Role of HTLV-1 HBZ in viral infection

人T细胞白血病病毒1型(HTLV-1)是一种复杂的逆转录病毒，主要在体内感染CD4T细胞。HTLV-1感染与多种病理效应有关，包括一种致命的白血病和一种进行性神经退行性疾病。由于这些疾病已被证明对许多治疗方法无效，目前的临床治疗显示出有限的疗效。另外，HTLV-1生物学的某些方面阻碍了疫苗的开发。一种相对未经测试的可能克服这些障碍的方法是抑制HTLV-1在宿主T细胞群体中的传染性传播，以此作为降低疾病发展和病毒传播风险的一种手段。基于这一概念开发新疗法的核心是彻底了解HTLV-1感染过程。HTLV-1在T细胞之间的感染需要被感染的细胞和靶细胞直接接触。这一事件触发了感染细胞中微管组织中心向靶细胞的极化，使HTLV-1包膜糖蛋白(Env)和其他病毒结构蛋白转移到细胞-细胞连接处。虽然环境病毒是感染的中心，但在细胞接触介导的感染之前和期间调节其细胞内运输的机制相对不清楚。我们最近发现HTLV-1编码的转录调节因子HBZ可以增强感染。我们认为这一功能源于HBZ对参与感染过程的某些细胞基因表达的影响。因此，我们最近发现HBZ激活了MYOF转录。这个细胞基因编码Myoferlin，它在膜分离中起作用，并在内体转运中发挥重要作用。我们的初步数据表明，HBZ通过将细胞共激活因子p300/CBP招募到MYOF基因来激活myoferlin的表达。与HBZ介导的激活一致，Myoferlin在HTLV-1感染的T细胞中异常表达。重要的是，这些细胞中Myoferlin的表达减少或功能抑制可以抑制病毒感染并降低Env的水平。基于这些初步数据和来自其他研究的数据，我们假设myoferlin通过有利于Env可用于病毒组装的内体途径促进Env的运输。如果没有myoferlin，我们假设Env被送到溶酶体进行降解。我们建议在特定目标1中解决这些假设，在该目标中，我们将表征Myoferlin如何影响HTLV-1感染的T细胞中的环境运输。这一目标的结果将阐明Env细胞内转运的调节机制，这是病毒感染的核心。聚焦于HBZ介导的MYOF转录激活，我们假设阻断HBZ和p300/CBP之间相互作用的特定化合物将减少myoferlin的表达，进而降低病毒感染。我们建议在特定目标2中测试这一假设，在该目标中，我们将识别阻止相互作用的化合物。对于HTLV-1携带者和患者来说，这一目标的结果将确定具有潜在治疗能力的化合物。

Human T-cell Leukemia Virus type 1 (HTLV-1) is a complex retrovirus that primarily infects CD4+ T- cells in vivo. HTLV-1 infection is associated with diverse pathological effects, including a fatal form of leukemia and a progressive neurodegenerative disease. As these diseases have proven refractory to numerous therapeutic approaches, current clinical treatments show limited efficacy. Separately, certain aspects of HTLV- 1 biology have hindered the development of a vaccine. One relatively untested approach that may overcome these obstacles is to inhibit the infectious spread of HTLV-1 within the host's T-cell population as a means of reducing the risk of disease development and viral transmission. Central to the development of novel therapies based on this concept is a thorough understanding of the HTLV-1 infection process. HTLV-1 infection between T-cells requires the infected and target cells to come into direct contact. This event triggers polarization of the microtubule organizing center in the infected cell towards the target cell, allowing the HTLV-1 envelope glycoprotein (Env) and other viral structural proteins to translocate to the cell-cell juncture. While Env is central to infection, mechanisms modulating its intracellular trafficking before and during cell-contact-mediated infection are relatively unclear. We recently discovered that the HTLV-1-encoded transcriptional regulator, HBZ, augments infection. We believe this function stems from effects of HBZ on the expression of certain cellular genes that participate in the infection process. Accordingly, we recently found that HBZ activates MYOF transcription. This cellular gene encodes myoferlin, which functions in membrane sorting and plays an important role in endosomal trafficking. Our preliminary data indicate that HBZ activates myoferlin expression by recruiting the cellular coactivator, p300/CBP, to the MYOF gene. Consistent with HBZ-mediated activation, myoferlin is aberrantly expressed in HTLV-1-infected T-cells. Importantly, reduced expression or functional inhibition of myoferlin in these cells inhibits viral infection and diminishes the level of Env. Based on these preliminary data and data from other studies, we hypothesize that myoferlin promotes the trafficking of Env through an endosomal pathway that favors the availability of Env for viral assembly. Without myoferlin, we hypothesize that Env is routed to lysosomes for degradation. We propose to address these hypotheses in Specific Aim 1 in which we will characterize how myoferlin affects Env trafficking in HTLV-1-infected T-cells. Results from this aim will clarify a regulatory mechanism of Env intracellular trafficking that is central to viral infection. Focusing on HBZ- mediated activation of MYOF transcription, we hypothesize that specific compounds that block the interaction between HBZ and p300/CBP will reduce myoferlin expression and, in turn, viral infection. We propose to test this hypothesis in Specific Aim 2 in which we will identify compounds that block the interaction. For HTLV-1 carriers and patients alike, results from this aim will identify compounds with potential therapeutic capabilities.