title: Naf1 Regulates HIV-1 Latency by Suppressing Viral Promoter-Driven Gene Expression in Primary CD4+ T Cells.
abstract: HIV-1 latency is characterized by reversible silencing of viral transcription driven by the long terminal repeat (LTR) promoter of HIV-1. Cellular and viral factors regulating LTR activity contribute to HIV-1 latency, and certain repressive cellular factors modulate viral transcription silencing. Nef-associated factor 1 (Naf1) is a host nucleocytoplasmic shuttling protein that regulates multiple cellular signaling pathways and HIV-1 production. We recently reported that nuclear Naf1 promoted nuclear export of unspliced HIV-1 gag mRNA, leading to increased Gag production. Here we demonstrate new functions of Naf1 in regulating HIV-1 persistence. We found that Naf1 contributes to the maintenance of HIV-1 latency by inhibiting LTR-driven HIV-1 gene transcription in a nuclear factor kappa B-dependent manner. Interestingly, Naf1 knockdown significantly enhanced viral reactivation in both latently HIV-1-infected Jurkat T cells and primary central memory CD4+T cells. Furthermore, Naf1 knockdown in resting CD4+T cells from HIV-1-infected individuals treated with antiretroviral therapy significantly increased viral reactivation upon T-cell activation, suggesting an important role of Naf1 in modulating HIV-1 latency in vivo Our findings provide new insights for a better understanding of HIV-1 latency and suggest that inhibition of Naf1 activity to activate latently HIV-1-infected cells may be a potential therapeutic strategy.
  
  
  OBJECTIVE
  HIV-1 latency is characterized mainly by a reversible silencing of LTR promoter-driven transcription of an integrated provirus. Cellular and viral proteins regulating LTR activity contribute to the modulation of HIV-1 latency. In this study, we found that the host protein Naf1 inhibited HIV-1 LTR-driven transcription of HIV genes and contributed to the maintenance of HIV-1 latency. Our findings provide new insights into the effects of host modulation on HIV-1 latency, which may lead to a potential therapeutic strategy for HIV persistence by targeting the Naf1 protein.
authors: CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.|Guangzhou Women and Children's Medical Center, Guangzhou, China.
authors: Chuan
authors: C
authors: Li
authors: CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
authors: Hai-Bo
authors: HB
authors: Wang
authors: CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
authors: Wen-Dong
authors: WD
authors: Kuang
authors: CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
authors: Xiao-Xin
authors: XX
authors: Ren
authors: CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
authors: Shu-Ting
authors: ST
authors: Song
authors: State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China.
authors: Huan-Zhang
authors: HZ
authors: Zhu
authors: Key Laboratory of Prevention and Treatment with Traditional Chinese Medicine of Viral Infectious Disease, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China.
authors: Qiang
authors: Q
authors: Li
authors: Key Laboratory of Prevention and Treatment with Traditional Chinese Medicine of Viral Infectious Disease, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China.
authors: Li-Ran
authors: LR
authors: Xu
authors: Key Laboratory of Prevention and Treatment with Traditional Chinese Medicine of Viral Infectious Disease, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China.
authors: Hui-Jun
authors: HJ
authors: Guo
authors: Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA wu.840@osu.edu jh_wang@sibs.ac.cn.|Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, USA.
authors: Li
authors: L
authors: Wu
authors: CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China wu.840@osu.edu jh_wang@sibs.ac.cn.|Guangzhou Women and Children's Medical Center, Guangzhou, China.
authors: Jian-Hua
authors: JH
authors: Wang
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000821:virology; D002467:Cell Nucleus / Q000378:metabolism / Q000821:virology; D015967:Gene Expression Regulation, Viral; D020868:Gene Silencing; D015658:HIV Infections / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D019169:Jurkat Cells; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D012261:Ribonucleoproteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D014775:Virus Activation; D017735:Virus Latency / Q000235:genetics*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism
chemical_list: C551999:NAF1 protein, human; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012367:RNA, Viral; D012261:Ribonucleoproteins; D054301:gag Gene Products, Human Immunodeficiency Virus
keywords: HIV-1 Nef-associated factor 1; HIV-1 latency; NF-κB; transcription