Abstract
Tetherin (BST-2/CD317) is an interferon-inducible antiviral protein that restricts the release of enveloped viruses from infected cells. The HIV-1 accessory protein Vpu can efficiently antagonize this restriction. In this study, we analyzed mutations of the transmembrane (TM) domain of Vpu, including deletions and substitutions, to delineate amino acids important for HIV-1 viral particle release and in interactions with tetherin. The mutants had similar subcellular localization patterns with that of wild-type Vpu and were functional with respect to CD4 downregulation. We showed that the hydrophobic binding surface for tetherin lies in the core of the Vpu TM domain. Three consecutive hydrophobic isoleucine residues in the middle region of the Vpu TM domain, I15, I16 and I17, were important for stabilizing the tetherin binding interface and determining its sensitivity to tetherin. Changing the polarity of the amino acids at these positions resulted in severe impairment of Vpu-induced tetherin targeting and antagonism. Taken together, these data reveal a model of specific hydrophobic interactions between Vpu and tetherin, which can be potentially targeted in the development of novel anti-HIV-1 drugs.
Highlights
Human immunodeficiency virus type 1 (HIV-1) interacts with a series of host proteins that facilitate its replication in the cell and exploits the host cell machinery to maximize viral particle production [1]
We focused on analyzing conserved amino acids within the native Vpu TM domain to determine their role and relative importance in HIV-1 viral particle release and the antagonistic activities against tetherin
To address whether the amino acid specificity or the polarity is the more important determinant in Vpu sensitivity to tetherin, the mutants Vpu TM M3IV and Vpu TM M3IT were generated by introducing substitutions of the hydrophobic Ile residues within the middle portion of the TM domain, where Ile15, Ile16 and Ile17 were replaced by Val or Thr [21]
Summary
Human immunodeficiency virus type 1 (HIV-1) interacts with a series of host proteins that facilitate its replication in the cell and exploits the host cell machinery to maximize viral particle production [1]. During the late phase of the viral replication pathway, tetherin blocks the release of nascent virions from HIV-1 infected cells at the plasma membrane and prevents viral spread [4]. It is a 28- to 36-kDa type II integral membrane glycoprotein with a unique topology which encodes a short N-terminal cytoplasmic tail, a single transmembrane (TM) spanning region, an extracellular coiled-coil domain and a putative glycosyl-phosphatidlyinositol (GPI) anchor at its Cterminus [7]. Tetherin is presumed to provide a physical tether between the plasma membrane and retained virions, and a recent study showed that an artificial tetherin-like protein, assembled from fragments of heterologous proteins, is able to mimic the biological activity of the native tetherin [11]
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