CD4 mimetics sensitize HIV-1-infected cells to ADCC

Jonathan Richard; Maxime Veillette; Nathalie Brassard; Shilpa S. Iyer; Michel Roger; Loïc Martin; Marzena Pazgier; Arne Schön; Ernesto Freire; Jean Pierre Routy; Amos B. Smith; Jongwoo Park; David M. Jones; Joel R. Courter; Bruno N. Melillo; Daniel E. Kaufmann; Beatrice H. Hahn; Sallie R. Permar; Barton F. Haynes; Navid Madani; Joseph G. Sodroski; Andrés Finzi

doi:10.1073/pnas.1506755112

CD4 mimetics sensitize HIV-1-infected cells to ADCC

Jonathan Richard, Maxime Veillette, Nathalie Brassard, Shilpa S. Iyer, Michel Roger, Loïc Martin, Marzena Pazgier, Arne Schön, Ernesto Freire, Jean Pierre Routy, Amos B. Smith, Jongwoo Park, David M. Jones, Joel R. Courter, Bruno N. Melillo, Daniel E. Kaufmann, Beatrice H. Hahn^*, Sallie R. Permar, Barton F. Haynes, Navid MadaniJoseph G. Sodroski, Andrés Finzi

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

115 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	E2687-E2694
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	112
Issue number	20
DOIs	https://doi.org/10.1073/pnas.1506755112
State	Published - 19 May 2015
Externally published	Yes

Keywords

ADCC
CD4 mimetics
Envelope glycoproteins
HIV-1
gp120

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10.1073/pnas.1506755112

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Richard, J., Veillette, M., Brassard, N., Iyer, S. S., Roger, M., Martin, L., Pazgier, M., Schön, A., Freire, E., Routy, J. P., Smith, A. B., Park, J., Jones, D. M., Courter, J. R., Melillo, B. N., Kaufmann, D. E., Hahn, B. H., Permar, S. R., Haynes, B. F., ... Finzi, A. (2015). CD4 mimetics sensitize HIV-1-infected cells to ADCC. Proceedings of the National Academy of Sciences of the United States of America, 112(20), E2687-E2694. https://doi.org/10.1073/pnas.1506755112

@article{ec1f499142ea4e68a410fe744f8538ce,

title = "CD4 mimetics sensitize HIV-1-infected cells to ADCC",

abstract = "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.",

keywords = "ADCC, CD4 mimetics, Envelope glycoproteins, HIV-1, gp120",

author = "Jonathan Richard and Maxime Veillette and Nathalie Brassard and Iyer, {Shilpa S.} and Michel Roger and Lo{\"i}c Martin and Marzena Pazgier and Arne Sch{\"o}n and Ernesto Freire and Routy, {Jean Pierre} and Smith, {Amos B.} and Jongwoo Park and Jones, {David M.} and Courter, {Joel R.} and Melillo, {Bruno N.} and Kaufmann, {Daniel E.} and Hahn, {Beatrice H.} and Permar, {Sallie R.} and Haynes, {Barton F.} and Navid Madani and Sodroski, {Joseph G.} and Andr{\'e}s Finzi",

year = "2015",

month = may,

day = "19",

doi = "10.1073/pnas.1506755112",

language = "English",

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Richard, J, Veillette, M, Brassard, N, Iyer, SS, Roger, M, Martin, L, Pazgier, M, Schön, A, Freire, E, Routy, JP, Smith, AB, Park, J, Jones, DM, Courter, JR, Melillo, BN, Kaufmann, DE, Hahn, BH, Permar, SR, Haynes, BF, Madani, N, Sodroski, JG & Finzi, A 2015, 'CD4 mimetics sensitize HIV-1-infected cells to ADCC', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 20, pp. E2687-E2694. https://doi.org/10.1073/pnas.1506755112

TY - JOUR

T1 - CD4 mimetics sensitize HIV-1-infected cells to ADCC

AU - Richard, Jonathan

AU - Veillette, Maxime

AU - Brassard, Nathalie

AU - Iyer, Shilpa S.

AU - Roger, Michel

AU - Martin, Loïc

AU - Pazgier, Marzena

AU - Schön, Arne

AU - Freire, Ernesto

AU - Routy, Jean Pierre

AU - Smith, Amos B.

AU - Park, Jongwoo

AU - Jones, David M.

AU - Courter, Joel R.

AU - Melillo, Bruno N.

AU - Kaufmann, Daniel E.

AU - Hahn, Beatrice H.

AU - Permar, Sallie R.

AU - Haynes, Barton F.

AU - Madani, Navid

AU - Sodroski, Joseph G.

AU - Finzi, Andrés

PY - 2015/5/19

Y1 - 2015/5/19

N2 - 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.

AB - 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.

KW - ADCC

KW - CD4 mimetics

KW - Envelope glycoproteins

KW - HIV-1

KW - gp120

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U2 - 10.1073/pnas.1506755112

DO - 10.1073/pnas.1506755112

M3 - Article

C2 - 25941367

AN - SCOPUS:84929590788

SN - 0027-8424

VL - 112

SP - E2687-E2694

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 20

ER -

CD4 mimetics sensitize HIV-1-infected cells to ADCC

Abstract

Keywords

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