Restriction factors in human retrovirus infections and the unprecedented case of CIITA as link of intrinsic and adaptive immunity against HTLV-1

Abstract

Background: Immunity against pathogens evolved through complex mechanisms that only for sake of simplicity are defined as innate immunity and adaptive immunity. Indeed innate and adaptive immunity are strongly intertwined each other during evolution. The complexity is further increased by intrinsic mechanisms of immunity that rely on the action of intracellular molecules defined as restriction factors (RFs) that, particularly in virus infections, counteract the action of pathogen gene products acting at different steps of virus life cycle.

Main body and conclusion: Here we provide an overview on the nature and the mode of action of restriction factors involved in retrovirus infection, particularly Human T Leukemia/Lymphoma Virus 1 (HTLV-1) infection. As it has been extensively studied by our group, special emphasis is given to the involvement of the MHC class II transactivator CIITA discovered in our laboratory as regulator of adaptive immunity and subsequently as restriction factor against HIV-1 and HTLV-1, a unique example of dual function linking adaptive and intrinsic immunity during evolution. We describe the multiple molecular mechanisms through which CIITA exerts its restriction on retroviruses. Of relevance, we review the unprecedented findings pointing to a concerted action of several restriction factors such as CIITA, TRIM22 and TRIM19/PML in synergizing against retroviral replication. Finally, as CIITA profoundly affects HTLV-1 replication by interacting and inhibiting the function of HTLV-1 Tax-1 molecule, the major viral product associated to the virus oncogenicity, we also put forward the hypothesis of CIITA as counteractor of HTLV-1-mediated cancer initiation.

Keywords: CIITA; HIV; HTLV-1; Intrinsic immunity; Restriction factors; Tax.

Fig. 1

Possible mechanisms of CIITA-mediated inhibition of Tax-1-mediated and Tax-2-mediated LTR transactivation. a CIITA-Tax-1 association may impair in various ways Tax-1-mediated proviral transcription. aI In the absence of CIITA, Tax-1 promotes proviral genome transcription by inducing the formation of a multiprotein complex containing CREB, CBP and PCAF on the viral LTR promoter. aII In presence of CIITA, Tax-1 is bound by the MHC class II transactivator, preventing the physical formation and assembling of the multiprotein complex on the viral promoter, resulting in inhibition of LTR transcription. aIII Alternatively, Tax-1 in presence of CIITA can still be recruited on the viral LTR promoter with an assembled multiprotein complex which however is still not functional likely because the binding of Tax-1 to PCAF is inefficient due to steric hinderance generated by the Tax-1-CIITA interaction and/or PCAF-CIITA interaction. b In absence of CIITA, Tax-2 may bind endogenous NF-Y transcription factor but this binding is not sufficient to inhibit activation of HTLV-2 LTR and consequent proviral transcription (bI). In presence of CIITA, the NF-Y-CIITA complex strongly increases the affinity of NF-Y for Tax-2 thus recruiting Tax-2 and displacing it from the HTLV-2 LTR promoter. As a consequence, inhibition of HTLV-2 LTR transcription occurs (bII)

Fig. 2

CIITA inhibits the Tax-1-mediated activation of the canonical NF-kB pathway. The oncogenic potential of Tax-1 is mostly due to its ability to constitutively activate NF-kB pathways. Tax-1 deregulates both the canonical and the noncanonical NF-kB pathway, by acting at different levels. In the canonical pathway, Tax-1 interacts with the gamma (γ) subunit of the trimeric IkB kinase (IKK), and activates IKK complex. The activated IKK phosphorylates IkB inhibitor bound to p50/RelA NFκB heterodimer. Following phosphorylation, IkB is degraded and the p50/RelA NF-kB complex migrates into the nucleus activating NF-kB target genes. In the non-canonical pathway, Tax-1 interacts and activates IKKα, which phosphorylates the inhibitory p100 subunit, thus inducing the activation and migration of the p52-/RelB NF-kB heterodimer into the nucleus. Moreover, Tax-1 promotes NF-kB activation in the nucleus by interacting with RelA and stabilizing the binding of p50/RelA to NF-kB-responsive promoters. CIITA exploits different strategies to suppress Tax-1-mediated NF-kB activation by acting in the nucleus and in the cytoplasm. In the cytoplasm [1], CIITA interacts with Tax-1 and this association does not prevent Tax-1 binding to IKKγ subunit of the IKK complex. Nevertheless, CIITA affects Tax-1-induced IKK activity, causing retention of the inactive p50/RelA/IkB complex in the cytoplasm. In the nucleus [2], nuclear CIITA associates with Tax-1/RelA in nuclear bodies, blocking Tax-1-dependent activation of NF-kB-responsive genes [2]