Sci Adv: The Jian Zhu team reveals that drug apron SPLK1 effectively assists in the removal of HIV-1 latent cell cells.

!---- combined antiretroviral therapy (combined antiretroviral therapy, cART) can effectively suppress the viral load of HIV-1 in the peripheral blood of patients and thus greatly delay the life of AIDS patients, but the presence of HIV-1 latent reservoir makes the virus under the pressure of strong drug treatment can continue to infect (persistence), so how to completely eliminate hiv-1 latent library has become the current primary barrier to cure AIDSIn recent years, researchers have worked on a functional cure for HIV-1, which aims to gradually shrink and eventually remove the virus latent pool in the body in different ways, allowing patients to have a long-term control of the virus load without rebounding after the suspension of cARTOne of the most promising methods is called "shock and kill", in which the pre-HIV-1 virus (provirus) in the latent cell is activated by developing and applying highly effective, low-toxic latent reversal factors (LRAs), so that the dormant cell cells can replicate the virus in large quantities again, with the help of the cytopathic effects (cypatoic, CPEs) and immune responses that are eventually destroyed and eliminatedHowever, the study found that while the highly-anticipated LRAs were able to effectively activate latent HIV-1 in vitro and in vivo, the latent reservoir cells were not reducedIn other words, there are theoretical and/or application deficiencies in strategies that rely solely on LRAs to narrow the latent librarySubsequent studies have found that HIV-1 latent infection cells have a unique mechanism to resist killing, thus stabilizing the presence of virus latent banksTherefore, finding out how HIV-1 regulates cellular pathways to improve its viability and how to break this regulation is critical to further optimizing the "shock and kill" functional cure strategyRecently, Science Advances online published the results of the team of Professor Jian Zhu of Ohio State University Wexner Medical Center in the United States Inhibition of Polo-like kinase 1 (PLK1) free-number of the s-viral s-viral s-1 reservoirs in CD4 plus T ex cells vio (first author Zhou Dawei)The study found that cell survival and cell cycle regulation kinase Polo-like kinase 1 (PLK1) play a key regulatory role in HIV-1's solid latent infection of cells to protect them from killingAs an important "whistle" molecule (checkpoint) for cell fistic division, PLK1's function in non-divided cells, especially in regulating cell survival and anti-apoptosis, is also of concernThe Jian Zhu team found that HIV-1 was replicated through both the initial infection (de novo infection) and the latent activation (reactivation from latency) both significantly increased the protein expression of PLK1 in the hiv-1 natural target cell, the progeny CD4 plus T cells, and found that the HIV-1 Nef protein was involved in the protein increase of PLK1The researchers further revealed that Nef could raise the protein levels of PLK1 by holding the intracellular phosphoinositide 3-kinase (PI3K) and aurora kinase A (AURKA) signaling pathwaysSubsequent studies have shown that the increase in levels of the HIV-1-mediated PLK1 protein is due to the sumoization that promotes the protein, while inhibiting the degradation of uphthinander and protease complexesSUMO-izedplek1 occurs in-nuclear and aggregates within the nucleus, stabilizes and increases protein levels while also enhancing cell survival signalingOn this basis, the researchers found that the drug atagonizing PLK1 and the low expression of PLK1 were effective in promoting HIV-1-induced cell death, while in the absence of HIV-1 replication cells, PLK1's antagonism and knock-down did not cause significant cell deathThe results show that the presence of PLK1 hinders HIV-1 replication-induced CPEs, and by breaking this barrier, the virus can effectively induce cell killingFurther studies have shown that with LRAs to activate latent HIV-1, PLK1's drug antagonism can significantly reduce the capacity of the virus's latent reservoir (size) in the peripheral hemorrthlidate CD4 plus T cells (primary y resting CD4 plus T cells) in HIV-1-positive patients In summary, PLK1 in HIV-1 participation in improving the survival of latent cells, resistance to cell death, stability of the latent bank playaning an important regulatory role, and antagonist PLK1 can effectively assist the removal of HIV-1 latent cell cells, which will further around the future HIV-1 functional cure research played a positive guiding role It is well known that although HIV-1 is not a typical cancer-causing virus ( oncovirus ), AIDS patients are prone to numerous AIDS-defined cancers due to immunodeficiency ADCs such as Kaposi sarcoma, KS, primary central nerve lymphoma (primary central nervous system lymphoma, PCNSL), non-Hodgkin lymphoma (non-Hodgkin lymoma, NHL), and other non-defined cancers including lung cancer, liver cancer (cancer), oral cancer (oral cancer), anal cancer, etc The study found that the vast majority of these cancers are associated with abnormal increases in PLK1, which is now an important cancer treatment target for inhibitor development and clinical intervention Therefore, another highlight of this study is to reveal the potential feasibility and significance of treatment with COMBINATION PLK1 inhibitors and cART for AIDS patients Ideally, PLK1 inhibitors can, on the one hand, break the inherent mechanism of HIV-1 latent cells to resist killing, assist the removal of latent cell cells, on the other hand, it will also curb the intensification and spread of cancer, play a double-edged effect Therefore, future studies should focus on inviviable trials and clinical trials to assess the effectiveness of the combined use of PLK1 inhibitors and cART Professor Jian Zhu of the Department of Pathology at Ohio State University Wexner Medical Center is the author of this paper Postdoctoral researcher Dawei Zhou is the first author of this article Wei Zhang at the University of Massachusetts at Boston, Jun Qi of the Dana-Farber Cancer Institute at Harvard Medical School, and Jay Bradner of the Novartis Institute for Biomedical Research at Harvard University