Filamin A is required for HIV‐1 Vpu to promote HIV‐1 release (950.2)

Abstract

The interferon‐induced tetherin is a restriction factor that inhibits the release of HIV‐1 and other enveloped viruses from infected cells. The unique topology of tetherin, featured with two different membrane anchors at the opposite ends, enables it to capture the mature virions at the cell surface through a direct tethering mechanism. HIV‐1 has evolved the strategy to overcome tetherin restriction by encoding an accessory protein, Vpu. HIV‐1 Vpu neutralizes tetherin through multiple mechanisms. Recently, we identified that the host cytoskeletal component, filamin A (FLNa) acts as a cofactor in HIV‐1 assembly and release. By cell‐based assays, we demonstrated that FLNa was capable of binding tetherin. FLNa depletion increased steady‐state and cell surface levels of tethrin expression, whereas FLNa overexpression reduced tetherin expression. Furthermore, FLNa depletion or overexpression redistributed tetherin subcellular localization. These findings suggest that FLNa is involved in tetherin turnover by mediating tetherin trafficking pathways. Transmission electron microscopy studies illustrated that FLNa depletion induces a defect in HIV‐1 particle release, characterized with virions tethered to each other as well as to cell surface. Finally, virus release experiments revealed that FLNa depletion abolished the activity of Vpu to enhance particle release. Taken together, our results suggest that HIV‐1 Vpu takes advantage of the FLNa‐dependent tetherin trafficking pathways to neutralize tetherin and promote virus release. These studies shed new insights into the mechanisms of Vpu‐mediated counteraction of tetherin restriction.Grant Funding Source: AI089330, GM059994