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HIV Tat acts on endogenous retroviruses of the W family and this occurs via Toll-like receptor 4: inference for neuroAIDS.

AbstractOBJECTIVE:
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.
DESIGN AND 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.
CONCLUSION:
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.
AuthorsElena Uleri, Alessandra Mei, Giuseppe Mameli, Luciana Poddighe, Caterina Serra, Antonina Dolei
JournalAIDS (London, England) (AIDS) Vol. 28 Issue 18 Pg. 2659-70 (Nov 28 2014) ISSN: 1473-5571 [Electronic] England
PMID25250834 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Gene Products, env
  • Pregnancy Proteins
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • syncytin
  • tat Gene Products, Human Immunodeficiency Virus
Topics
  • AIDS Dementia Complex (pathology)
  • Astrocytes (virology)
  • Cells, Cultured
  • Endogenous Retroviruses (genetics)
  • Gene Products, env (genetics)
  • HIV (growth & development)
  • Humans
  • Leukocytes, Mononuclear (virology)
  • Pregnancy Proteins (genetics)
  • Toll-Like Receptor 4 (metabolism)
  • Transcription, Genetic
  • tat Gene Products, Human Immunodeficiency Virus (metabolism)

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