Tetherin restricts direct cell-cell viral transfer and transmission of HIV-1

Background: Tetherin (BST-2/CD317/HM1.24) is an interferon-inducible factor of the innate immune system, recently shown to exert antiviral activity against HIV-1 and other enveloped viruses by tethering nascent viral particles to the cell surface, thereby inhibiting viral release. In HIV-1 infection, the viral protein U (Vpu) counteracts this antiviral action by down-modulating tetherin from the cell surface. Viral transmission between T cells can occur via cell-free transmission or the more efficient direct cell-cell route through virological synapses. Virological synapses are associated with lipid raft-rich microdomains in the membrane. Tetherin is known to localize to these microdomains and is capable of modulating actin architecture, which is crucial for viral entry, assembly and budding. Methods: We established a flow cytometry-based co-culture assay to distinguish viral transfer from viral transmission and investigated the impact of tetherin on cell-cell spread of HIV-1. Sup-T1 cells inducible for tetherin expression were used to examine the impact of effector and target cell tetherin expression on virus transfer and transmission. Results: We show that tetherin, in addition to inhibiting viral release, also inhibits direct cell-cell virus transfer and transmission. Viral Vpu promotes viral transmission from tetherin-expressing cells by down-modulating tetherin from the effector cell surface, outweighing its possible cost of fitness in cell-cell transmission. Further, we have shown that tetherin on the target cell promotes viral transfer and transmission in a manner that favours Vpu-deficient virus. Conclusions: The results suggest a role for tetherin in cell-cell contacts, specifically at virological synapses. Our data further contribute to the body of knowledge that the targeting of Vpu could be a valuable strategy aimed at blocking HIV replication. Supplement: Workshop Report and Abstracts “Towards a Cure”: HIV Reservoirs and Strategies to Control Them Shirin Heidari, Marie-Capucine Penicaud, Celine Cheng, International AIDS Society http://www.biomedcentral.com/content/pdf/1758-2652-13-S3-info.pdf Conference: International AIDS Society’s Workshop “Towards a Cure”: HIV Reservoirs and Strategies to Control Them 16–17 July 2010 Vienna, Austria (Published: 4 November 2010) doi:10.1186/1758-2652-13-S3-O8 Cite this article as: Kuhl et al.: Tetherin restricts direct cell-cell viral transfer and transmission of HIV-1. Journal of the International AIDS Society 2010 13(Suppl 3):O8. Full text: PubMed Central: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2999393/