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. 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.
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Authors | Elena Uleri, Alessandra Mei, Giuseppe Mameli, Luciana Poddighe, Caterina Serra, Antonina Dolei |
Journal | AIDS (London, England)
(AIDS)
Vol. 28
Issue 18
Pg. 2659-70
(Nov 28 2014)
ISSN: 1473-5571 [Electronic] England |
PMID | 25250834
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Gene Products, env
- Pregnancy Proteins
- TLR4 protein, human
- Toll-Like Receptor 4
- syncytin
- tat Gene Products, Human Immunodeficiency Virus
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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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