VAPA

在一项新的研究中，来自美国托罗大学和德国德累斯顿工业大学等研究机构的研究人员发现了人类免疫缺陷病毒（HIV）进入健康T细胞的细胞核的新途径，这种病毒可以在那里复制并继续入侵其他细胞。他们还确定了这种病 在一项新的研究中，来自美国托罗大学和德国德累斯顿工业大学等研究机构的研究人员发现了人类免疫缺陷病毒（HIV）进入健康T细胞的细胞核的新途径，这种病毒可以在那里复制并继续入侵其他细胞。他们还确定了这种病毒进行入侵细胞核所需的三种蛋白：外核膜蛋白VAP-A、高度磷酸化的ORP3和Rab7，并进而合成了能够靶向其中一种蛋白的分子（潜在药物），从而有可能开发出治疗艾滋病的新疗法。相关研究结果于2023年8月10日发表在Nature Communications期刊上，论文标题为“HIV-1-induced nuclear invaginations mediated by VAP-A, ORP3, and Rab7 complex explain infection of activated T cells”。 论文共同通讯作者、托罗大学内华达骨科医学院病理学教授Aurelio Lorico 博士说，“我们揭示了一种似乎对疾病有直接影响的蛋白通路，这为潜在药物开发开辟了一个新领域。” HIV感染需要这种病毒进入T细胞，侵入受到严密保护的细胞核，才能将这种病毒的遗传物质整合到健康T细胞的 DNA 中。但这种病毒如何穿过保护的核膜并不十分清楚，这也是争论的焦点。 这种新发现的途径是，HIV 首先通过包裹在一种称为“内体（endosome）”的膜包内进入T细胞。然后，含有这种病毒的内体将保护性核膜向内推，形成一种称为核内陷（nuclear invagination）的凹痕。然后，内体在核内陷中移动到它的内侧顶端，在那里内体中的这种病毒随即滑入细胞核。 这项新的研究发现三种蛋白对HIV侵入细胞核中至关重要： 一种蛋白（Rab7）位于内体的膜上，第二种蛋白（VAP-A）位于发生核内陷的核膜上，第三种蛋白（ORP3）将前两种蛋白连接在一起。HIV成功侵入T细胞核需要这三种蛋白之间的相互作用，因此针对其中的任何一种蛋白都能阻止HIV感染。他们合成并测试了能中断这三蛋白之间相互作用的分子。他们观察到，在这类分子存在的情况下，HIV复制不会发生。 由Rab7、VAP-A和ORP3组成的VOR复合物抑制HIV-1整合酶转运到核质网和生产性感染。图片来自Nature Communications, 2023, doi:10.1038/s41467-023-40227-8。 这种进入细胞核的途径是这些作者在癌症转移研究中首次发现的，很可能还涉及其他疾病。Lorico说，“这是一种全新的途径，我们已开发出了阻断这种途径的分子（药物）。虽然我们的研究还处于临床前阶段，但合成的新药很可能对HIV、其他病毒性疾病、转移性癌症以及其他涉及核转运的疾病具有治疗活性。”他们目前正在研究该途径在阿尔茨海默病和多种癌症转移中的作用。 论文共同通讯作者、德累斯顿工业大学生物技术中心研究小组组长Denis Corbeil博士说，“由于我们发现的途径可能适用于多种类型的疾病，因此要了解这项研究的全部益处，还有大量研究工作要做。”这种途径在改善患者护理方面的潜在治疗应用是巨大的，可能会帮助人们更好地应对下一次大流行病。（生物谷 Bioon.com） 参考资料： Mark F. Santos et al. HIV-1-induced nuclear invaginations mediated by VAP-A, ORP3, and Rab7 complex explain infection of activated T cells. Nature Communications, 2023, doi:10.1038/s41467-023-40227-8.

Discovery May Lead to New Treatments for AIDS HENDERSON, Nev., Aug. 10, 2023 /PRNewswire/ -- A study published August 10, 2023 in the journal Nature Communications has identified a new pathway that human immunodeficiency virus (HIV) uses to enter the nucleus of a healthy cell, where it can then replicate and go on to invade other cells. The researchers also identified three proteins that are needed for the virus to carry out the invasion and have in turn synthesized molecules (potential drugs) that can target one of the proteins, potentially leading to new treatments for AIDS. Continue Reading HIV virus (yellow) infecting a human cell © Photo by National Cancer Institute on Unsplash "We have revealed a protein pathway that appears to have a direct impact on diseases, which opens up a new area for potential drug development," says the study's senior author Aurelio Lorico, MD PhD, Professor of Pathology and interim Chief Research Officer at Touro University Nevada College of Osteopathic Medicine. HIV infection requires the virus to enter a cell and gain access to the well-guarded nucleus in order for the viral components to be integrated into the healthy cell's DNA. But how the viruses get past the protective membrane is not well understood and is the subject of much debate. The newly identified pathway begins with HIV entering a cell wrapped inside a membrane package, called an endosome. The virus-containing endosome then pushes the protective nuclear membrane inward, forming an indentation known as a nuclear invagination. The endosome then moves inside the invagination to its inner tip, where the virus then slips into the nucleus. The study found that three proteins were critical to the invasion: One protein (Rab7) is located on the membrane of the endosome, the second (VAP-A) is on the nuclear membrane where the invagination occurs, and the third (ORP3) connects the first two proteins together. An interaction among the three proteins is needed for the invasion to be successful, so targeting any of these proteins could halt the infection. The team has synthesized and tested molecules that interrupt the interaction among the proteins. The researchers observed that, in the presence of these molecules, HIV replication does not occur. This pathway for nuclear access was first discovered in the team's research on cancer metastasis and is likely involved in other diseases as well. "This is an entirely new pathway and we have developed molecules (drugs) that block it," says Lorico. "Although our research is at a pre-clinical stage, it is likely that the new drugs synthesized may have therapeutic activity in AIDS, other viral diseases, and possibly metastatic cancer and other diseases where nuclear transport is involved." The team is currently looking at the pathway's role in Alzheimer's disease and metastasis of many types of cancer. "Because the pathway we found may apply to many types of disease, there is a tremendous amount of work that needs to be done to understand the full benefits of this research," says Dr. Denis Corbeil, co-leading author of the study, research group leader at the Biotechnology Center (BIOTEC) of TUD Dresden University of Technology in Germany. "The ground-breaking research of Dr. Lorico and his team is a testimony to the importance that Touro University gives to its mission of service to humanity. The potential therapeutic applications of this new pathway to improve patient care are immense and may help us better navigate the next pandemic," said Dr. Alan Kadish, Touro University President. The study, HIV-1-induced nuclear invaginations mediated by VAP-A, ORP3, and Rab7 complex explain infection of activated T cells, was the result of a collaboration of researchers from Touro University Nevada College of Osteopathic Medicine, Touro College of Osteopathic Medicine in New York, researchers from the Biotechnology Center (BIOTEC) of TUD Dresden University of Technology in Germany, and researchers from Italy. For more information, visit . ABOUT TOURO UNIVERSITY NEVADA Touro University Nevada is Nevada's largest school of medicine and largest school of physician assistant studies, fully accredited, and a private, non-profit, Jewish-sponsored institution. Opened in 2004, Touro Nevada was established to help address critical needs in health care and education and as a resource for community service throughout Nevada. Its mission is to provide quality education programs in the fields of health care and education in concert with the Judaic commitment to social justice, intellectual pursuit, and service to humanity. Touro Nevada is home to more than 1,500 students in a wide variety of degree programs including osteopathic medicine, physician assistant studies, education, nursing, occupational therapy, physical therapy, and medical health sciences. The University's Henderson campus houses the Engelstad Research Complex for Biomedical and Human Performance Research that is committed to serving humanity and contributing to intellectual progress through insightful scientific research. For more information, visit . ABOUT THE BIOTECHNOLOGY CENTER (BIOTEC) OF TUD DRESDEN UNIVERSITY OF TECHNOLOGY The Biotechnology Center (BIOTEC) was founded in 2000 as a central scientific unit of the TUD Dresden University of Technology with the goal of combining modern approaches in molecular and cell biology with the traditionally strong engineering in Dresden. Since 2016, the BIOTEC is part of the central scientific unit Center for Molecular and Cellular Bioengineering (CMCB) of the TU Dresden. The BIOTEC is fostering developments in research and teaching within the Molecular Bioengineering research field and combines approaches in cell biology, biophysics and bioinformatics. It plays a central role within the research priority area Health Sciences, Biomedicine and Bioengineering of the TU Dresden. Contact: USA+: Michael Sherry at BerlinRosen at [email protected] Germany: Dr. Denis Corbeil at BIOTEC, TUD at [email protected] SOURCE Touro University Nevada