title: Vpu augments the initial burst phase of HIV-1 propagation and downregulates BST2 and CD4 in humanized mice.
abstract: While human cells express potent antiviral proteins as part of the host defense repertoire, viruses have evolved their own arsenal of proteins to antagonize them. BST2 was identified as an inhibitory cellular protein of HIV-1 replication, which tethers virions to the cell surface to prevent their release. On the other hand, the HIV-1 accessory protein, Vpu, has the ability to downregulate and counteract BST2. Vpu also possesses the ability to downmodulate cellular CD4 and SLAMF6 molecules expressed on infected cells. However, the role of Vpu in HIV-1 infection in vivo remains unclear. Here, using a human hematopoietic stem cell-transplanted humanized mouse model, we demonstrate that Vpu contributes to the efficient spread of HIV-1 in vivo during the acute phase of infection. Although Vpu did not affect viral cytopathicity, target cell preference, and the level of viral protein expression, the amount of cell-free virions in vpu-deficient HIV-1-infected mice was profoundly lower than that in wild-type HIV-1-infected mice. We provide a novel insight suggesting that Vpu concomitantly downregulates BST2 and CD4, but not SLAMF6, from the surface of infected cells. Furthermore, we show evidence suggesting that BST2 and CD4 impair the production of cell-free infectious virions but do not associate with the efficiency of cell-to-cell HIV-1 transmission. Taken together, our findings suggest that Vpu downmodulates BST2 and CD4 in infected cells and augments the initial burst of HIV-1 replication in vivo. This is the first report demonstrating the role of Vpu in HIV-1 infection in an in vivo model.
authors.affiliation: Center for Emerging Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Sato
authors.forename: Naoko
authors.initials: N
authors.lastname: Misawa
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Fukuhara
authors.forename: Shingo
authors.initials: S
authors.lastname: Iwami
authors.forename: Dong Sung
authors.initials: DS
authors.lastname: An
authors.forename: Mamoru
authors.initials: M
authors.lastname: Ito
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Koyanagi
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D015704:CD4 Antigens / Q000378:metabolism*; D002450:Cell Communication; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D011485:Protein Binding; D013154:Spleen / Q000378:metabolism / Q000821:virology; D013997:Time Factors; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000378:metabolism*; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
chemical_list: D015703:Antigens, CD; D015704:CD4 Antigens; D054298:Human Immunodeficiency Virus Proteins; D008562:Membrane Glycoproteins; D054334:Viral Regulatory and Accessory Proteins; C513868:BST2 protein, mouse; D000074010:Bone Marrow Stromal Antigen 2; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins