Upregulation of BST-2 by Type I Interferons Reduces the Capacity of Vpu To Protect HIV-1-Infected Cells from NK Cell Responses

mBio

Mathieu Dubé¹  Halima Medjahed¹  Daniel E. Kaufmann¹  Gabrielle Gendron-Lepage¹  Jérémie Prévost¹  Andrés Finzi¹  Gloria G. Delgado¹  Jonathan Richard¹  Stuart J. D. Neil²  Suzanne Pickering²  Beatrice H. Hahn³  Frederic Bibollet-Ruche³  Mitchell J. Mumby⁴  Jimmy D. Dikeakos⁴  Brennan S. Dirk⁴  Christina M. Stürzel⁵  Daniel Sauter⁵  Frank Kirchhoff⁵ 

[1]Centre de Recherche du CHUM, Montreal, Quebec, Canada

[2]Department of Infectious Disease, King’s College London School of Life Sciences and Medicine, Guy’s Hospital, London, United Kingdom

[3]Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

[4]Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada

[5]Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany

关键词: ADCC;    DNAM-1;    HIV;    NK cells;    NTB-A;    PVR;   

DOI  :  10.1128/mBio.01113-19

来源: DOAJ

【 摘 要 】

ABSTRACT The HIV-1 accessory protein Vpu enhances viral release by counteracting the restriction factor BST-2. Furthermore, Vpu promotes NK cell evasion by downmodulating cell surface NTB-A and PVR, known ligands of the NK cell receptors NTB-A and DNAM-1, respectively. While it has been established that Vpu’s transmembrane domain (TMD) is required for the interaction and intracellular sequestration of BST-2, NTB-A, and PVR, it remains unclear how Vpu manages to target these proteins simultaneously. In this study, we show that upon upregulation, BST-2 is preferentially downregulated by Vpu over its other TMD substrates. We found that type I interferon (IFN)-mediated BST-2 upregulation greatly impairs the ability of Vpu to downregulate NTB-A and PVR. Our results suggest that occupation of Vpu by BST-2 affects its ability to downregulate other TMD substrates. Accordingly, knockdown of BST-2 increases Vpu’s potency to downmodulate NTB-A and PVR in the presence of type I IFN treatment. Moreover, we show that expression of human BST-2, but not that of the macaque orthologue, decreases Vpu’s capacity to downregulate NTB-A. Importantly, we show that type I IFNs efficiently sensitize HIV-1-infected cells to NTB-A- and DNAM-1-mediated direct and antibody-dependent NK cell responses. Altogether, our results reveal that type I IFNs decrease Vpu’s polyfunctionality, thus reducing its capacity to protect HIV-1-infected cells from NK cell responses. IMPORTANCE The restriction factor BST-2 and the NK cell ligands NTB-A and PVR are among a growing list of membrane proteins found to be downregulated by HIV-1 Vpu. BST-2 antagonism enhances viral release, while NTB-A and PVR downmodulation contributes to NK cell evasion. However, it remains unclear how Vpu can target multiple cellular factors simultaneously. Here we provide evidence that under physiological conditions, BST-2 is preferentially targeted by Vpu over NTB-A and PVR. Specifically, we show that type I IFNs decrease Vpu’s polyfunctionality by upregulating BST-2, thus reducing its capacity to protect HIV-1-infected cells from NK cell responses. This indicates that there is a hierarchy of Vpu substrates upon IFN treatment, revealing that for the virus, targeting BST-2 as part of its resistance to IFN takes precedence over evading NK cell responses. This reveals a potential weakness in HIV-1’s immunoevasion mechanisms that may be exploited therapeutically to harness NK cell responses against HIV-1.

【 授权许可】

Unknown