Research Article: Preservation of Tetherin and CD4 Counter-Activities in Circulating Vpu Alleles despite Extensive Sequence Variation within HIV-1 Infected Individuals

Date Published: January 23, 2014

Publisher: Public Library of Science

Author(s): Suzanne Pickering, Stephane Hué, Eun-Young Kim, Susheel Reddy, Steven M. Wolinsky, Stuart J. D. Neil, Jeremy Luban.


The HIV-1 Vpu protein is expressed from a bi-cistronic message late in the viral life cycle. It functions during viral assembly to maximise infectious virus release by targeting CD4 for proteosomal degradation and counteracting the antiviral protein tetherin (BST2/CD317). Single genome analysis of vpu repertoires throughout infection in 14 individuals infected with HIV-1 clade B revealed extensive amino acid diversity of the Vpu protein. For the most part, this variation in Vpu increases over the course of infection and is associated with predicted epitopes of the individual’s MHC class I haplotype, suggesting CD8+ T cell pressure is the major driver of Vpu sequence diversity within the host. Despite this variability, the Vpu functions of targeting CD4 and counteracting both physical virus restriction and NF-κB activation by tetherin are rigorously maintained throughout HIV-1 infection. Only a minority of circulating alleles bear lesions in either of these activities at any given time, suggesting functional Vpu mutants are heavily selected against even at later stages of infection. Comparison of Vpu proteins defective for one or several functions reveals novel determinants of CD4 downregulation, counteraction of tetherin restriction, and inhibition of NF-κB signalling. These data affirm the importance of Vpu functions for in vivo persistence of HIV-1 within infected individuals, not simply for transmission, and highlight its potential as a target for antiviral therapy.

Partial Text

The HIV-1 genes nef, vpu, vif and vpr are known as accessory genes and early in vitro studies showed them dispensable for viral replication in some tissue culture cell lines [1]. In vivo, however, these proteins are essential for the transmission and persistence of immunodeficiency viruses. Vpu, in particular, is thought to have been pivotal to the ability of HIV-1 group M to establish pandemic infection in humans following transmission from chimpanzees [2], [3]. Expressed late in the viral life cycle, it functions during viral assembly to facilitate efficient egress of infectious viral particles, through the degradation of CD4 in the endoplasmic reticulum (ER) and the counteraction of the interferon-induced antiviral protein tetherin (BST2/CD317) [4], [5]. By antagonising tetherin, Vpu also acts to evade innate immune sensing of budding viral particles by repressing pro-inflammatory signalling events triggered by tetherin [6]–[8]. In recent years, Vpu has been implicated in other immunomodulatory functions, such as the downregulation of NTB-A/SLAMF6 [9] and poliovirus receptor (PVR/CD155) [10] to evade NK cell recognition of HIV-1 infected cells, and the removal of CD1d from the surface of dendritic cells, inhibiting lipid antigen presentation to NK-T cells [11]. Furthermore, signature residues in the C-terminus of Vpu are associated with NK cell escape in KIR2DL2 positive individuals [12].

Using single genome sequencing we have carried out a full characterisation of the sequence and function of the HIV-1 vpu gene throughout infection, and demonstrate that the Vpu protein has a considerable capacity for diversification and adaptation, consistent with it being one of the most variable regions of the HIV-1 genome [44]. In the face of predicted CD8 T cell pressure and significant sequence variation, it is able to maintain function regardless of disease stage or severity, with no indication of hierarchy of function.




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