CD4 Mimetics Sensitize HIV-1-infected Cells to ADCC

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2015 May 6

PMID 25941367

Citations 105

Authors

Jonathan Richard

Maxime Veillette

Nathalie Brassard

Shilpa S Iyer

Michel Roger

Loic Martin

Marzena Pazgier

Arne Schon

Ernesto Freire

Jean-Pierre Routy

Amos B Smith 3rd

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

Andres Finzi

Affiliations

Soon will be listed here.

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.

Citing Articles

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CD4 downregulation precedes Env expression and protects HIV-1-infected cells from ADCC mediated by non-neutralizing antibodies.

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The combination of three CD4-induced antibodies targeting highly conserved Env regions with a small CD4-mimetic achieves potent ADCC activity.

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