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A Small-Molecule CD4-Mimetic Compound Protects Bone Marrow-Liver-Thymus Humanized Mice From HIV-1 Infection.

ABSTRACT: Background:Small-molecule CD4-mimetic compounds (CD4mc) inhibit human immunodeficiency virus (HIV-1) entry by blocking binding to the CD4 receptor and by premature triggering of the viral envelope glycoprotein (Env) spike. Methods:The efficacy of a CD4mc in protecting bone marrow-liver-thymus (BLT) humanized mice from vaginal HIV-1 challenge was evaluated. Results:Intravaginal application of the CD4mc JP-III-48, either before or simultaneously with virus challenge, protected BLT humanized mice from HIV-1JR-CSF infection in a dose- dependent manner. Conclusion:The direct antiviral effects of a CD4mc prevent HIV-1 infection in a murine model of sexual transmission.

SUBMITTER: Princiotto AM

PROVIDER: S-EPMC6049021 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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A Small-Molecule CD4-Mimetic Compound Protects Bone Marrow-Liver-Thymus Humanized Mice From HIV-1 Infection.

Princiotto Amy M AM Vrbanac Vladimir D VD Melillo Bruno B Park Jongwoo J Tager Andrew M AM Smith Amos B AB Sodroski Joseph J Madani Navid N

The Journal of infectious diseases 20180701 3

<h4>Background</h4>Small-molecule CD4-mimetic compounds (CD4mc) inhibit human immunodeficiency virus (HIV-1) entry by blocking binding to the CD4 receptor and by premature triggering of the viral envelope glycoprotein (Env) spike.<h4>Methods</h4>The efficacy of a CD4mc in protecting bone marrow-liver-thymus (BLT) humanized mice from vaginal HIV-1 challenge was evaluated.<h4>Results</h4>Intravaginal application of the CD4mc JP-III-48, either before or simultaneously with virus challenge, protecte ...[more]

PMID: 29617845

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Project description:Small CD4-mimetic compound (CD4mc), which inhibits the interaction between gp120 with CD4, acts as an entry inhibitor and induces structural changes in the HIV-1 envelope glycoprotein trimer (Env) through its insertion within the Phe43 cavity of gp120. We recently developed YIR-821, a novel CD4mc, that has potent antiviral activity and lower toxicity than the prototype NBD-556. To assess the possibility of clinical application of YIR-821, we tested its antiviral activity using a panel of HIV-1 pseudoviruses from different subtypes. YIR-821 displayed entry inhibitor activity against 53.5% (21/40) of the pseudoviruses tested and enhanced neutralization mediated by coreceptor binding site (CoRBS) antibodies in 50% (16/32) of these. Furthermore, when we assessed the antiviral effects using a panel of pseudoviruses and autologous plasma IgG, enhancement of antibody-mediated neutralization activity was observed for 48% (15/31) of subtype B strains and 51% (28/55) of non-B strains. The direct antiviral activity of YIR-821 as an entry inhibitor was observed in 53% of both subtype B (27/51) and non-B subtype (40/75) pseudoviruses. Enhancement of antibody-dependent cellular cytotoxicity was also observed with YIR-821 for all six selected clinical isolates, as well as for the transmitted/founder (T/F) CH58 virus-infected cells. The sequence diversity in the CD4 binding site as well as other regions, such as the gp120 inner domain layers or gp41, may be involved in the multiple mechanisms related to the sensitive/resistant phenotype of the virus to YIR-821. Our findings may facilitate the clinical application of YIR-821. IMPORTANCE Small CD4-mimetic compound (CD4mc) interacts with the Phe43 cavity and triggers conformational changes, enhancing antibody-mediated neutralization and antibody-dependent cellular cytotoxicity (ADCC). Here, we evaluated the effect of YIR-821, a novel CD4mc, against clinical isolates, including both subtype B and non-B subtype viruses. Our results confirm the desirable properties of YIR-821, which include entry inhibition, enhancement of IgG-neutralization, binding, and ADCC, in addition to low toxicity and long half-life in a rhesus macaque model, that might facilitate the clinical application of this novel CD4mc. Our observation of primary viruses that are resistant to YIR-821 suggests that further development of CD4mcs with different structural properties is required.

Dataset Information

A Small-Molecule CD4-Mimetic Compound Protects Bone Marrow-Liver-Thymus Humanized Mice From HIV-1 Infection.

Publications

A Small-Molecule CD4-Mimetic Compound Protects Bone Marrow-Liver-Thymus Humanized Mice From HIV-1 Infection.

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