The ability of the Lentivirus HIV-1 to inhibit T-cell activation by its gp41 fusion protein is well documented, yet limited data exists regarding other viral fusion proteins. HIV-1 utilizes membrane binding region of gp41 to inhibit T-cell receptor (TCR) complex activation. Here we examined whether this T-cell suppression strategy is unique to the HIV-1 gp41. We focused on T-cell modulation by the gp21 fusion peptide (FP) of the Human T-lymphotropic Virus 1 (HTLV-1), a Deltaretrovirus that like HIV infects CD4⁺ T-cells. Using mouse and human in-vitro T-cell models together with in-vivo T-cell hyper activation mouse model, we reveal that HTLV-1’s FP inhibits T-cell activation and unlike the HIV FP, bypasses the TCR complex. HTLV FP inhibition induces a decrease in Th1 and an elevation in Th2 responses observed in mRNA, cytokine and transcription factor profiles. Administration of the HTLV FP in a T-cell hyper activation mouse model of multiple sclerosis alleviated symptoms and delayed disease onset. We further pinpointed the modulatory region within HTLV-1’s FP to the same region previously identified as the HIV-1 FP active region, suggesting that through convergent evolution both viruses have obtained the ability to modulate T-cells using the same region of their fusion protein. Overall, our findings suggest that fusion protein based T-cell modulation may be a common viral trait.

慢病毒HIV-1通过其gp41融合蛋白抑制T细胞活化的能力已得到充分证明，但有关其他病毒融合蛋白的数据有限。HIV-1利用gp41的膜结合区来抑制T细胞受体（TCR）复合物的激活。在这里，我们检查了这种T细胞抑制策略是否是HIV-1 gp41特有的。我们专注于人类T淋巴病毒1（HTLV-1）的gp21融合肽（FP）对T细胞的调节，该病毒是一种像HIV一样感染CD4 ⁺ T细胞的三角洲逆转录病毒。结合使用小鼠和人类体外T细胞模型以及体内在T细胞超活化小鼠模型中，我们揭示了HTLV-1的FP抑制T细胞活化，并且与HIV FP不同，它绕过了TCR复合体。HTLV FP抑制诱导mRNA，细胞因子和转录因子谱中观察到的Th1减少和Th2反应的升高。在多发性硬化症的T细胞过度激活小鼠模型中施用HTLV FP可以缓解症状并延缓疾病发作。我们进一步将HTLV-1 FP内的调节区精确定位为先前鉴定为HIV-1 FP活性区的相同区域，这表明通过融合进化，两种病毒都获得了使用其融合蛋白相同区域调节T细胞的能力。 。总体而言，我们的发现表明基于融合蛋白的T细胞调节可能是常见的病毒性状。