IDENTIFICATION OF AN ION-CHANNEL ACTIVITY OF THE VPU TRANSMEMBRANE DOMAIN AND ITS INVOLVEMENT IN THE REGULATION OF VIRUS RELEASE FROM HIV-1-INFECTED CELLS

HIV-1 Vpu catalyzes two independent functions, degradation of the viru s receptor CD4 in the endoplasmic reticulum and enhancement of virus r elease from the cell surface, These activities are confined to distinc t structural domains of Vpu, the cytoplasmic tail and the transmembran e (TM) anchor, respectively, It was recently reported that Vpu forms c ation-selective ion channels in lipid bilayers, Here we report that th is property of Vpu is a characteristic of its TM anchor. Expression of full-length Vpu in Xenopus oocytes increases membrane conductance. Th e Vpu-induced conductance is selective to monovalent cations over anio ns, does not discriminate Na+ over K+ and shows marginal permeability to divalent cations, Notably, introduction of the scrambled TM sequenc e into full-length Vpu abrogates its capacity to increase membrane con ductance in oocytes and to promote virus release from infected cells, Reconstitution of synthetic Vpu fragments in lipid bilayers identified an ion channel activity for a sequence corresponding to the TM domain of Vpu. In contrast, a peptide with the same amino acid composition b ut with a scrambled sequence does not form ion channels, Our findings therefore suggest that the ability of Vpu to increase virus release fr om infected cells may be correlated with an ion channel activity of th e TM domain, thereby providing a potential target for drug interventio n based on the development of Vpu-specific channel blockers.