PMID- 29976660
OWN - NLM
STAT- MEDLINE
DCOM- 20180910
LR  - 20181114
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Linking)
VI  - 92
IP  - 18
DP  - 2018 Sep 15
TI  - Upregulation of MicroRNA 711 Mediates HIV-1 Vpr Promotion of Kaposi's
      Sarcoma-Associated Herpesvirus Latency and Induction of Pro-proliferation and
      Pro-survival Cytokines by Targeting the Notch/NF-kappaB-Signaling Axis.
LID - e00580-18 [pii]
LID - 10.1128/JVI.00580-18 [doi]
AB  - Coinfection with HIV-1 and Kaposi's sarcoma-associated herpesvirus (KSHV) often
      leads to AIDS-related malignancies, including Kaposi's sarcoma (KS) and primary
      effusion lymphoma (PEL). The interaction between HIV and KSHV plays a pivotal
      role in the progression of these malignancies. We have previously demonstrated
      that, by upregulating miR-942-5p, HIV-1 viral protein R (Vpr) inhibits KSHV lytic
      replication by targeting IkappaBalpha to activate the NF-kappaB signaling (Q.
      Yan, C. Shen, J. Qin, W. Li, M. Hu, H. Lu, D. Qin, J. Zhu, S. J. Gao, C. Lu, J
      Virol 90:8739-8753, 2016). Here, we show that Vpr inactivates Notch signaling,
      resulting in inhibition of KSHV lytic replication and induction of
      pro-proliferative and -survival cytokines, including interleukin-2 (IL-2),
      TIMP-1, IGF-1, and NT-4. Mechanistically, Vpr upregulates miR-711, which directly
      targets the Notch1 3' untranslated region. Suppression of miR-711 relieved Notch1
      and reduced Vpr inhibition of KSHV lytic replication and Vpr induction of
      pro-proliferation and -survival cytokines, while overexpression of miR-711
      exhibited the opposite effect. Finally, overexpression of Notch1 reduced Vpr
      induction of NF-kappaB activity by promoting IkappaBalpha promoter activity. Our 
      novel findings reveal that by upregulating miR-711 to target Notch1, Vpr silences
      Notch signaling to activate the NF-kappaB pathway by reducing IkappaBalpha
      expression, leading to inhibition of KSHV lytic replication and induction of
      pro-proliferation and -survival cytokines. Therefore, the miR-711/Notch/NF-kappaB
      axis is important in the pathogenesis of AIDS-related malignancies and could be
      an attractive therapeutic target.IMPORTANCE HIV-1 infection significantly
      increases the risk of KS and PEL in KSHV-infected individuals. Our previous study
      has shown that HIV-1 Vpr regulates the KSHV life cycle by targeting IkappaBalpha 
      to activate NF-kappaB signaling through upregulating cellular miR-942-5p. In this
      study, we have further found that Vpr inactivates Notch signaling to promote KSHV
      latency and production of pro-proliferation and -survival cytokines. Another
      Vpr-upregulated cellular microRNA, miR-711, participates in this process by
      directly targeting Notch1. As a result, Notch1 upregulation of the IkappaBalpha
      promoter activity is attenuated, resulting in reduced levels of IkappaBalpha
      transcript and protein. Overall, these results illustrate an alternative
      mechanism of HIV-1 Vpr regulation of KSHV latency and aberrant cytokines through 
      the miR-711/Notch/NF-kappaB axis. Our novel findings further demonstrate the role
      of an HIV-1-secreted regulatory protein in the KSHV life cycle and KSHV-related
      malignancies.
CI  - Copyright (c) 2018 American Society for Microbiology.
FAU - Yan, Qin
AU  - Yan Q
AD  - State Key Laboratory of Reproductive Medicine, Nanjing Medical University,
      Nanjing, People's Republic of China.
AD  - Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical
      University, Nanjing, People's Republic of China.
AD  - Department of Microbiology, Nanjing Medical University, Nanjing, People's
      Republic of China.
FAU - Zhao, Runran
AU  - Zhao R
AD  - Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical
      University, Nanjing, People's Republic of China.
AD  - Department of Microbiology, Nanjing Medical University, Nanjing, People's
      Republic of China.
FAU - Shen, Chenyou
AU  - Shen C
AD  - Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical
      University, Nanjing, People's Republic of China.
AD  - Department of Microbiology, Nanjing Medical University, Nanjing, People's
      Republic of China.
FAU - Wang, Fei
AU  - Wang F
AD  - Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical
      University, Nanjing, People's Republic of China.
AD  - Department of Microbiology, Nanjing Medical University, Nanjing, People's
      Republic of China.
FAU - Li, Wan
AU  - Li W
AD  - Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical
      University, Nanjing, People's Republic of China.
AD  - Department of Microbiology, Nanjing Medical University, Nanjing, People's
      Republic of China.
FAU - Gao, Shou-Jiang
AU  - Gao SJ
AD  - Department of Microbiology, Nanjing Medical University, Nanjing, People's
      Republic of China.
AD  - Laboratory of Human Virology and Oncology, Shantou University Medical College,
      Shantou, Guangdong, People's Republic of China.
AD  - UPMC Hillman Cancer Center, Department of Microbiology and Molecular Genetics,
      University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
FAU - Lu, Chun
AU  - Lu C
AD  - State Key Laboratory of Reproductive Medicine, Nanjing Medical University,
      Nanjing, People's Republic of China clu@njmu.edu.cn.
AD  - Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical
      University, Nanjing, People's Republic of China.
AD  - Department of Microbiology, Nanjing Medical University, Nanjing, People's
      Republic of China.
LA  - eng
GR  - R01 CA132637/CA/NCI NIH HHS/United States
GR  - R01 CA177377/CA/NCI NIH HHS/United States
GR  - R01 CA213275/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20180829
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (Cytokines)
RN  - 0 (MicroRNAs)
RN  - 0 (NF-kappa B)
RN  - 0 (Receptors, Notch)
RN  - 0 (vpr Gene Products, Human Immunodeficiency Virus)
RN  - 0 (vpr protein, Human immunodeficiency virus 1)
SB  - IM
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Coinfection/immunology/virology
MH  - Cytokines/genetics/*immunology
MH  - HIV-1/*genetics
MH  - Herpesvirus 8, Human/*physiology
MH  - Humans
MH  - MicroRNAs/*genetics
MH  - NF-kappa B/*metabolism
MH  - Receptors, Notch/genetics/metabolism
MH  - Sarcoma, Kaposi/immunology/virology
MH  - Signal Transduction/genetics/immunology
MH  - Transcriptional Activation
MH  - Up-Regulation
MH  - Virus Activation/genetics
MH  - Virus Latency/genetics
MH  - Virus Replication/genetics
MH  - vpr Gene Products, Human Immunodeficiency Virus/*genetics
PMC - PMC6146700
OTO - NOTNLM
OT  - *KSHV
OT  - *NF-kappaB signaling
OT  - *Notch signaling
OT  - *cytokines
OT  - *latency and reactivation
OT  - *microRNAs
EDAT- 2018/07/07 06:00
MHDA- 2018/09/11 06:00
CRDT- 2018/07/07 06:00
PMCR- 2019/02/28 00:00
PHST- 2018/04/05 00:00 [received]
PHST- 2018/06/21 00:00 [accepted]
PHST- 2019/02/28 00:00 [pmc-release]
PHST- 2018/07/07 06:00 [pubmed]
PHST- 2018/09/11 06:00 [medline]
PHST- 2018/07/07 06:00 [entrez]
AID - JVI.00580-18 [pii]
AID - 10.1128/JVI.00580-18 [doi]
PST - epublish
SO  - J Virol. 2018 Aug 29;92(18). pii: JVI.00580-18. doi: 10.1128/JVI.00580-18. Print 
      2018 Sep 15.