Casoli Claudio, De Lerma Barbaro Andrea, Pilotti Elisabetta, Bertazzoni Umberto, Tosi Giovanna, Accolla Roberto S
Department of Clinical Medicine, Nephrology, and Health Sciences, School of Medicine, University of Parma; Via Gramsci 14, 43100 Parma, Italy.
Blood. 2004 Feb 1;103(3):995-1001. doi: 10.1182/blood-2003-07-2503. Epub 2003 Oct 2.
The human T-cell leukemia virus type 2 (HTLV-2), an oncogenic retrovirus closely related to HTLV-1, produces a lifelong infection whose possible association to certain human diseases is still debated. Although some viral products can influence the expression and action of cellular genes, very little is known about the molecular mechanisms involved. Here we show that the AIR-1-encoded human major histocompatibility complex (MHC) class II transactivator (CIITA) strongly inhibits viral replication, but not virus entry, in human B- and T-cell susceptible targets. This effect results from CIITA inhibiting the Tax-mediated transactivation of the HTLV-2 long-term repeat. Further molecular analysis shows that the N-terminal region of CIITA encompassing the first 321 amino acids is responsible for the inhibitory effect on viral replication. This region is crucial for the transactivation of human MHC class II genes and includes the activation domain as well as domains interacting with coactivators that also are used by the viral transactivator Tax to modulate cellular functions. These results represent the first evidence that a cellular transcriptional activator, controlling the coordinate expression of the entire family of MHC class II antigen-presenting molecules, inhibits HTLV-2 viral replication by a distinct mechanism. In this new role CIITA may represent a new tool for therapeutic strategies aimed at counteracting HTLV-2 replication and spreading.
人类T细胞白血病病毒2型（HTLV-2）是一种与HTLV-1密切相关的致癌逆转录病毒，可导致终身感染，其与某些人类疾病的可能关联仍存在争议。尽管一些病毒产物可影响细胞基因的表达和作用，但对其中涉及的分子机制却知之甚少。在此，我们表明，AIR-1编码的人类主要组织相容性复合体（MHC）II类反式激活因子（CIITA）在人类B细胞和T细胞易感靶标中强烈抑制病毒复制，但不抑制病毒进入。这种效应是由于CIITA抑制了Tax介导的HTLV-2长末端重复序列的反式激活。进一步的分子分析表明，CIITA包含前321个氨基酸的N末端区域对病毒复制的抑制作用负责。该区域对于人类MHC II类基因的反式激活至关重要，包括激活结构域以及与共激活因子相互作用的结构域，病毒反式激活因子Tax也利用这些结构域来调节细胞功能。这些结果首次证明，一种控制MHC II类抗原呈递分子整个家族协同表达的细胞转录激活因子，通过一种独特的机制抑制HTLV-2病毒复制。在这一新角色中，CIITA可能代表了一种旨在对抗HTLV-2复制和传播的治疗策略的新工具。
