BST-2 Expression Modulates Small CD4-Mimetic Sensitization of HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity

• Published in: Journal of virology Vol. 91; no. 11
• Main Authors: Richard, Jonathan, Prévost, Jérémie, von Bredow, Benjamin, Ding, Shilei, Brassard, Nathalie, Medjahed, Halima, Coutu, Mathieu, Melillo, Bruno, Bibollet-Ruche, Frédéric, Hahn, Beatrice H, Kaufmann, Daniel E, Smith, 3rd, Amos B, Sodroski, Joseph, Sauter, Daniel, Kirchhoff, Frank, Gee, Katrina, Neil, Stuart J, Evans, David T, Finzi, Andrés
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.06.2017
• Subjects: Antibody-Dependent Cell Cytotoxicity; Antigens, CD - genetics; Antigens, CD - metabolism; CD4 Antigens - immunology; CD4 Antigens - metabolism; env Gene Products, Human Immunodeficiency Virus - genetics; env Gene Products, Human Immunodeficiency Virus - immunology; Epitopes - immunology; GPI-Linked Proteins - deficiency; GPI-Linked Proteins - genetics; GPI-Linked Proteins - metabolism; HIV-1 - genetics; HIV-1 - immunology; Human immunodeficiency virus 1; Human Immunodeficiency Virus Proteins - genetics; Human Immunodeficiency Virus Proteins - metabolism; Humans; Immune Evasion; Interferon-beta - pharmacology; Interleukins - pharmacology; Jurkat Cells; Lentivirus; Molecular Mimicry; Pathogenesis and Immunity; Retroviridae; Up-Regulation; Viral Regulatory and Accessory Proteins - genetics; Viral Regulatory and Accessory Proteins - metabolism; HIV-1; BST-2; nonneutralizing antibodies; CD4-bound conformation; IL-27; CD4 mimetics; Env; IFN-α; CD4; interferons; envelope glycoproteins; gp120; ADCC
• ISSN: 0022-538X; 1098-5514
• DOI: 10.1128/JVI.00219-17

Antibodies recognizing conserved CD4-induced (CD4i) epitopes on human immunodeficiency virus type 1 (HIV-1) Env and able to mediate antibody-dependent cellular cytotoxicity (ADCC) have been shown to be present in sera from most HIV-1-infected individuals. These antibodies preferentially recognize Env in its CD4-bound conformation. CD4 downregulation by Nef and Vpu dramatically reduces exposure of CD4i HIV-1 Env epitopes and therefore reduce the susceptibility of HIV-1-infected cells to ADCC mediated by HIV-positive (HIV+) sera. Importantly, this mechanism of immune evasion can be circumvented with small-molecule CD4 mimetics (CD4mc) that are able to transition Env into the CD4-bound conformation and sensitize HIV-1-infected cells to ADCC mediated by HIV+ sera. However, HIV-1 developed additional mechanisms to avoid ADCC, including Vpu-mediated BST-2 antagonism, which decreases the overall amount of Env present at the cell surface. Accordingly, BST-2 upregulation in response to alpha interferon (IFN-α) was shown to increase the susceptibility of HIV-1-infected cells to ADCC despite the activity of Vpu. Here we show that BST-2 upregulation by IFN-β and interleukin-27 (IL-27) also increases the surface expression of Env and thus boosts the ability of CD4mc to sensitize HIV-1-infected cells to ADCC by sera from HIV-1-infected individuals. HIV-1 evolved sophisticated strategies to conceal Env epitopes from ADCC-mediating antibodies present in HIV+ sera. Vpu-mediated BST-2 downregulation was shown to decrease ADCC responses by limiting the amount of Env present at the cell surface. This effect of Vpu was shown to be attenuated by IFN-α treatment. Here we show that in addition to IFN-α, IFN-β and IL-27 also affect Vpu-mediated BST-2 downregulation and greatly enhance ADCC responses against HIV-1-infected cells in the presence of CD4mc. These findings may inform strategies aimed at HIV prevention and eradication.