Major histocompatibility complex class II transactivator CIITA is a viral restriction factor that targets human T-cell lymphotropic virus type 1 tax-1 function and inhibits viral replication

Giovanna Tosi, Greta Forlani, Vibeke Andresen, Marco Turci, Umberto Bertazzoni, Genoveffa Franchini, Guido Poli, Roberto S. Accolla

Research output: Contribution to journalArticle

Abstract

Human T-cell lymphotropic virus type 1 (HTLV-1) is the causative agent of an aggressive malignancy of CD4 + T lymphocytes. Since the viral transactivator Tax-1 is a major player in T-cell transformation, targeting Tax-1 protein is regarded as a possible strategy to arrest viral replication and to counteract neoplastic transformation. We demonstrate that CIITA, the master regulator of major histocompatibility complex class II gene transcription, inhibits HTLV-1 replication by blocking the transactivating function of Tax-1 both when exogenously transfected in 293T cells and when endogenously expressed by a subset of U937 promonocytic cells. Tax-1 and CIITA physically interact in vivo via the first 108 amino acids of Tax-1 and two CIITA adjacent regions (amino acids 1 to 252 and 253 to 410). Interestingly, only CIITA 1-252 mediated Tax-1 inhibition, in agreement with the fact that CIITA residues from positions 64 to 124 were required to block Tax-1 transactivation. CIITA inhibitory action on Tax-1 correlated with the nuclear localization of CIITA and was independent of the transcription factor NF-YB, previously involved in CIITA-mediated inhibition of Tax-2 of HTLV-2. Instead, CIITA severely impaired the physical and functional interaction of Tax-1 with the cellular coactivators p300/CBP-associated factor (PCAF), cyclic AMP-responsive element binding protein (CREB), and activating transcription factor 1 (ATF1), which are required for the optimal activation of HTLV-1 promoter. Accordingly, the overexpression of PCAF, CREB, and ATF1 restored Tax-1-dependent transactivation of the viral longterminal-repeat promoter inhibited by CIITA. These findings strongly support our original observation that CIITA, beside increasing the antigen-presenting function for pathogen antigens, acts as an endogenous restriction factor against human retroviruses by blocking virus replication and spreading.

Original languageEnglish
Pages (from-to)10719-10729
Number of pages11
JournalJournal of Virology
Volume85
Issue number20
DOIs
Publication statusPublished - Oct 2011

Fingerprint

Primate T-lymphotropic virus 1
Human T-lymphotropic virus 1
major histocompatibility complex
taxes
virus replication
Major Histocompatibility Complex
T-Lymphocytes
Activating Transcription Factor 1
Virus Replication
Cyclic AMP
Transcriptional Activation
Carrier Proteins
tax Gene Products
Human T-lymphotropic virus 2
Antigens
Amino Acids
U937 Cells
MHC Class II Genes
Trans-Activators
HEK293 Cells

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Major histocompatibility complex class II transactivator CIITA is a viral restriction factor that targets human T-cell lymphotropic virus type 1 tax-1 function and inhibits viral replication. / Tosi, Giovanna; Forlani, Greta; Andresen, Vibeke; Turci, Marco; Bertazzoni, Umberto; Franchini, Genoveffa; Poli, Guido; Accolla, Roberto S.

In: Journal of Virology, Vol. 85, No. 20, 10.2011, p. 10719-10729.

Research output: Contribution to journalArticle

Tosi, Giovanna ; Forlani, Greta ; Andresen, Vibeke ; Turci, Marco ; Bertazzoni, Umberto ; Franchini, Genoveffa ; Poli, Guido ; Accolla, Roberto S. / Major histocompatibility complex class II transactivator CIITA is a viral restriction factor that targets human T-cell lymphotropic virus type 1 tax-1 function and inhibits viral replication. In: Journal of Virology. 2011 ; Vol. 85, No. 20. pp. 10719-10729.
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abstract = "Human T-cell lymphotropic virus type 1 (HTLV-1) is the causative agent of an aggressive malignancy of CD4 + T lymphocytes. Since the viral transactivator Tax-1 is a major player in T-cell transformation, targeting Tax-1 protein is regarded as a possible strategy to arrest viral replication and to counteract neoplastic transformation. We demonstrate that CIITA, the master regulator of major histocompatibility complex class II gene transcription, inhibits HTLV-1 replication by blocking the transactivating function of Tax-1 both when exogenously transfected in 293T cells and when endogenously expressed by a subset of U937 promonocytic cells. Tax-1 and CIITA physically interact in vivo via the first 108 amino acids of Tax-1 and two CIITA adjacent regions (amino acids 1 to 252 and 253 to 410). Interestingly, only CIITA 1-252 mediated Tax-1 inhibition, in agreement with the fact that CIITA residues from positions 64 to 124 were required to block Tax-1 transactivation. CIITA inhibitory action on Tax-1 correlated with the nuclear localization of CIITA and was independent of the transcription factor NF-YB, previously involved in CIITA-mediated inhibition of Tax-2 of HTLV-2. Instead, CIITA severely impaired the physical and functional interaction of Tax-1 with the cellular coactivators p300/CBP-associated factor (PCAF), cyclic AMP-responsive element binding protein (CREB), and activating transcription factor 1 (ATF1), which are required for the optimal activation of HTLV-1 promoter. Accordingly, the overexpression of PCAF, CREB, and ATF1 restored Tax-1-dependent transactivation of the viral longterminal-repeat promoter inhibited by CIITA. These findings strongly support our original observation that CIITA, beside increasing the antigen-presenting function for pathogen antigens, acts as an endogenous restriction factor against human retroviruses by blocking virus replication and spreading.",
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AU - Andresen, Vibeke

AU - Turci, Marco

AU - Bertazzoni, Umberto

AU - Franchini, Genoveffa

AU - Poli, Guido

AU - Accolla, Roberto S.

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