title: Sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1)-facilitated HIV restriction in astrocytes is regulated by miRNA-181a.
abstract: BACKGROUND
  Although highly active antiretroviral therapy (HAART) has significantly reduced the morbidity and mortality in HIV patients, virus continues to reside in the central nervous system (CNS) reservoir. Hence, a complete eradication of virus remains a challenge. HIV productively infects microglia/macrophages, but astrocytes are generally restricted to HIV infection. The relative importance of the possible replication blocks in astrocytes, however, is yet to be delineated. A recently identified restriction factor, sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1), restricts HIV infection in resting CD4(+)T cells and in monocyte-derived dendritic cells. However, SAMHD1 expression and HIV-1 restriction activity regulation in the CNS cells are unknown. Though, certain miRNAs have been implicated in HIV restriction in resting CD4(+)T cells, their role in the CNS HIV restriction and their mode of action are not established. We hypothesized that varying SAMHD1 expression would lead to restricted HIV infection and host miRNAs would regulate SAMHD1 expression in astrocytes.
  
  
  RESULTS
  We found increased SAMHD1 expression and decreased miRNA expression (miR-181a and miR-155) in the astrocytes compared to microglia. We report for the first time that miR-155 and miR-181a regulated the SAMHD1 expression. Overexpression of these cellular miRNAs increased viral replication in the astrocytes, through SAMHD1 modulation. Reactivation of HIV replication was accompanied by decrease in SAMHD1 expression.
  
  
  CONCLUSIONS
  Here, we provide a proof of concept that increased SAMHD1 in human astrocytes is in part responsible for the HIV restriction, silencing of which relieves this restriction. At this time, this concept is of theoretical nature. Further experiments are needed to confirm if HIV replication can be reactivated in the CNS reservoir.
authors.affiliation: Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, AHC-1, 418A, 11200 SW 8th Street, Miami, FL, 33199, USA. spilakka@fiu.edu.|Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, AHC-1, 418A, 11200 SW 8th Street, Miami, FL, 33199, USA. spilakka@fiu.edu.|Center for Personalized Nanomedicine, Herbert Wertheim College of Medicine, Florida International University, AHC-1, 418A, 11200 SW 8th Street, Miami, FL, 33199, USA. spilakka@fiu.edu.
authors.forename: Sudheesh
authors.initials: S
authors.lastname: Pilakka-Kanthikeel
authors.affiliation: Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, AHC-1, 418A, 11200 SW 8th Street, Miami, FL, 33199, USA. adraymon@fiu.edu.|Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, AHC-1, 418A, 11200 SW 8th Street, Miami, FL, 33199, USA. adraymon@fiu.edu.
authors.forename: Andrea
authors.initials: A
authors.lastname: Raymond
authors.affiliation: Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, AHC-1, 418A, 11200 SW 8th Street, Miami, FL, 33199, USA. vatluri@fiu.edu.|Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, AHC-1, 418A, 11200 SW 8th Street, Miami, FL, 33199, USA. vatluri@fiu.edu.
authors.forename: Venkata Subba Rao
authors.initials: VS
authors.lastname: Atluri
authors.affiliation: Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, AHC-1, 418A, 11200 SW 8th Street, Miami, FL, 33199, USA. vsagar@fiu.edu.|Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, AHC-1, 418A, 11200 SW 8th Street, Miami, FL, 33199, USA. vsagar@fiu.edu.|Center for Personalized Nanomedicine, Herbert Wertheim College of Medicine, Florida International University, AHC-1, 418A, 11200 SW 8th Street, Miami, FL, 33199, USA. vsagar@fiu.edu.
authors.forename: Vidya
authors.initials: V
authors.lastname: Sagar
authors.affiliation: CSIR-Centre for Cellular & Molecular Biology, Uppal Road, Hyderabad, 500007, India. shailen1@gmail.com.
authors.forename: Shailendra K
authors.initials: SK
authors.lastname: Saxena
authors.affiliation: Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, AHC-1, 418A, 11200 SW 8th Street, Miami, FL, 33199, USA. mynameissudhi@yahoo.co.in.|Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, AHC-1, 418A, 11200 SW 8th Street, Miami, FL, 33199, USA. mynameissudhi@yahoo.co.in.
authors.forename: Patricia
authors.initials: P
authors.lastname: Diaz
authors.affiliation: Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, AHC-1, 418A, 11200 SW 8th Street, Miami, FL, 33199, USA. mynameissudhi@yahoo.co.in.|Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, AHC-1, 418A, 11200 SW 8th Street, Miami, FL, 33199, USA. mynameissudhi@yahoo.co.in.
authors.forename: Semithe
authors.initials: S
authors.lastname: Chevelon
authors.affiliation: Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, AHC-1, 418A, 11200 SW 8th Street, Miami, FL, 33199, USA. sudheeshpeekey@gmail.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Concepcion
authors.affiliation: Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, AHC-1, 418A, 11200 SW 8th Street, Miami, FL, 33199, USA. nairm@fiu.edu.|Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, AHC-1, 418A, 11200 SW 8th Street, Miami, FL, 33199, USA. nairm@fiu.edu.|Center for Personalized Nanomedicine, Herbert Wertheim College of Medicine, Florida International University, AHC-1, 418A, 11200 SW 8th Street, Miami, FL, 33199, USA. nairm@fiu.edu.
authors.forename: Madhavan
authors.initials: M
authors.lastname: Nair
mesh_terms: D001253:Astrocytes / Q000378:metabolism* / Q000821:virology*; D020868:Gene Silencing; D015658:HIV Infections / Q000235:genetics / Q000821:virology*; D015497:HIV-1; D006801:Humans; D007700:Kinetics; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics*; D017628:Microglia / Q000378:metabolism / Q000821:virology; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics*; D000076106:SAM Domain and HD Domain-Containing Protein 1; D014775:Virus Activation / Q000235:genetics; D014779:Virus Replication / Q000235:genetics
chemical_list: C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins