CD4 mimetics sensitize HIV-1-infected cells to ADCC

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

doi:10.1073/pnas.1506755112

Cited by 120 publications

(292 citation statements)

References 52 publications

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“…These strategies rely on the unique ability of the CD4-mimetic inhibitors to expose, upon Env binding, epitopes recognized by antibodies present in HIV-infected individuals. 9,10 That we have already demonstrated the capability of the earlier congeners of (+)-(R,R)-6, namely, 3 and 4, to enhance the efficacy of immune responses both against the HIV virus itself 7 and against infected cells 10 is very encouraging.…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 79%

“…Importantly, we have demonstrated that antibodies can indeed recognize gp120 bound to the CD4 small-molecule mimics, both on the surface of the virion 9 and, more recently, on the surface of infected cells. 10 Thus, in our efforts to enhance the direct inhibitory activity of the smallmolecule CD4 mimetics, we have sought to improve our understanding of the underlying molecular mechanisms. Logically, we chose 3 as the starting point for the design of a new generation of more potent small-molecule entry inhibitors.…”

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confidence: 99%

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Small-Molecule CD4-Mimics: Structure-Based Optimization of HIV-1 Entry Inhibition

Melillo

Liang

Park

et al. 2016

ACS Med. Chem. Lett.

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148

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The optimization, based on computational, thermodynamic, and crystallographic data, of a series of small-molecule ligands of the Phe43 cavity of the envelope glycoprotein gp120 of human immunodeficiency virus (HIV) has been achieved. Importantly, biological evaluation revealed that the small-molecule CD4 mimics (4−7) inhibit HIV-1 entry into target cells with both significantly higher potency and neutralization breadth than previous congeners, while maintaining high selectivity for the target virus. Their binding mode was characterized via thermodynamic and crystallographic studies.

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Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 79%

mentioning

confidence: 99%

Small-Molecule CD4-Mimics: Structure-Based Optimization of HIV-1 Entry Inhibition

Melillo

Liang

Park

et al. 2016

ACS Med. Chem. Lett.

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148

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“…To evaluate whether the enhanced recognition of HIV-1-infected cells by A32 and antibodies within HIV ϩ sera translated into increased susceptibility to ADCC responses, we used a previously described fluorescence-activated cell sorter (FACS)-based ADCC assay (18,21). Briefly, primary CD4 ϩ T cells infected for 48 h were incubated with autologous peripheral blood mononuclear cells (PBMCs) (effector-to-target cell ratio of Error bars indicate means Ϯ standard errors of the means.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, decreased amounts of Env at the cell surface due to efficient internalization also help the virus to avoid ADCC responses (17). In agreement with the need for HIV-1 to avoid exposing Env in the CD4-bound conformation, it was recently shown that forcing Env to adopt this conformation with small CD4-mimetic compounds (CD4mcs) sensitizes HIV-1-infected cells to ADCC responses (18)(19)(20). Accordingly, we recently reported that the transition of Env to the CD4-bound conformation is required for efficient interactions with ADCC-mediating antibodies (14).…”

mentioning

confidence: 88%

“…Accordingly, we recently reported that the transition of Env to the CD4-bound conformation is required for efficient interactions with ADCC-mediating antibodies (14). We reported that the replacement of serine 375 by a tryptophan residue (S375W) enhanced the exposure of epitopes recognized by anti-cluster A antibodies, known to mediate potent ADCC responses (13,14,18,(20)(21)(22)(23)(24)(25)(26). Thus, the transition of Env from the unbound to the CD4-bound conformation appears to be a prerequisite for the exposure of inner-domain ADCC epitopes.…”

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confidence: 99%

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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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Mechanisms of HIV persistence in HIV reservoirs

Mzingwane

Tiemessen

2017

Reviews in Medical Virology

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The establishment and maintenance of HIV reservoirs that lead to persistent viremia in patients on antiretroviral drugs remains the greatest challenge of the highly active antiretroviral therapy era. Cellular reservoirs include resting memory CD4+ T lymphocytes, implicated as the major HIV reservoir, having a half-life of approximately 44 months while this is less than 6 hours for HIV in plasma. In some individuals, persistent viremia consists of invariant HIV clones not detected in circulating resting CD4+ T lymphocytes suggesting other possible sources of residual viremia. Some anatomical reservoirs that may harbor such cells include the brain and the central nervous system, the gastrointestinal tract and the gut-associated lymphoid tissue and other lymphoid organs, and the genital tract. The presence of immune cells and other HIV susceptible cells, occurring in differing compositions in anatomical reservoirs, coupled with variable and poor drug penetration that results in suboptimal drug concentrations in some sites, are all likely factors that fuel the continued low-level replication and persistent viremia during treatment. Latently, HIV-infected CD4+ T cells harboring replication-competent virus, HIV cell-to-cell spread, and HIV-infected T cell homeostatic proliferation due to chronic immune activation represent further drivers of this persistent HIV viremia during highly active antiretroviral therapy.

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CD4 mimetics sensitize HIV-1-infected cells to ADCC

Cited by 120 publications

References 52 publications

Small-Molecule CD4-Mimics: Structure-Based Optimization of HIV-1 Entry Inhibition

Small-Molecule CD4-Mimics: Structure-Based Optimization of HIV-1 Entry Inhibition

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

Mechanisms of HIV persistence in HIV reservoirs

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