Curaxin CBL0100 Blocks HIV-1 Replication and Reactivation through Inhibition of Viral Transcriptional Elongation
Despite combination antiretroviral therapy (cART), acquired immunodeficiency syndrome (AIDS), predominantly caused by the human immunodeficiency virus type 1 (HIV-1), remains incurable. The barrier to a cure lies in the virus' ability to establish a latent infection in HIV/AIDS patients. Unsurp...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-10-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fmicb.2017.02007/full |
| _version_ | 1811201288434614272 |
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| author | Maxime J. Jean Tsuyoshi Hayashi Huachao Huang Justin Brennan Sydney Simpson Andrei Purmal Katerina Gurova Michael C. Keefer James J. Kobie Netty G. Santoso Jian Zhu Jian Zhu |
| author_facet | Maxime J. Jean Tsuyoshi Hayashi Huachao Huang Justin Brennan Sydney Simpson Andrei Purmal Katerina Gurova Michael C. Keefer James J. Kobie Netty G. Santoso Jian Zhu Jian Zhu |
| author_sort | Maxime J. Jean |
| collection | DOAJ |
| description | Despite combination antiretroviral therapy (cART), acquired immunodeficiency syndrome (AIDS), predominantly caused by the human immunodeficiency virus type 1 (HIV-1), remains incurable. The barrier to a cure lies in the virus' ability to establish a latent infection in HIV/AIDS patients. Unsurprisingly, efforts for a sterilizing cure have focused on the “shock and kill” strategy using latency-reversing agents (LRAs) to complement cART in order to eliminate these latent reservoirs. However, this method faces numerous challenges. Recently, the “block and lock” strategy has been proposed. It aims to reinforce a deep state of latency and prevent sporadic reactivation (“blip”) of HIV-1 using latency-promoting agents (LPAs) for a functional cure. Our studies of curaxin 100 (CBL0100), a small-molecule targeting the facilitates chromatin transcription (FACT) complex, show that it blocks both HIV-1 replication and reactivation in in vitro and ex vivo models of HIV-1. Mechanistic investigation elucidated that CBL0100 preferentially targets HIV-1 transcriptional elongation and decreases the occupancy of RNA Polymerase II (Pol II) and FACT at the HIV-1 promoter region. In conclusion, CBL0100 is a newly identified inhibitor of HIV-1 transcription that can be used as an LPA in the “block and lock” cure strategy. |
| first_indexed | 2024-04-12T02:19:36Z |
| format | Article |
| id | doaj.art-0186659eae02410ab9fa01aa141857c2 |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-04-12T02:19:36Z |
| publishDate | 2017-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-0186659eae02410ab9fa01aa141857c22022-12-22T03:52:09ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2017-10-01810.3389/fmicb.2017.02007307347Curaxin CBL0100 Blocks HIV-1 Replication and Reactivation through Inhibition of Viral Transcriptional ElongationMaxime J. Jean0Tsuyoshi Hayashi1Huachao Huang2Justin Brennan3Sydney Simpson4Andrei Purmal5Katerina Gurova6Michael C. Keefer7James J. Kobie8Netty G. Santoso9Jian Zhu10Jian Zhu11Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, United StatesDepartment of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, United StatesDepartment of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, United StatesDepartment of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, United StatesDepartment of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, United StatesIncuron LLC, Buffalo, NY, United StatesDepartment of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, United StatesDepartment of Medicine, Infectious Diseases, University of Rochester Medical Center, Rochester, NY, United StatesDepartment of Medicine, Infectious Diseases, University of Rochester Medical Center, Rochester, NY, United StatesDepartment of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, United StatesDepartment of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, United StatesDepartment of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY, United StatesDespite combination antiretroviral therapy (cART), acquired immunodeficiency syndrome (AIDS), predominantly caused by the human immunodeficiency virus type 1 (HIV-1), remains incurable. The barrier to a cure lies in the virus' ability to establish a latent infection in HIV/AIDS patients. Unsurprisingly, efforts for a sterilizing cure have focused on the “shock and kill” strategy using latency-reversing agents (LRAs) to complement cART in order to eliminate these latent reservoirs. However, this method faces numerous challenges. Recently, the “block and lock” strategy has been proposed. It aims to reinforce a deep state of latency and prevent sporadic reactivation (“blip”) of HIV-1 using latency-promoting agents (LPAs) for a functional cure. Our studies of curaxin 100 (CBL0100), a small-molecule targeting the facilitates chromatin transcription (FACT) complex, show that it blocks both HIV-1 replication and reactivation in in vitro and ex vivo models of HIV-1. Mechanistic investigation elucidated that CBL0100 preferentially targets HIV-1 transcriptional elongation and decreases the occupancy of RNA Polymerase II (Pol II) and FACT at the HIV-1 promoter region. In conclusion, CBL0100 is a newly identified inhibitor of HIV-1 transcription that can be used as an LPA in the “block and lock” cure strategy.http://journal.frontiersin.org/article/10.3389/fmicb.2017.02007/fullhuman immunodeficiency virus (HIV)HIV latencylatency-promoting agents (LPA)FACT complexcuraxins |
| spellingShingle | Maxime J. Jean Tsuyoshi Hayashi Huachao Huang Justin Brennan Sydney Simpson Andrei Purmal Katerina Gurova Michael C. Keefer James J. Kobie Netty G. Santoso Jian Zhu Jian Zhu Curaxin CBL0100 Blocks HIV-1 Replication and Reactivation through Inhibition of Viral Transcriptional Elongation Frontiers in Microbiology human immunodeficiency virus (HIV) HIV latency latency-promoting agents (LPA) FACT complex curaxins |
| title | Curaxin CBL0100 Blocks HIV-1 Replication and Reactivation through Inhibition of Viral Transcriptional Elongation |
| title_full | Curaxin CBL0100 Blocks HIV-1 Replication and Reactivation through Inhibition of Viral Transcriptional Elongation |
| title_fullStr | Curaxin CBL0100 Blocks HIV-1 Replication and Reactivation through Inhibition of Viral Transcriptional Elongation |
| title_full_unstemmed | Curaxin CBL0100 Blocks HIV-1 Replication and Reactivation through Inhibition of Viral Transcriptional Elongation |
| title_short | Curaxin CBL0100 Blocks HIV-1 Replication and Reactivation through Inhibition of Viral Transcriptional Elongation |
| title_sort | curaxin cbl0100 blocks hiv 1 replication and reactivation through inhibition of viral transcriptional elongation |
| topic | human immunodeficiency virus (HIV) HIV latency latency-promoting agents (LPA) FACT complex curaxins |
| url | http://journal.frontiersin.org/article/10.3389/fmicb.2017.02007/full |
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