HTLV-1 (Human T cell Lymphotropic Virus type 1) and HTLV-2 (Human T cell Lymphotropic virus type 2) are closely related human retroviruses that belong to deltaviridae family, subfamily oncovirus type C, characterized by similar genomic organization and common modes of transmission but different disease manifestations . It is estimated that about 15-20 millions of people live with HTLV infection worldwide . HTLV-1 infection is endemic in Japan, Africa, South America, and the Caribbean basin. HTLV-2 infection is highly concentrated in Central and West Africa, in native Amerindian populations in North, Central, and South America, and among cohorts of intravenous drug users (IVDUs) in the United States and Europe . HTLVs are transmitted sexually, by breast feeding or by blood transfusions .
HTLV-1 and HTLV-2 show a differential cellular tropism. HTLV-1 has a preferential tropism for CD4+ T cells  while HTLV-2 preferentially infects CD8+ T cells, although this restriction is not absolute, as both viruses may also infect B cells, monocytes, microglial and endothelial cells, at least in vitro [6–8]. HTLV-1 is the etiologic agent of adult T-cell leukaemia/lymphoma (ATLL) and of the tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM) [9–12]. Conversely, no clear association to specific diseases has been described for HTLV-2 infection .
The basis of HTLV mediated cellular transformation is not completely understood, but it involves the viral transactivator protein Tax. Tax is essential for HTLV-1- and HTLV-2-mediated immortalization of primary human T cells [13, 14] and for tumors induction in transgenic mice [15, 16]. The precise mechanism by which Tax initiates the malignant process is unclear, but it seems to involve the de-regulation of several steps both at transcriptional and post-transcriptional level . Tax activates transcription of many cellular genes, including interleukin-2 (IL-2) and IL-2Ra [18, 19] and affects critical signal transduction pathways regulating cell cycle, cell growth, DNA repair and apoptosis . Many evidences indicate that the transcriptional activation of cellular genes is mediated by Tax-dependent activation of transcriptional factors, such as CREB/ATF, NF-kB and SRF (Serum Responsive Factor). As Tax plays such an important role in gene expression and pathogenesis of HTLV viruses, numerous studies have been directed toward the understanding of the mechanism of Tax transactivation.
We reported that Tax-2 transactivation of the HTLV-2 LTR is strongly inhibited by the host transcription factor CIITA. As a consequence, susceptible T and B human cells do not support HTLV-2 replication when expressing CIITA [21, 22]. Similarly, CIITA targets the viral transactivator Tat to inhibit the replication of the HIV-1 virus [23, 24].
The AIR-1 locus-encoded class II transactivator CIITA is the master regulator of the expression of Major Histocompatibility Complex class II (MHC-II) genes [25–27]. MHC-II-encoded molecules play a key role in the homeostasis of the immune system. They present peptides to the antigen receptor of CD4+ T cells (TH), whose activation is required to trigger and modulate both humoral and cellular immune responses . CIITA is a non-DNA-binding transcriptional integrator recruited to MHC-II promoters via multiple interactions with transcription factors bound to DNA, including the RFX and the NF-Y complexes [29–34]. It interacts with CBP, p300, PCAF as well as the cyclin T1 subunit of the positive transcription elongation factor b (P-TEFb) to enhance MHC-II gene transcription [35–38]. P-TEFb is also used by Tat to promote the elongation of HIV-1 viral transcripts  and we have shown that sequestration of cyclin T1 is the major mechanism by which CIITA blocks the transactivating function of Tat . On the contrary, the molecular basis of the CIITA-mediated inhibition of Tax-2 is still not completely understood. Previous investigations have established that the CIITA 1-321 N-terminal region, with an exclusive nuclear distribution, inhibits Tax-2 function and viral replication. We identified CBP and p300 as crucial factors for the Tax-2-directed LTR transactivation. However, they are not involved in CIITA-mediated inhibition of Tax-2. Instead the overexpression of the ubiquitous transcription factor NF-YB, that interacts with CIITA in the MHC class II enhanceosome, was found to inhibit Tax-2 transactivating function .
In this paper we have investigated the intimate molecular nature of the CIITA mediated inhibition of Tax-2. We found that both CIITA and NF-Y interact in vivo with Tax-2. We identified both an N-terminal and a C-terminal region of CIITA interacting with the viral transactivator, although, as stated above, only the N-terminal region is involved in the inhibition of Tax-2 function. Interestingly, in absence of CIITA, endogenous NF-YB can still bind to Tax-2, although, as we have previously shown, this interaction does not results in functional inactivation of Tax-2 on the HTLV-2 LTR promoter. CIITA-NF-YB interaction in vivo is stabilized and/or favoured by the presence of Tax-2. Thus concomitant interaction of Tax-2 with CIITA and NF-YB, most likely in the CIITA-NF-YB molecular complex, is at the basis of the functional inactivation of Tax-2 leading to the inhibition of HTLV-2 retrovirus replication. Further studies of subcellular localization unveiled the co-localization of Tax-2 and CIITA both in the cytoplasm and the nucleus, and the role of CIITA in redirecting, upon binding, Tax-2 molecules mostly in the cytoplasm.
These results are discussed within the present knowledge of cell host-pathogen interaction and the identification of the dual role of CIITA as modulator of adaptive immunity and restriction factor against human retroviruses.