title: HIV Tat acts on endogenous retroviruses of the W family and this occurs via Toll-like receptor 4: inference for neuroAIDS.
abstract: OBJECTIVE
  The objective of this study is to verify whether HIV activates two endogenous retroviruses of the human endogenous retrovirus (HERV)-W family, multiple sclerosis-associated retrovirus (MSRV) and Syncytin-1, whose neuropathogenic and immunopathogenic properties could contribute to HIV-related neurodegeneration.
  
  
  METHODS
  Peripheral blood mononuclear cells, monocyte-macrophages and astrocytes were either infected by HIV or exposed to HIV-Tat, and/or other treatments. The expression of transcripts and proteins of interest was evaluated by real-time RT-PCR and western blotting assays, respectively.
  
  
  RESULTS
  HIV and Tat increase the levels of MSRVenv mRNAs and HERV-Wenv proteins in astrocytes and in blood cells. In monocyte-macrophages, Tat also induces high levels of CCR2, CD16 and Toll-like receptor 4 (TLR4) molecules. Syncytin-1 response to Tat depends on the cell context: in monocytes, Tat stimulates MSRVenv and inhibits Syncytin-1, while in differentiated macrophages, it stimulates both elements. In primary astrocytes, Tat stimulates MSRV and Syncytin-1 indirectly, through interaction with TLR4 and induction of tumour necrosis factor-alpha (TNFα), without internalization.
  
  
  CONCLUSIONS
  In-vivo consequence of the study could be that, through increase of CD16 and CCR2, Tat promotes neuroinvasion not only by HIV-infected monocytes/macrophages but also by the HERV-Ws, with their neuropathogenic potential. Also, the novel finding of TLR4 stimulation by Tat may be of relevance, as TLR4 is critical in neuroinflammation. Within central nervous system (CNS), Tat-induced TNFα could induce high levels of the HERV-Ws, in both macrophages and astrocytes, also without HIV replication. The indirect mechanism by which Tat activates the HERV-Ws through induction of TNFα could add a new piece to the puzzle of CNS pathogenesis, that is the HERV-Wenv contribute to the HIV-related neurodegeneration.
authors.affiliation: Department of Biomedical Sciences, University of Sassari, Sassari, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Uleri
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mei
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mameli
authors.forename: Luciana
authors.initials: L
authors.lastname: Poddighe
authors.forename: Caterina
authors.initials: C
authors.lastname: Serra
authors.forename: Antonina
authors.initials: A
authors.lastname: Dolei
mesh_terms: D015526:AIDS Dementia Complex / Q000473:pathology; D001253:Astrocytes / Q000821:virology*; D002478:Cells, Cultured; D020077:Endogenous Retroviruses / Q000235:genetics*; D015686:Gene Products, env / Q000235:genetics*; D006678:HIV / Q000254:growth & development; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology*; D011257:Pregnancy Proteins / Q000235:genetics*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014158:Transcription, Genetic; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D015686:Gene Products, env; D011257:Pregnancy Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C405335:syncytin; D054322:tat Gene Products, Human Immunodeficiency Virus