CD4 mimetic miniproteins: potent anti-HIV compounds with promising activity as microbicides

Herrewege, Yven Y. Van; Morellato, Laurence L.; Descours, Anne; Aerts, Laetitia; Michiels, Jo; Heyndríckx, Leo; Martin, Loı̈c; Vanham, Guido

doi:10.1093/jac/dkn042

Cited by 56 publications

(76 citation statements)

References 39 publications

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“…One of these variants, M48U1, displayed remarkably potent neutralization of three HIV-1 isolates (27). Its crystal structure in complex with HIV-1 gp120 was recently solved, showing that M48U1 engages the Phe-43 cavity in a manner similar to that of CD4 (28); thus, M48U1 might induce gp120 to adopt the CD4-bound conformation and expose CD4i epitopes.…”

Section: Significancementioning

confidence: 99%

“…Its crystal structure in complex with HIV-1 gp120 was recently solved, showing that M48U1 engages the Phe-43 cavity in a manner similar to that of CD4 (28); thus, M48U1 might induce gp120 to adopt the CD4-bound conformation and expose CD4i epitopes. Previous studies exploring the antiviral properties of CD4mc were performed on viral particles (17,25,27). However, whether these compounds are able to engage the large amounts of Env present at the surface of infected cells and modulate Env conformation in a way that allows exposure of ADCC-mediating epitopes is currently not known.…”

Section: Significancementioning

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: Significancementioning

confidence: 99%

Section: Significancementioning

confidence: 99%

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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“…Furthermore, the antibodies used in the immunochemical characterization of gp140 (12,17) cover the most pertinent gp120 and gp41 epitopes, namely the CD4 binding site (CD4BS-IgGCD4 and sCD4), the coreceptor binding site (CrBS-17b and 447D), a neutralizing epitope on gp41 (2F5), and a glycan-dependent epitope (2G12), thus thoroughly covering the topology of gp140 so as to display its similarity to native Env trimers. The CD4 miniprotein (CD4m) used to elicit the liganded conformation displays nanomolar affinity to gp120 (19), and elicits a nearly identical gp120 conformation as does soluble CD4 (sCD4) (20). The small size of CD4m allowed the structural analysis in this work to focus on the quaternary changes in gp140 and circumvent possible steric aggregation induced by stoichiometric sCD4-gp140 binding.…”

mentioning

confidence: 99%

Quaternary structures of HIV Env immunogen exhibit conformational vicissitudes and interface diminution elicited by ligand binding

Moscoso

Sun²,

Poon

et al. 2011

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

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The human immunodeficiency virus envelope protein is the key element mediating entry into host cells. Conformational rearrangement of Env upon binding to the host CD4 receptor and chemokine coreceptor drives membrane fusion. We elucidated the quaternary arrangement of the soluble Env trimeric immunogen o-gp140ΔV2TV1, in both its native (unliganded) and CD4-induced (liganded) states by cryoelectron microscopy and molecular modeling. The liganded conformation was elicited by binding gp140 to the synthetic CD4-mimicking miniprotein CD4m. Upon CD4m binding, an outward domain shift of the three gp120 subunits diminishes gp120-gp41 interactions, whereas a "flat open" concave trimer apex is observed consequent to gp120 tilting away from threefold axis, likely juxtaposing the fusion peptide with the host membrane. Additional features observed in the liganded conformation include rotations of individual gp120 subunits that may release gp41 for N-and C-helix refolding and also may lead to optimal exposure of the elicited coreceptor binding site. Such quaternary arrangements of gp140 lead to the metastable liganded conformation, with putative locations of exposed epitopes contributing to a description of sequential events occurring prior to membrane fusion. Our observations imply a mechanism whereby a soluble Env trimeric construct, as opposed to trimers extracted from virions, may better expose crucial epitopes such as the CD4 binding site and V3, as well as epitopes in the vicinity of gp41, subsequent to conjugation with CD4m. Structural features gleaned from our studies should aid the design of Env-based immunogens for inducement of potent broadly neutralizing antibodies against exposed conformational epitopes.T he human immunodeficiency virus envelope proteins gp120 and gp41 associate in a trimeric arrangement (1-3) and mediate membrane fusion through conformational rearrangement and fusion peptide insertion into the host membrane. The gp120 tertiary conformational change observed via X-ray crystallography has not been definitively characterized in the context of a quaternary structure. Several observations have been gleaned from tomography studies, though with inconclusive and sometimes contradictory results. Quaternary structural features reported previously include trimer morphology, with some groups reporting a mushroom-like shape and others a more rod-like arrangement, as well as the relative location of the primary epitope, hypervariable loops, and N-and C-termini, which have some variation among the different tomograms. Another point of conflict is the presence of a cavity at the threefold axis, capped by a density. One final feature is the arrangement of gp41, with some groups reporting a thin, stalk-like rod arrangement of gp41 and another group reporting a more splayed out, tripod-like conformation of gp41 proximal to the viral membrane. Taken together, these contrasting features portray a heterogeneous set of registers that seem to hinder a cohesive and thorough model of ligand-induced quaternary arrangement...

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“…However, it must be emphasized that M64U1-SH oxidizes relatively quickly in physiological medium, which could explain this result. Nevertheless, our goal in this study was not to find a new entry inhibitor of the virus, as our miniCD4s are already high affinity entry inhibitors (54), but to obtain a new potential vaccine candidate.…”

Section: Discussionmentioning

confidence: 99%

Stabilization of HIV-1 Envelope in the CD4-bound Conformation through Specific Cross-linking of a CD4 Mimetic

Martin¹,

Burke

Thaï³

et al. 2011

Journal of Biological Chemistry

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CD4 binding on gp120 leads to the exposure of highly conserved regions recognized by the HIV co-receptor CCR5 and by CD4-induced (CD4i) antibodies. A covalent gp120-CD4 complex was shown to elicit CD4i antibody responses in monkeys, which was correlated with control of the HIV virus infection (DeVico, A., Fouts, T., Lewis, G. K., Gallo, R. C., Godfrey, K., Charurat, M., Harris, I., Galmin, L., and Pal, R. (2007) Proc. Natl. Acad. Sci. U.S.A. 104, 17477-17482). Because the inclusion of CD4 in a vaccine formulation should be avoided, due to potential autoimmune reactions, we engineered small sized CD4 mimetics (miniCD4s) that are poorly immunogenic and do not induce anti-CD4 antibodies. We made covalent complexes between such an engineered miniCD4 and gp120 or gp140, through a site-directed coupling reaction. These complexes were recognized by CD4i antibodies as well as by the HIV co-receptor CCR5. In addition, they elicit CD4i antibody responses in rabbits and therefore represent potential vaccine candidates that mimic an important HIV fusion intermediate, without autoimmune hazard.

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CD4 mimetic miniproteins: potent anti-HIV compounds with promising activity as microbicides

Abstract: These novel CD4 miniproteins might constitute a promising class of HIV microbicides.

Cited by 56 publications

References 39 publications

CD4 mimetics sensitize HIV-1-infected cells to ADCC

CD4 mimetics sensitize HIV-1-infected cells to ADCC

Quaternary structures of HIV Env immunogen exhibit conformational vicissitudes and interface diminution elicited by ligand binding

Stabilization of HIV-1 Envelope in the CD4-bound Conformation through Specific Cross-linking of a CD4 Mimetic

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