Class II transactivator restricts viral replication, extending its effect to HBV: Editorial on “Novel role of MHC class II transactivator in hepatitis B virus replication and viral counteraction”

Class II Transactivator (CIITA) is a master regulator of major histocompatibility complex class II (MHC class II) gene expression. The expression of CIITA is highly restricted to cells or tissues expressing MHC class II. Also, CIITA does not appear to directly bind to DNA. Thus, CIITA works as a non-DNA-binding co-activator with remarkable specificity for MHC class II genes.

The regulation of MHC class II expression, finely tuned and controlled at a cell-type-specific level, is predominantly managed by the CIITA [1]. CIITA induces the expression of MHC class II molecules on the surface of antigen-presenting cells such as dendritic cells, macrophages, and B cells. MHC class II molecules are crucial for presenting viral antigens to CD4⁺ T helper cells, thereby initiating a specific immune response. By promoting MHC class II expression, CIITA facilitates the presentation of viral peptides to CD4⁺ T cells. This activation is essential for the proliferation of helper T cells and their secretion of cytokines during the viral infections, which coordinate the immune response, including the activation of CD8+ cytotoxic T cells and B cells [1,2]. In addition to the immune cells, CIITA known to be expressed in hepatocellular carcinoma cells [3]. Also, recently, Dezhbord et al. [4] have shown that CIITA expression is induced by interferon gamma (IFN-γ) in primary normal human hepatocytes. Thus, CIITA has a role in the non-immune cells during the infections including viruses.

Some viruses have evolved mechanisms to evade the immune system by interfering with CIITA expression or function, eventually regulating MHC class II expression(Table 1). To identify immune evasion mechanisms against opportunistic herpes viruses, it is necessary to understand the regulation of immune responses by human cytomegalovirus (HCMV) regarding endogenous MHC class II regulation. Using Kasumi-3 cells as a myeloid progenitor cell model endogenously expressing MHC class II (HLA-DR), altered surface levels of HLA-DR were attributed not to increased endocytosis and degradation, but rather to reduced HLA-DR transcripts caused by decreased expression of CIITA [5]. Additionally, in HCMV-infected human fibroblasts and endothelial cells, HCMV disrupts IFN-γ-stimulated MHC class II expression by inhibiting the JAK/STAT pathway and its disruption prevents the upregulation of CIITA and activation of MHC class II transcription [6]. The Epstein–Barr virus is also known to evade the immune response by inhibiting CIITA. An important regulator of EBV lytic replication, termed Zta (BZLF1, ZEBRA, EB1), is a transcription and replication factor. Expression of Zta in Raji cells has been shown to inhibit the expression of CIITA and Zta-mediated repression is specific to the CIITA promoter [7]. Additionally, LANA, a major latent protein encoded by Kaposi’s sarcoma-associated herpesvirus (KSHV), is critical for the maintenance, replication, and efficient segregation of the viral genome. LANA down-regulates MHC class II expression and presentation by inhibiting the transcriptional activity on CIITA promoter. The inhibition of CIITA by LANA of KSHV is independent of IL-4 or IFN-γ signaling but depends on the direct interaction of LANA with IRF-4, an activator of the CIITA promoter [8]. In addition, it has been reported that the hepatitis C virus suppresses the cell surface expression of HLA-DR, as well as the promoter activity of CIITA, the IFN-γ activation site (GAS), and HLA-DR in HT1080 cells, which are known to be sensitive to HLA-DR induction by IFNs [9].

Table 1.

Role of CIITA in viral infections

Viruses	Mechanisms
Immune evasion by viruses
HCMV	HCMV decreases MHC Class II (HLA-DR) by reducing CIITA levels and inhibiting the Jak/Stat pathway
EBV	CIITA is repressed by EBV transcription factor, Zta
KSHV	IRF-4-mediated CIITA transcription is blocked by KSHV encoded LANA
HCV	HCV inhibits HLA-DR by inhibition of promoter of CIITA
HIV	Tat protein by HIV interferes with the function of CIITA by competing with CIITA for binding to cyclin T1
ASFV	CIITA is important for productive ASFV infection.
Enhancing anti-viral immunity
HIV	CIITA inhibits viral replication by blocking the function of the viral transactivator Tat
SARS-CoV-2	CIITA upregulates CD74/p41, which inhibits cathepsins and prevents genome release into the cytoplasm
EBOV
HTLV-1	CIITA inhibits viral replication by blocking the function of the viral transactivators Tax-1 and Tax-2
HTLV-2
HBV	CIITA inhibits viral replication by ERK regulation

HCMV, human cytomegalovirus; EBV, Epstein-Barr virus; KSHV, Kaposi’s sarcoma-associated herpesvirus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; ASFV, African swine fever virus; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; EBOV, Ebola virus; HTLV-1, human T-cell lymphotropic virus type 1; HTLV-2, human T-cell lymphotropic virus type 2; HBV, hepatitis B virus.

Conversely, through CRISPR/Cas9 knockout screening in porcine cells infected with African swine fever virus (ASFV), it was found that MHC class II-related expression factors and membrane proteins, including CIITA, RFXANK, RFXAP, SLA-DMA, and SLA-DMB, play a crucial role in productive ASFV infection. Targeted knockouts of these genes led to rather severe viral replication defects [10].

CIITA is part of the IFN-stimulated immune response and it plays a role in the antiviral response as well as in antigen presentation(Table 1). Low CIITA levels have been associated with disease severity in both children and adults with COVID-19 [11]. Recently, Bruchez and colleagues demonstrated that CIITA induces resistance to viral infection by activating the expression of the p41 isoform of CD74. This isoform inhibits viral entry by blocking cathepsin-mediated processing of the glycoprotein of Ebola virus and Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), thereby preventing viral fusion. Further analysis revealed that CD74 p41 can block the endosomal entry pathway of SARS-CoV-2 [12]. In addition, CIITA induces antiviral activity against other pathogenic filoviruses through the inhibition of viral glycoprotein-mediated entry [12].

To inhibit the expression of MHC class II molecules, Tat protein of HIV interferes with the function of CIITA by competing with CIITA for binding to cyclin T1, a subunit of the transcription elongation factor P-TEFb complex which is crucial for HIV transcription [13]. But conversely, CIITA can inhibit the replication of HIV by blocking the function of the viral transactivator Tat [13,14]. Also, CIITA acts as a restriction factor against human T cell leukemia virus-1 (HTLV-1) and human T cell leukemia virus-2 (HTLV-2) by targeting their viral transactivators, Tax-1 and Tax-2, respectively. CIITA inhibits Tax-1-mediated NF-κB activation. Furthermore, nuclear bodies containing CIITA bind Tax-1/RelA, thereby blocking the activation of NF-κB-controlled genes in the nucleus [15-18]. Therefore, CIITA effectively contributes to antiviral defense by promoting antigen presentation against viruses and suppressing viral gene expression through targeting the activity of viral transcriptional activators.

In the current Clinical and Molecular Hepatology issue, Dezhbord et al. [4] unveiled a novel antiviral mechanism of CIITA on hepatitis B virus (HBV) replication in the infected hepatocytes. Achieving a complete cure for HBV is challenging with the existing nucleos(t)ide analogs and interferon therapies. To overcome the limitations of these current treatments in completely curing HBV, there is a growing need for drug candidates that target new therapeutic mechanisms of the virus [19,20]. Dezhbord et al. [4] confirmed that CIITA inhibits virus replication in hepatocytes by downregulating hepatocyte nuclear factors HNF1α and HNF4α via ERK1/2 signaling pathways, which are critical for viral replication. Moreover, HBx hinders CIITA function by directly binding to it, potentially leading to resistance against CIITA’s inhibition of HBV. This underscores its potential utility as a novel transcriptional regulator with anti-HBV properties for therapeutic intervention against HBV infection. Thus, Dezhbord et al.’s study provided a novel antiviral mechanism of CIITA that involves the modulation of the ERK pathway to restrict HBV transcription in the hepatocytes.

Abbreviations

CIITA

class II transactivator

MHC

class II

IIFN-γ

interferon gamma

HCMV

human cytomegalovirus

KSHV

Kaposi’s sarcomaassociated herpesvirus

ASFV

African swine fever virus

SARS-CoV-2

severe acute respiratory syndrome coronavirus 2

HTLV

human T cell leukemia virus

HBV

hepatitis B virus