Tetherin antagonism by Vpu protects HIV-infected cells from antibody-dependent cell-mediated cytotoxicity

Arias, Juan F.; Heyer, Lisa N.; Bredow, Benjamin von; Weisgrau, Kim L.; Moldt, Brian; Burton, Dennis R.; Rakasz, Eva G.; Evans, David T.

doi:10.1073/pnas.1321507111

Cited by 150 publications

(175 citation statements)

References 53 publications

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“…The HIV-1 accessory proteins Nef and Vpu help protect HIV-1-infected cells from ADCC by decreasing the overall amount of Env at the cell surface (11)(12)(13)(14), and by down-regulating CD4 (11,12), which otherwise engages Env, induces the CD4-bound conformation and exposes CD4i epitopes. These epitopes are readily recognized by several well-established ADCC-mediating Abs isolated from chronically infected individuals or RV144 vaccinees (12) or by sera from HIV-1-infected individuals, which are known to have a large fraction of nonneutralizing CD4i Abs (11,17).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to its role in CD4 degradation, Vpu also antagonizes a restriction factor, Tetherin/bone marrow stromal antigen 2 (BST-2), which normally inhibits retroviral release (31,32). Viruses lacking Vpu remain trapped at the cell surface, resulting in an accumulation of exposed Env (11)(12)(13)(14). Therefore, Nef and Vpu can indirectly modulate Env-CD4 interaction at the surface of infected cells through CD4 and BST-2 down-regulation (11,12).…”

Section: Env-cd4 Interaction Enhances Recognition Of Hiv-1-infected Cmentioning

confidence: 99%

“…Analysis of the correlates of protection in the RV144 vaccine trial suggested that increased ADCC activity was linked with decreased HIV-1 acquisition (9), and Abs with potent ADCC activity were isolated from some RV144 vaccinees (10). Recent studies reported that the viral accessory proteins Nef and Vpu protect HIV-1-infected cells from anti-HIV-1 envelope (Env)-mediated ADCC responses (11)(12)(13)(14). Importantly, we and others reported that Env in the CD4-bound conformation was preferentially targeted by ADCC-mediating Abs and sera from HIV-1-infected individuals (11,12,15,16), which represent a significant proportion of anti-Env Abs elicited during natural HIV infection (11,17).…”

mentioning

confidence: 99%

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CD4 mimetics sensitize HIV-1-infected cells to ADCC

Richard

Veillette

Brassard

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

128

291

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HIV-1-infected cells presenting envelope glycoproteins (Env) in the CD4-bound conformation on their surface are preferentially targeted by antibody-dependent cell-mediated cytotoxicity (ADCC). HIV-1 has evolved a sophisticated mechanism to avoid exposure of ADCC-mediating Env epitopes by down-regulating CD4 and by limiting the overall amount of Env at the cell surface. Here we report that small-molecule CD4-mimetic compounds induce the CD4-bound conformation of Env, and thereby sensitize cells infected with primary HIV-1 isolates to ADCC mediated by antibodies present in sera, cervicovaginal lavages, and breast milk from HIV-1-infected individuals. Importantly, we identified one CD4 mimetic with the capacity to sensitize endogenously infected ex vivo-amplified primary CD4 T cells to ADCC killing mediated by autologous sera and effector cells. Thus, CD4 mimetics hold the promise of therapeutic utility in preventing and controlling HIV-1 infection.

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Section: Discussionmentioning

confidence: 99%

Section: Env-cd4 Interaction Enhances Recognition Of Hiv-1-infected Cmentioning

confidence: 99%

mentioning

confidence: 99%

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CD4 mimetics sensitize HIV-1-infected cells to ADCC

Richard

Veillette

Brassard

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

128

291

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“…Vpu potently counteracts BST‐2‐mediated ADCC activity 54, 55 via a mechanism that is not clearly understood (Fig. 2 #4).…”

Section: Viral Antagonists Of Bst‐2 and Neutralization Of Bst‐2 Antivmentioning

confidence: 99%

The role of BST‐2/Tetherin in host protection and disease manifestation

Mahauad‐Fernandez

Okeoma

2015

Immunity, Inflammation and Disease

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Host cells respond to viral infections by activating immune response genes that are not only involved in inflammation, but may also predispose cells to cancerous transformation. One such gene is BST‐2, a type II transmembrane protein with a unique topology that endows it tethering and signaling potential. Through this ability to tether and signal, BST‐2 regulates host response to viral infection either by inhibiting release of nascent viral particles or in some models inhibiting viral dissemination. However, despite its antiviral functions, BST‐2 is involved in disease manifestation, a function linked to the ability of BST‐2 to promote cell‐to‐cell interaction. Therefore, modulating BST‐2 expression and/or activity has the potential to influence course of disease.

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“…It has been shown that HIV-1 minimizes the exposure of this ADCC-susceptible Env conformation using a highly sophisticated strategy to keep Env on the surface of infected cells in the unbound "closed" conformation. HIV-1 accomplishes this through its accessory proteins Nef and Vpu, which decrease the overall amounts of Env (via Vpu-mediated BST-2 downregulation) and CD4 at the cell surface (13)(14)(15)(16). In addition, decreased amounts of Env at the cell surface due to efficient internalization also help the virus to avoid ADCC responses (17).…”

mentioning

confidence: 99%

Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody-Dependent Cell-Mediated Cytotoxicity Responses

Prévost

Zoubchenok

Richard

et al. 2017

J Virol

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HIV-1-infected cells presenting envelope glycoproteins (Env) in the CD4-bound conformation on their surface are preferentially targeted by antibodydependent cellular-mediated cytotoxicity (ADCC). HIV-1 has evolved sophisticated mechanisms to avoid the exposure of Env ADCC epitopes by downregulating CD4 and by limiting the overall amount of Env on the cell surface. In HIV-1, substitution of large residues such as histidine or tryptophan for serine 375 (S375H/W) in the gp120 Phe 43 cavity, where Phe 43 of CD4 contacts gp120, results in the spontaneous sampling of an Env conformation closer to the CD4-bound state. While residue S375 is well conserved in the majority of group M HIV-1 isolates, CRF01_ AE strains have a naturally occurring histidine at this position (H375). Interestingly, CRF01_AE is the predominant circulating strain in Thailand, where the RV144 trial took place. In this trial, which resulted in a modest degree of protection, ADCC responses were identified as being part of the correlate of protection. Here we investigate the influence of the Phe 43 cavity on ADCC responses. Filling this cavity with a histidine or tryptophan residue in Env with a natural serine residue at this position (S375H/W) increased the susceptibility of HIV-1-infected cells to ADCC. Conversely, the replacement of His 375 by a serine residue (H375S) within HIV-1 CRF01_AE decreased the efficiency of the ADCC response. Our results raise the intriguing possibility that the presence of His 375 in the circulating strain where the RV144 trial was held contributed to the observed vaccine efficacy.

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Tetherin antagonism by Vpu protects HIV-infected cells from antibody-dependent cell-mediated cytotoxicity

Cited by 150 publications

References 53 publications

CD4 mimetics sensitize HIV-1-infected cells to ADCC

CD4 mimetics sensitize HIV-1-infected cells to ADCC

The role of BST‐2/Tetherin in host protection and disease manifestation

Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody-Dependent Cell-Mediated Cytotoxicity Responses

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