Abstract
HIV-1 Vpu is a small, single-span membrane protein with two attributed functions that increase the virus' pathogenicity: degradation of CD4 and inactivation of BST-2. Vpu has also been shown to posses ion channel activity, yet no correlation has been found between this attribute and Vpu's role in viral release. In order to gain further insight into the channel activity of Vpu we devised two bacteria-based assays that can examine this function in detail. In the first assay Vpu was over-expressed, such that it was deleterious to bacterial growth due to membrane permeabilization. In the second and more sensitive assay, the channel was expressed at low levels in K+ transport deficient bacteria. Consequently, Vpu expression enabled the bacteria to grow at otherwise non permissive low K+ concentrations. Hence, Vpu had the opposite impact on bacterial growth in the two assays: detrimental in the former and beneficial in the latter. Furthermore, we show that channel blockers also behave reciprocally in the two assays, promoting growth in the first assay and hindering it in the second assay. Taken together, we investigated Vpu's channel activity in a rapid and quantitative approach that is amenable to high-throughput screening, in search of novel blockers.
Highlights
Vpu is a small accessory protein found in HIV-1 [1] that was shown to increase the transmission efficiency of the virus [2]
The channel negatively impacts bacterial growth, while in the second assay it is vital to the bacteria
Channel expression leads to bacterial death, while in the positive assay it leads to growth
Summary
Vpu is a small accessory protein found in HIV-1 [1] that was shown to increase the transmission efficiency of the virus [2]. During the synthesis of new viral progeny, CD4 interacts with GP160 in the ER to form trafficking-incapable complexes that hinder viral maturation [5,6,7]. Vpu inhibits this process by causing rapid degradation of CD4 [8,9], thereby facilitating viral protein maturation. BST-2 (or tetherin) is part of the cellular anti-viral defense system that theaters mature viral progeny to lipid rafts. It inhibits HIV-1 and other viruses such as Lassa and Marburg virus [10]. Our current understanding places Vpu’s contribution to HIV-1 infectivity, mostly on its antagonistic role versus BST-2
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