Abstract
Binding of anti-HIV antibodies (Abs) to envelope (Env) glycoproteins on infected cells can mark them for elimination via antibody-dependent cell-mediated cytotoxicity (ADCC). BST2, a type I interferon (IFN)-stimulated restriction factor that anchors nascent Env-containing virions at the surface of infected cells has been shown to enhance ADCC functions. In a comprehensive analysis of ADCC potency by neutralizing anti-HIV Abs (NAbs), we show in this study that NAbs are capable of mediating ADCC against HIV-infected T cells with 3BNC117, PGT126 and PG9 being most efficient. We demonstrate that HIV-induced BST2 antagonism effectively attenuates Ab binding and ADCC responses mediated by all classes of NAbs that were tested. Interestingly, IFNα treatment can reverse this effect in a BST2-dependent manner. Importantly, while reactivated latent T cell lines display some susceptibility to ADCC mediated by broadly NAbs, inactivating BST2 viral countermeasures and/or exogenous IFNα augment their elimination. Overall, our findings support the notion that NAbs can induce ADCC. They highlight that while BST2 antagonism by HIV promotes ADCC evasion, strategies aimed at restoring BST2 restriction could improve anti-HIV responses and potentially provide a means to eliminate reactivated cells in latent reservoirs.
Highlights
Human immunodeficiency virus (HIV)-type 1 enters target cells, primarily CD4+ T cells and macrophages, through sequential interactions between viral envelope (Env), composed of a trimer of gp[120] and gp[41] heterodimers, and cell surface receptors CD4 and CCR5[1]
Our study suggests that strategies aimed at improving antibody-dependent cell-mediated cytotoxicity (ADCC) function using IFNαand/or small molecule inhibitors of BST2 antagonists represent a promising avenue to promote a more effective elimination of productively infected cells and clearance of latent viral reservoirs in “Shock and Kill” HIV cure approaches
Neutralizing Abs mediate efficient ADCC against CEM CD4+ T cells infected with different HIV-1 primary isolates
Summary
Human immunodeficiency virus (HIV)-type 1 enters target cells, primarily CD4+ T cells and macrophages, through sequential interactions between viral envelope (Env), composed of a trimer of gp[120] and gp[41] heterodimers, and cell surface receptors CD4 and CCR5 (or CXCR4)[1]. Co-receptor engagement triggers additional remodeling within the gp[41] transmembrane subunits, rearranging them into a stable six-helix bundle that facilitates fusion between viral and cellular membranes This multi-stage mechanism of entry allows HIV-1 to mask conserved functional sites from humoral immunity[2,3]. Our study suggests that strategies aimed at improving ADCC function using IFNαand/or small molecule inhibitors of BST2 antagonists represent a promising avenue to promote a more effective elimination of productively infected cells and clearance of latent viral reservoirs in “Shock and Kill” HIV cure approaches
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