine & Pharmacotherapy

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Review

Long non-coding RNAs and immune cells: Unveiling the role in

viral infections
Dan Zhang a, 1, Mengna Zhang a, 1, Liqin Zhang a, Weijuan Wang a, Stéphane Hua b, Chan Zhou c,
Xiaoming Sun a, d, *
a
Department of Immunology and Pathogen Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China
b
Laboratory of Cellular Immunology and Biotechnology, Molecular Engineering for Health Unit CEA Saclay, 91191 Gif-sur-Yvette cedex, France
c
Department of Population and Quantitative Health Sciences, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
d
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003,
China

A R T I C L E I N F O A B S T R A C T

Keywords: Viral infections present significant challenges to human health, underscoring the importance of understanding
LncRNA the immune response for effective therapeutic strategies. Immune cell activation leads to dynamic changes in
Long non-coding RNAs gene expression. Numerous studies have demonstrated the crucial role of long noncoding RNAs (lncRNAs) in
Viral infection
immune activation and disease processes, including viral infections. This review provides a comprehensive
Innate immune cells
Adaptive immune cells
overview of lncRNAs expressed in immune cells, including CD8 T cells, CD4 T cells, B cells, monocytes, mac­
rophages, dendritic cells, and granulocytes, during both acute and chronic viral infections. LncRNA-mediated
gene regulation encompasses various mechanisms, including the modulation of viral replication, the establish­
ment of latency, activation of interferon pathways and other critical signaling pathways, regulation of immune
exhaustion and aging, and control of cytokine and chemokine production, as well as the modulation of
interferon-stimulated genes. By highlighting specific lncRNAs in different immune cell types, this review en­
hances our understanding of immune responses to viral infections from a lncRNA perspective and suggests po­
tential avenues for exploring lncRNAs as therapeutic targets against viral diseases.

1. Introduction LncRNAs were first described in the early 1990s, with the discovery
of lncRNAs involved in epigenetic regulation, such as H19 [7] and Xist
Viral infections, ranging from acute illnesses like influenza and [8,9]. LncRNAs are a class of noncoding RNAs that exceed 200 nucle­
COVID-19 to chronic conditions like viral hepatitis and AIDS, pose sig­ otides in length and do not encode proteins or only encode short poly­
nificant challenges to human health [1]. Additionally, viral infections peptides [10]. They are transcribed by RNA Polymerase II and undergo
have been implicated in the development of certain cancers, such as 5’ capping, 3’ polyadenylation, and splicing. Based on their transcrip­
hepatocellular carcinoma [2]. In response to the viral invasion, the host tional direction and proximity to neighboring genes, lncRNAs can be
immune system activates a comprehensive defense mechanism, classified into antisense, divergent, and intergenic lncRNAs [11,12]. The
involving both the innate and adaptive immune responses. While number of lncRNA transcripts being identified keeps increasing these
protein-based immunoregulatory mechanisms have been extensively years. A comprehensive bioinformatics analysis incorporating data from
studied, the role of noncoding RNAs, particularly long noncoding RNAs 25 independent studies has led to the identification of 58,648 genes as
(lncRNAs), in shaping the immune response to viral infections remains lncRNAs in humans [13,14]. New bioinformatics tools, such as Flnc
incompletely understood. LncRNAs have emerged as key regulators in [15], have been developed to improve the identification of novel
the complex immune networks involved in viral infections, contributing lncRNAs directly from RNA sequencing data. Recent studies show
to our understanding of host-virus interactions [3–6]. 40–70% of previously unknown lncRNAs across multiple human

* Correspondence to: Department of Immunology and Pathogen Biology, School of Basic Medical Sciences, Hangzhou Normal University, NO.2318, Yuhangtang
Rd, Yuhang District, Hangzhou 311121, Zhejiang, China.
E-mail address: xiaoming@[Link] (X. Sun).
1
Equally contributed.

[Link]
Received 1 October 2023; Received in revised form 26 November 2023; Accepted 29 November 2023
Available online 5 December 2023
0753-3322/© 2023 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
([Link]
D. Zhang et al. Biomedicine & Pharmacotherapy 170 (2024) 115978

biospecimens and cell types [15]. This large number of lncRNAs un­ 2. LncRNAs in different immune cells
derscores the prevalence of lncRNAs in the human transcriptome.
Notably, the expression profiles of lncRNAs exhibit greater tissue spec­ 2.1. CD8 T cells
ificity and cell-type selectivity compared to coding RNAs, indicating
their propensity to perform subtle functions in a cell-type-specific CD8 T cells play a critical role in controlling viral infections and
manner [16]. However, despite their abundance, the majority of accumulating evidence suggests that numerous lncRNAs are involved in
lncRNAs remain poorly functionally characterized. regulating gene expression in CD8 T cells, affecting cell differentiation,
The immune system plays a crucial role in defending the body activation, and cellular functions [23,24]. Although many lncRNAs are
against viral infections. Within the immune system, different types of differentially expressed between CD8 T cell subsets in mice and humans,
immune cells, such as T cells, B cells, natural killer (NK) cells, mono­ only a few of them have been experimentally validated for their bio­
cytes, macrophages, and dendritic cells, work together to mount an logical relevance to CD8 T cell differentiation and function, particularly
effective immune response. Accumulated evidence has indicated that in virus infections [25]. The first genome-wide screening of lncRNAs
lncRNAs are involved in various aspects of immune cell development, expressed in CD8 T cells with lymphoid specificity and/or changes in
differentiation, activation, and effector functions, including the RIG- dynamics during lymphocyte differentiation or activation was con­
mediated inflammation or IFN signaling pathway of these immune ducted [26]. Using microarray analysis, Pang et al. uncovered hundreds
cells in antiviral innate immunity [17]. Targeting these lncRNAs or their of lymphoid-specific lncRNAs that showed altered expression during
associated pathways may offer new opportunities for modulating im­ CD8 T cell activation and subsequent differentiation into CD8 memory
mune responses to enhance viral clearance or suppress and effector T cells upon influenza virus challenge. This implies that
immune-mediated pathologies and could pave the way for the devel­ these lncRNAs may play a role in fate decisions during antigen-driven
opment of novel therapeutic strategies. differentiation [26]. Additionally, Hudson et al. profiled the lncRNA
Previous reviews have extensively covered the role of lncRNAs in repertoires of LCMV-specific CD8 T cells and confirmed that expression
immune cell development, differentiation, and activation under both profiles of lncRNAs are sufficient to define naive, effector, and memory
physiological and disease conditions, including tumor biology and viral CD8 T cell subsets [27]. For instance, one recent study found a key
infections [17–22]. However, the roles of lncRNAs expressed in specific lncRNA-Snhg1 can promote memory formation through the IL-7
immune cell types in the context of viral infection have not been signaling pathway while impeding effector CD8 T cells in LCMV acute
extensively summarized. In this review, we aim to provide a compre­ viral infection in both mice and humans [28]. Another study demon­
hensive overview of the roles of lncRNAs expressed in immune cells strated that MALAT1 interaction with miR-15/16 decreased cytotoxic T
during acute and chronic viral infections (Fig. 1 and Table 1). By cell activation and mutation of MALAT1 diminished memory cell
highlighting the specific lncRNAs involved in different immune cell persistence following LCMV infection [29].
types, we can gain insights into their functions and potential as thera­ In addition to their role in antigen-stimulated T cell differentiation,
peutic targets. Further investigation into the regulatory mechanisms and lncRNAs have been shown to regulate CD8 T cell effector functions.
functional implications of these lncRNAs will deepen our understanding Interferons and tumor necrosis factor-alpha (TNF-α) are key cytokines
of immune responses to viral infections and may lead to the develop­ that enable CD8 T cells to exert their effector function upon antigen
ment of innovative approaches for viral disease management. stimulation [30]. Recent studies have revealed the involvement of
lncRNAs in regulating these effector functions during viral infections.
For instance, the lncRNA NeST (also known as IFNG-AS1 or Tmevpg1)
controls Theiler’s virus infection by epigenetically activating the IFN-γ
locus in CD8 T cells [31]. Similarly, LncRNA-CD160 can inhibit the
secretion of IFN-γ and TNF-α by CD8 T cells through the recruitment of

Fig. 1. Overiew of lncRNAs summarized in this study. The diagram shows lncRNAs along with their respective virus and associated diseases/functions in CD4 T,
CD8 T, macrophages, DC, B cells, monocytes, NK cells, granulocytes, and other cells.

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Table 1
Summary of lncRNA type, location, pathways and functions of lncRNAs in different immune cells.
CD8
lncRNA LncRNA type Species Viral RNA Affected signaling Molecules/ Function Ref.
infection location Pathway

Snhg1 Intergenic M LCMV Nucleus Snhg1/VPS13D/IL7R/TCF7/IL-7 Positive regulator of memory formation while impeding [28]
signaling effector CD8
NeST Antisense M TMEV Nucleus NeST/WDR5/ IFN-γ Positive regulator of H3K4me3 at the IFN-γ [31]
Lnc- N/A H, M HBV Nucleus HDAC11/IFN-γ/TNF-α Negative regulator of IFN-γ and TNF-α through HDAC11 [32]
CD160
Morrbid N/A M LCMV Nucleus Bcl2L11/ PI3K-AKT signaling Negative regulator of PI3K-AKT signaling [34]
NRON Intronic, H CMV Cytoplasm IL-4-dependent NFAT signaling Negative regulator of CMV-enhanced CD8+ T cell aging [42]
sense

CD4
lncRNA LncRNA Species Viral RNA location Affected signaling Molecules/ Function Ref.
type infection Pathway

LINC00173 Intergenic H HIV-1 Nucleus Regulation of cytokines Negative regulator of immune response [46]
PVT1 Intergenic H HIV-1 Nucleus/ p53 signaling pathway Positive regulator of potential targets for HIV [47]
Cytoplasm latency reversal
RP11–347C18.3 Intronic, H HIV-1 N/A p53 signaling pathway Positive regulator of Potential targets for HIV [47]
sense latency reversal
MALAT1 Intergenic H HIV-1 Nucleus MALAT1- PRC2 Positive regulator of HIV-1 transcription and [50]
infection
MALAT1 Intergenic M CVB3 Nucleus/ IL-17/TNF-α/ IL-21 Positive regulator of Th17 cells differentiation [67]
Cytoplasm
HEAL Intergenic H HIV-1 Nucleus P300-P-TEFb/CDK2 Positive regulator of P-TEFb and CDK2 [51]
NRON Antisense H HIV-1 Cytoplasm NFAT signaling Negative regulator of NFAT-mediated viral gene [54]
activation
NEAT1 Intergenic H HIV-1 Nucleus NEAT1 may interact with HIV- Potential biomarker for HIV-1 infection [58]
1
LincRNA- Intergenic H HIV-1 Nucleus RUNX1b/c/ Tat Positive regulator of HIV-1 replication, and LTR [59]
uc002yug.2 activity
AK130181 N/A H HIV-1 N/A NF-κB signaling Positive regulator of HIV-1 Transcription and [60]
Participate
Lnc-7SK N/A H HIV-1 Nucleus P-TEFb Negative regulator of P-TEFb [61]
LincRNA-p21 Intergenic H HIV-1 Nucleus/ MAP2K1/ERK2 pathway Positive regulators of mammalian apoptosis and [62]
Cytoplasm DNA damage
GAS5 Sense H, M HIV-1 Nucleus/ Gas5-miR-21-mediated Negative regulator of miR-21 to increase [64]
Cytoplasm signaling pathway dysfunction and apoptosis
CCR5AS Intergenic H HIV-1 Cytoplasm ATF1/Raly Positive regulator of HIV infection [65]
ANRIL Antisense H HTLV Nucleus NF-κB signaling Negative regulator of p21/CDKN1A [68]
transcription

Monocytes
lncRNA LncRNA Species Viral RNA location Affected signaling Molecules/ Function Ref.
type infection Pathway

PIRAT Antisense H SARS-CoV-2 Nucleus PU.1-S100A8/S100A9 Negative regulator of PU.1 [70]

LUCAT1 Antisense H SARS-CoV-2 Nucleus NF-κB signaling Negative regulator of NF-κB [70]
HEIM N/A H HBV Nucleus/ TGF-β signaling Positive regulator of liver fibrosis by upregulating the [71]
Cytoplasm pathway TGF-β production

DC
lncRNA LncRNA Species Viral RNA location Affected signaling Function Ref.
type infection Molecules/Pathway

Lnc-DC Intergenic H HBV Cytoplasm TLR9/STAT3 signaling Positive regulator of IL-1β in DCs [73]
MIR4435–2HG Intergenic H HIV-1 Nucleus/ TLR3/mTOR signaling Positive regulator of oxidative phosphorylation and glycolysis [75]
Cytoplasm pathway activities in response to TLR3 stimulation

Macrophage
lncRNA LncRNA Species Viral RNA location Affected signaling Molecules/ Function Ref.
type infection Pathway

Lnc FTX Intergenic H HBV Nucleus/ FTX/miR-545 signaling pathway Negative regulator of Tim-3 to the abnormal [81]
Cytoplasm activation of macrophage
NEAT1 Intergenic H, M HTNV Nucleus SREBP2 /Srebf1 Positive regulator of Srebf1 expression [87]
lnczc3h7a N/A H VSV Nucleus/ lnczc3H7a/ TRIM25/K63- RIG-I Positive regulator of TRIM25-mediated K63- [88]
Cytoplasm linked ubiquitination
Lnc-Lsm3b Intergenic H VSV Nucleus/ RIG-I signaling Negative regulator of RIG-I-mediated signaling [89]
Cytoplasm
LncRNA-SAF Antisense H HIV-1 Cytoplasm Caspase-3/7 Negative regulator of Caspases-3/7 [93]
LincRNA-p21 Intergenic H HIV-1 Nucleus/ MAP2K1/ERK2 pathway Positive regulators of mammalian apoptosis [62]
Cytoplasm and DNA damage
LncRNA-GM N/A H HIV-1 Cytoplasm GSTM1/ TBK1/IFN-I Positive regulators of viral escape [94]
HEAL Intergenic H HIV-1 N/A HEAL-FUS- p300- H3K27- p-tefB Positive regulator of HIV-1 replication [51]
NRIR Intergenic H HIV-1 Nucleus IFN Negative regulator of IFN response against HIV- [97]
1
(continued on next page)

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Table 1 (continued )
Macrophage
lncRNA LncRNA Species Viral RNA location Affected signaling Molecules/ Function Ref.
type infection Pathway

LncRNA- Intergenic H VSV Cytoplasm Cellular metabolism Positive regulator of cellular metabolism [99]
ACOD1
AK085865 N/A M CVB3 Nucleus ILF2-ILF3 complex-mediated Positive regulator of macrophage M2 [101,
miRNA-192 biogenesis polarization 102]

B cell
lncRNA LncRNA Species Viral RNA location Affected signaling Molecules/Pathway Function Ref.
type infection

IGFBP7- Antisense H EBV Nucleus/ NPPB-cGMP-PKG-pCREB1-Bcl-2/Bax/ Negative regulator of the cGMP-PKG [106]
AS1 Cytoplasm Casepase3 signaling pathway

NK
lncRNA LncRNA type Species Viral infection RNA location Affected signaling Molecules/Pathway Function Ref.

IGFBP7-AS1 Intergenic H HBV Nucleus/Cytoplasm HIF-1α/IFN-γ Negative regulator of IFN-γ [109]

Neutrophils

lLnc DFRV N/A H IAV Nucleus/Cytoplasm NF-κB signaling Dual-regulator to preserve innateimmune homeostasis [112]
Lnc AVAN N/A H, M IAV Nucleus/Cytoplasm TRIM25/ Foxo3a Positive regulator of the transcription of FOXO3a [109]

MDSCs

Lnc HOTAIRM1 Intergenic H HCV/HIV-1 Nucleus/Cytoplasm HOXA1 ositive regulator of HOXA1 [114–116]

LncRNA type: N/A, Not applicable; Species: H, Homo sapiens; M, Mice.

Viral infection: LCMV, Lymphocytic Choriomeningitis Virus; TMEV, Theiler’s murine encephalomyelitis virus; HBV, Hepatitis B virus; CMV, Cytomegalovirus; HIV-1,
Human Immunodeficiency Virus 1; CVB3, Coxsackievirus B3; SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2; HTNV, Hantaan virus; VSV, Vesicular
stomatitis virus; EBV, Epstein-Barr virus; IAV, Influenza A virus; HCV, hepatitis C virus.

histone-modification enzyme gene histone deacetylase 11 (HDAC11) in identified an age-accumulated lncRNA called NRON (non-protein cod­
chronic HBV infection. Mechanistically, lncRNA-CD160 and HDAC11 ing RNA repressing NFAT), which showed decreased expression in CD8
form a copolymer that anchors at the IFN-γ and TNF-α promoters, T cells from elderly individuals with persistent CMV infection. The
leading to H3K9Me1 methylation and subsequent abnormal chromatin findings suggest that NRON may contribute to CMV-enhanced
formation. This, in turn, blocks the transcription and translation of IFN-γ CD28nullCD8+ T cell aging potentially by influencing phosphorylation
and TNF-α [32]. Additionally, lncRNA Morrbid is an important lncRNA and/or IL-4-dependent NFAT signaling pathways [42].
for T cell function. It was initially identified as a key regulator of Collectively, these studies provide compelling evidence for the reg­
myeloid cells under homeostatic conditions [33]but a recent study ulatory role of lncRNAs in the exhaustion and cytotoxicity of virus-
showed it also tightly regulates CD8 T cell expansion and effector specific CD8 T cells (Fig. 2). These findings hold promise for manipu­
function by repressing the PI3K-AKT pathway in LCMV infection [34]. lating these processes to overcome virus immune evasion and enhance
During chronic viral infections, on the one hand, CD8 T cells can the efficacy of antiviral immunotherapy and vaccine strategies.
become functionally exhausted, leading to impaired antiviral responses.
LncRNAs have been shown to contribute to the regulation of CD8 T cell 2.2. CD4 T cells
exhaustion by modulating the expression of immune-regulating mole­
cules. Through direct or indirect mechanisms, lncRNAs can influence the The unique expression profiles of lncRNAs in different CD4 T cell
expression of immune checkpoint molecules, such as PD-1, CTLA4, and subsets revealed that lncRNAs have critical roles in Th cell function
TIM-3, which are critical regulators of T-cell exhaustion [35]. Surpris­ during homeostasis and disease have already been summarized in pre­
ingly, to the best of our knowledge, there is no lncRNAs have been vious reviews [43,44]. In this part, we practically focus on the functions
identified associated with T cell exhaustion during either acute or of lncRNAs from CD4 T cells during viral infections. CD4 T cells are the
chronic viral infection, while several lncRNAs have been reported in primary target for HIV infection and several lncRNAs have been linked
tumor and bacterial infection studies. For instance, Lnc-Tim3 is the first to the function of CD4+ T cells in the context of HIV infection (Fig. 3 and
well-documented lncRNA associated with T-cell exhaustion in hepato­ Table 1).
cellular carcinoma. Lnc-Tim3 exacerbates CD8 T exhaustion by specif­ Deep sequencing of HIV-1-infected human CD4 T cells and SUP-T1
ically binding to Tim-3 and blocking its interaction with Bat3 leading to cells revealed the differential expression of several lncRNAs during
suppression of downstream Lck/NFAT1/AP-1 signaling, and promoting HIV-1 infection [45]. Among them, lncRNA lnc00173 was selected for
the survival of the exhausted CD8 T cells by enhancing activation of further investigation and demonstrated an impact on the regulation of
anti-apoptosis genes including MDM2 and Bcl-2 [36]. In addition, cytokines production but not on HIV-1 replication in T cells [46].
lncRNA such as lncNDEPD1[37], and KCNQ1OT1[38] are associated Another high-throughput RNA sequencing study by Trypsteen et al.
with T cell exhaustion in cancer studies, but molecular mechanisms identified several differentially expressed lncRNAs, including PVT1 and
remain unknown. In sepsis infection, lncRNAs such as HOTAIRM1 and RP11–347C18.3, which were upregulated, and RP11–539L10.2, which
lncRNA-CD244 have also been shown associated with CD8 T cell was downregulated and associated with important cellular pathways
exhaustion [39,40]. Of note, Wang et al. recently demonstrated that [47].
exhausted CD8 T cells may promote an exhausted phenotype in Numerous studies have highlighted the significance of lncRNAs in
bystander CD8 T cells within the tumor microenvironment via the epigenetic, transcriptional, and post-transcriptional regulation of
exosome-associated lncRNAs [41]. Further studies might be interesting HIV-1 replication and latency which have been summarized previously
to investigate the functional roles of those lncRNAs in virus infection. [48,49]. Briefly, the lncRNA Malat1 promotes viral reactivation by
On the other hand, during chronic viral infection, CD8 T cells could epigenetically regulating HIV-1 gene expression through its interaction
show signs of immune aging, which refers to the gradual deterioration of with EZH2, preventing PRC2 translocation to the HIV-1 LTR region [50].
the immune system that occurs with advancing age. One recent study Another lncRNA, HEAL/linc02574–201, promotes viral reactivation by

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Fig. 2. LncRNAs in CD8 T cells. Different types of viruses, including TMEV, HBV, LCMV, and CMV, infect the host and then induce functional lncRNAs in CD8 T
cells, which have been demonstrated to control and regulate infections. TMEV, Theiler’s virus; HBV, hepatitis B virus; LCMV, lymphocytic choriomeningitis virus;
CMV, cytomegalovirus.

recruitment of histone acetyltransferase p300 to the HIV-1 promoter of miR-21 can contribute to cellular dysfunction and apoptosis in CD4 T
region [51]. cells [64].
The NRON, not only plays a role in the immune aging of CD8 T cells Another lncRNA called CCR5AS plays a role in HIV infection.
during CMV infection, as mentioned earlier [42], but also serves as an CCR5AS interferes with the interaction between the RNA-binding pro­
important regulator of HIV transcription throughout different stages of tein Raly and the 3’ untranslated region of CCR5, which is an HIV co-
the viral life cycle. Notably, viral proteins Nef and Vpu exert distinct receptor. This interference protects CCR5 mRNA from Raly-mediated
effects on NRON expression, thus modulating the activity of NFAT by degradation. Knockdown of CCR5AS reduces the susceptibility of CD4
influencing its nuclear transport [52–54]. Recent studies have high­ T cells to HIV-1 infection, indicating that the expression of lncRNA-
lighted the downregulation of the lncRNA NEAT1 in PBMCs upon CCR5AS affects the level of HIV infection and disease progression [65].
stimulation with phytohemagglutinin (PHA) in both healthy donors and In addition to its role in HIV infection, lncRNAs also play significant
HIV patients [55]. Knocking out NEAT1 in HIV-infected CD4 T cells roles in other viral infections. One example is the lncRNA Malat1, which
increased viral replication, suggesting a potential antiviral effect. has been implicated in various inflammatory diseases. Surprisingly, a
NEAT1 was also found to modulate the balance of T helper to T regu­ study by Yao et al. showed that although Malat1 is highly expressed in T
latory cells in the CD4 T lymphocyte population and showed potential as cell subsets, it is not essential for T cell development or the T cell-
a diagnostic biomarker for HIV [56–58]. Other lncRNAs, such as the mediated response against liver lymphocytic choriomeningitis virus
uc002yug.2 [59], the AK130181 [60], and the human 7SK [61] have (LCMV). This suggests that Malat1 may not function as a master regu­
also been implicated in the regulation of HIV-1 replication and latency lator in T cells [66]. However, another study by Xue et al. demonstrated
through various mechanisms. that knockdown of Malat1 suppressed the differentiation of naïve CD4 T
Cell survival mechanisms play a crucial role in the establishment and cells into Th17 cells, resulting in a reduction in CVB3-induced acute viral
maintenance of HIV-1 latency. One example is the lincRNA-p21, which myocarditis (AVMC) in mice (44). This suggests that Malat1 may have a
promotes viral persistence by inhibition of DNA DSB-induced cell death specific role in modulating the differentiation of CD4 T cells into Th17
[62]. Similarly, another p53-dependent lncRNA, PANDA inhibits cells and influencing the immune response during certain viral in­
apoptosis through binding to a subunit of nuclear transcription factor Y fections [67].
(NF-YA) and preventing its re-localization at promoter regions of Human T-cell leukemia virus type 1 (HTLV-1) infection results in a
apoptotic genes [63]. Furthermore, the LncRNA-GAS5 controls signaling highly aggressive lymphoproliferative neoplasm called adult T-cell
molecules that are crucial for DNA damage responses and cellular re­ leukemia (ATL), which affects mature CD4 T cells. In a study by Song
actions following T cell receptor (TCR) stimulation. In the context of et al., it was discovered that the lncRNA ANRIL plays a significant role in
HIV-1 infection, sustained T cell stimulation leads to decreased expres­ the proliferation of ATL cells, both in vitro and in vivo. ANRIL was found
sion of GAS5, resulting in increased levels of miR-21. This dysregulation to activate NF-κB signaling by forming a complex involving EZH2 and

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Fig. 3. LncRNAs in CD4 T cells. Numerous lncRNAs associated with viral infection, including LINC00173, HEAL, GAS5, MALAT1, uc002yug.2, 7SK, AK130181,
p21, PVT1, RP11–347C18.3, CCR5AS, ANRIL, NRON, regulate the immune response through different mechanisms. HIV, human immunodeficiency virus; HTLV-1,
Human T-cell leukemia virus type 1.

p65. Furthermore, ANRIL exhibited oncogenic properties by epigeneti­ In the context of chronic hepatitis B virus (HBV) infection, particu­
cally silencing p21/CDKN1A, a gene involved in cell cycle regulation larly during fibrosis, lncRNA-HEIM demonstrated significantly elevated
[68]. expression in CD14 + monocytes, further enhanced upon HBV infection.
These findings highlight the diverse functions of lncRNAs in different Its heightened expression exhibited a strong correlation with the TGF-β
viral infections and emphasize their potential as therapeutic targets and signaling pathway, specifically with TGF-β and SMAD4. Importantly,
biomarkers in various diseases. Further research in this field is war­ manipulation of endogenous lncRNA-HEIM levels in monocytes had a
ranted to fully understand the intricate mechanisms underlying lncRNA- substantial impact on the production of TGF-β in the context of HBV-
mediated regulation. induced fibrosis [71].
These findings shed light on the intricate regulatory roles played by
lncRNAs in viral infections, such as COVID-19 and chronic HBV infec­
2.3. Monocytes tion. Understanding the underlying mechanisms through which
lncRNAs modulate immune responses and signaling pathways holds
Increasing evidence demonstrated that lncRNAs can play diverse significant promise for the development of targeted therapeutic strate­
roles in monocytes during different viral infections, influencing various gies against these viral diseases.
aspects of immune response including inflammation, and viral replica­
tion [69] (Fig. 4 and Table 1). In a recent study by Aznaourova et al.,
single-cell RNA sequencing was employed to investigate the role of long 2.4. Dendritic cells
regulatory RNAs in COVID-19 [70]. One of the identified nuclear RNAs,
lncRNA-PIRAT, exhibited predominant expression in CD14 monocytes LncRNAs have been found to play a crucial role in regulating the
and was found to regulate the excessive production of PU.1-dependent differentiation and activation of dendritic cells (DCs) [72]. To date,
alarmins during SARS-CoV-2 infection. Mechanistically, PIRAT facili­ there are only a few lncRNAs, including lnc-DC, MIR4435–2HG, and
tated the recruitment of the PU.1 transcription factor, thereby sup­ n337374, which have been reported to play a regulatory role in viral
pressing its binding to the promoters of S100A8 and S100A9 alarmins. infection. The lnc-DC is specifically expressed in human DCs and plays a
Notably, the downregulation of PIRAT coincided with the upregulation critical role in their optimal differentiation and activation of T cells [72].
of another lncRNA, LUCAT1, in monocytes. LUCAT1, in turn, promoted In the context of the immune response induced by HBV, the lnc-DC plays
alarmin induction through NF-κB-dependent mechanisms. LncRNAs a vital role in dendritic cell growth, apoptosis, and immune response
such as PIRAT and LUCAT1 exerted control over immune through the TLR9/STAT3 signaling pathway. Notably, the lnc-DC
master-transcription factors like PU.1 and STAT1, thereby contributing modulates the HBV-induced immune response by reducing the secre­
to the progression of COVID-19 [70]. tion of TNF-α, IL-6, IL-12, and IFN-γ, while increasing the concentration

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Fig. 4. LncRNAs in monocytes and DC. The diagram shows lncRNAs involved in the regulation of macrophage and DC function after different viral infection. The
left column is monocytes, and the right column is DC.

of IL-1β in dendritic cells [73]. inhibitory receptor Tim-3 and is responsible for the abnormal activation
One recent study demonstrated that the lncRNA n337374 over­ of macrophages in cirrhosis caused by HBV. This effect is due to the
expression may suppress DC maturation by downregulating the CD86 regulation of FTX via the FTX-miR-545-Tim3 axis [81]. Studies have
and ERK pathway in the context of RSV infection in an asthmatic mouse shown that Toll-like receptor (TLR) stimulation induces the expression
model [74]. Another study demonstrated that the MIR4435–2HG is of several lncRNAs in macrophages. LincRNA-Cox2 represses CCL5
significantly upregulated in mDCs from HIV-1 elite controllers while enhancing TLR-induced IL-6 expression, and its inhibition is
compared to progressors. Elevated expression of MIR4435–2HG is mediated by interactions with heterogeneous nuclear ribonucleopro­
associated with enhanced metabolic function in mDCs, including teins hnRNP-A/B and hnRNP-A2/B1 [82]. Similarly, lincRNA-THRIL
increased mitochondrial respiration and glycolysis. Furthermore, interacts with hnRNPL, binding to the TNFα promoter and driving
MIR4435–2HG is shown to promote the expression of genes related to transcription in macrophages [83]. In addition, the lncRNA NORAD has
metabolic pathways, particularly those involved in oxidative phos­ been shown can target five of the ten cytokines involved in cytokine
phorylation and glycolysis [75]. storms in SARS-CoV2 infection [84].
Although there are a handful of lncRNAs, including lnc-DC, In addition, Zhang et al. found that NEAT1 is associated with
HOTAIRM1 [76], MALAT1 [77], NEAT1 [78], and lncIRF8 [79], inflammasomes in mouse macrophages, promoting inflammasome as­
which have been shown to play a regulatory role in human DC, their sembly, pro-caspase-1 processing, and the stabilization of mature
roles in viral infection remains unexplored. In addition, one recent study caspase-1, leading to IL-1 generation [85] and the same mechanism have
also demonstrated that lncRNAs modulate chicken DC innate response also been found in human macrophage from COVID-19 patients [86].
through MAPK and JAK-STAT pathways in infectious bursal disease Another study demonstrated a different mechanism that the NEAT1
viruses [80], further exploring the functions of lncRNA in different could interact with SREBP2, thus stimulating inflammatory macro­
systems will help the understanding of the conservation and evolution of phages and limiting HTNV propagation [87]. Another lncRNA,
lncRNAs (Fig. 4 and Table 1). lnczc3h7a, acts as a molecular scaffold in murine macrophages during
RNA virus vesicular stomatitis virus (VSV) infection. It promotes the
stabilization of the RIG-I–TRIM25 complex, facilitating RIG-I ubiquiti­
2.5. Macrophages nation and downstream type I interferon (IFN) production by macro­
phages [88]. Similarly, Lnc-Lsm3b was upregulated following VSV
Both monocytes and macrophages are integral components of the infection, shutting down RIG-I activation and thus inhibiting the
immune system, contributing to both innate and adaptive immune re­ downstream antiviral effector response [89].
sponses. Their functions are critical in maintaining tissue homeostasis Tissue-resident macrophages, which serve as HIV-1 sanctuaries, are
and orchestrating immune defense mechanisms against infections and resistant to virus-induced cell death [90–92]. LncRNA-SAF is
diseases. Dysregulation of LncRNA FTX downregulates the expression of

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D. Zhang et al. Biomedicine & Pharmacotherapy 170 (2024) 115978

significantly upregulated in HIV-1-infected human monocyte-derived demonstrate the intricate regulatory mechanisms in macrophages dur­
macrophages (MDMs) and its inhibition leads to reduced HIV-1 repli­ ing viral infections (Fig. 5 and Table 1).
cation and viral burden in macrophages [93]. LincRNA-p21 is reported
to be a central target in HIV-1 infection, promoting double-strand breaks
in macrophages and preventing apoptosis by involving the MAP2­ 2.6. B Cells
K1/ERK2 pathway [62].
During viral infection, the host-negative regulator lncRNA-GM is B cells are essential components of the adaptive immune response,
downregulated, facilitating virus escape. LncRNA-GM interacts with playing a crucial role in humoral immunity in mammals. Previous re­
glutathione S-transferase M1 (GSTM1) and inhibits the kinase activity of views have extensively covered the functions of lncRNAs in B cell
TBK1 through s-glutathionylation, promoting the antiviral innate development, functions, and malignancies [103]. In this part, we will
response [94,95]. In HIV-1-infected macrophages, lncRNA-HEAL en­ focus on the roles of lncRNAs in virus infections (Fig. 6 and Table 1).
hances the replication of multiple HIV-1 strains. It forms a complex with Epstein-Barr virus (EBV) is a ubiquitous γ-herpesvirus, which is the first
the RNA-binding protein FUS, facilitating HIV replication by enhancing confirmed human tumor virus and can establish latent infection in B
the recruitment of the histone acetyltransferase p300 and increasing lymphocytes. Upon herpesvirus infection, host lncRNAs such as NEAT1
CDK2 expression [51,96]. Furthermore, IFN-induced lncRNAs, and B-cell integration cluster act as either negative or positive regulators
including NRIR, GBP1P1, and MIR3945HG, are induced in macrophages of antiviral responses in the immune system [104,105]. Another study
by both IFNs and HIV-1 infection, potentially negatively affecting the found that the expression of both IGFBP7-AS1 and its sense gene IGFBP7
IFN response against HIV in macrophages [97,98]. Interestingly, a is decreased in EBV-positive B-cell lymphoma (B-CL) cells and clinical
lncRNA, LncRNA-ACOD1, has been identified which promotes VSV tissues, indicating that EBV promotes the development of B-CL by sup­
infection. The expression of this lncRNA is significantly upregulated pressing the p53-responsive lncRNA IGFBP7-AS1 [106].
independently of IFN signaling pathways and triggers the production of In addition to their involvement in herpesvirus infections, lncRNAs
various metabolites, which play a vital role in facilitating VSV replica­ have also been implicated in immune responses and viral infections in
tion through a mechanism that is currently unknown [99]. the context of COVID-19. Analysis of single-cell RNA sequencing profiles
In addition, macrophage polarization is influenced by several revealed an increased presence of the lncRNA BIC, which promotes B
lncRNAs, such as H19, NRON, MEG3, GAS5, RN7SK, and AK085865 cell proliferation, in B lymphocytes. Furthermore, the lincRNA MaIL1,
[100]. Among them, AK085865 plays a crucial role in viral infectious known for its ability to induce type I interferon, showed expected
diseases. It promotes macrophage M2 polarization in CVB3-induced upregulation not only in all monocyte populations but also in B cells of
viral myocarditis by regulating ILF2-ILF3 complex-mediated infected patients. These findings suggest that lncRNAs play significant
miRNA-192 biogenesis [101,102]. These lncRNAs collectively roles in regulating immune responses and viral infections, including
those related to COVID-19 [107].

Fig. 5. LncRNAs in macrophages. The diagram shows lncRNAs that play diverse roles of in macrophages during virus infection, including ACOD1, zc3h7a, Lsm3b,
GM, SAF, FTX, HEAL, NRIR, p21, NEAT1, AK085865. VSV, vesicular stomatitis virus; CVB3, coxsackievirus B3; HTNV, Hantaan virus.

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D. Zhang et al. Biomedicine & Pharmacotherapy 170 (2024) 115978

Fig. 6. LncRNAs in B/NK/Neutrophils/MDSCs. The schematic shows lncRNAs and their mechanisms that play different roles in B, NK, Neutrophils, and MDSCs
during virus infection. EBV, Epstein-Barr virus; IAV, influenza A virus; HCV, hepatitis C virus.

2.7. NK cells, granulocytes, and other cell types 3. Conclusion and future perspectives

Natural killer (NK) cells are a subtype of type 1 innate lymphoid cells The discovery of lncRNAs as regulators of gene expression has
that function as a first line of innate immune defense. There are fewer significantly advanced our understanding of immune regulation and its
studies focused on lncRNA than there are on microRNA in NK cells, implications for viral infections. While thousands of lncRNAs are
especially in the context of virus infection [108] (Fig. 6 and Table 1). expressed following viral infection, the number of lncRNAs with
Notably, MALAT1 is widely expressed in several immune cell types as experimentally validated functions remains limited. In our comprehen­
mentioned above. One study by Guo et al. investigated the roles of sive review, we have compiled information on 35 distinct lncRNAs
MALAT1 in NK cells from pregnant women with HBV infection and they originating from various immune cell types involved in different viral
revealed that MALAT1 regulates HIF-1α expression by sequestering infections. It’s worth noting that evidence suggests immune-regulatory
has-miR-155–5p [109]. Moreover, lncRNAs such as Lnc-CD56, LncRNA lncRNAs can wield their influence through various mechanisms. More­
IFNG-AS1 [108,110], and LncRNA NCAL1 [111] play significant roles over, intriguingly, the same lncRNAs have been shown to employ
in NK cell biology, and investigating their alterations and functions in different mechanisms in diverse cell types, as depicted in Fig. 7.
the context of viral infections would be an intriguing area to explore. Nonetheless, our quest to unravel the precise roles played by
Granulocytes, which include neutrophils, eosinophils, and basophils, lncRNAs within the realm of immunity is still in its infancy. There is an
are critical innate immune cells that form one of the first lines of immune urgent need for deeper exploration into how the lncRNA transcriptome
defense against pathogens. Among them, the roles of lncRNAs from is modulated within infected cells and how these modifications impact
neutrophils in viral infection have been more extensively reported than the intricate interplay between the host and the virus. Such in­
others. The lncRNAs modulated antiviral innate immunity and cell vestigations hold the potential to unveil novel cellular pathways that are
survival in different viral infections. The lncRNA DFRV was upregulated integral to the antivirus response. It is worth noting that our summary
during influenza virus infection and modulated innate immune re­ underscores the scarcity of lncRNAs that have been investigated in both
sponses through activating pro-inflammatory signaling [112]. Also, human and animal models. This observation aligns with the notion that
another lncRNA AVAN reported in influenza virus infection was shown lncRNAs relevant to immune processes exhibit a degree of conservation
to promote antiviral innate immunity by interacting with TRIM25 and in their primary sequence between mice and humans. However, we must
enhancing the transcription of FOXO3a [113]. Additionally, the lncRNA acknowledge that we are still a long way from comprehending how the
HOTAIRM1 regulated myeloid-derived suppressor cell differentiation sequences and structural characteristics of lncRNAs are linked to their
and maturation in both HCV infection and HIV infection [114–116]. functions, particularly given their non-coding nature and the relatively
low level of sequence conservation across species.

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D. Zhang et al. Biomedicine & Pharmacotherapy 170 (2024) 115978

Fig. 7. Common lncRNAs in different immune cells. (A) Some lncRNAs play regulatory roles in several different immune cells, such as NRON in CD8 and CD4 T
cells, Linc-p21, NEAT1, HEAL in CD4 T and macrophages, Malat1 in NK and CD4 T cells. The Venn diagram shows common lncRNAs that function between different
immune cells, and the histogram shows the number of lncRNAs that play roles in these immune cells respectively. (B) The biological functions of NRON, Linc-p21,
NEAT1, HEAL and Malat1 in immune cells during virus infection.

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