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AIDS. 2014 Nov 28;28(18):2659-70. doi: 10.1097/QAD.0000000000000477.

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

Author information

1
Department of Biomedical Sciences, University of Sassari, Sassari, Italy.

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.

PMID:
25250834
DOI:
10.1097/QAD.0000000000000477
[Indexed for MEDLINE]

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