BST-2 Expression Modulates Small CD4 Mimetic Sensitization of HIV-1-infected cells to ADCC.

TitleBST-2 Expression Modulates Small CD4 Mimetic Sensitization of HIV-1-infected cells to ADCC.
Publication TypeJournal Article
Year of Publication2017
AuthorsRichard J, Prévost J, von Bredow B, Ding S, Brassard N, Medjahed H, Coutu M, Melillo B, Bibollet-Ruche F, Hahn BH, Kaufmann DE, Smith AB, Sodroski J, Sauter D, Kirchhoff F, Gee K, Neil SJ, Evans DT, Finzi A
JournalJ Virol
Volume91
Issue11
Paginationpii:e00219-17
Date Published03/22/2017
ISSN1098-5514
Abstract

Antibodies recognizing conserved CD4-induced (CD4i) epitopes on 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+ sera. Importantly, this mechanism of immune evasion can be circumvented with small-molecule CD4-mimetics (CD4mc) which 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 up-regulation in response to 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 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.IMPORTANCE 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.

DOI10.1128/JVI.00219-17
Alternate JournalJ. Virol.
PubMed ID28331088
PubMed Central IDPMC5432882
Grant ListR01 HL092565 / HL / NHLBI NIH HHS / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
CHAVI-ID: 
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