Griffithsin Retains Anti-HIV-1 Potency with Changes in gp120 Glycosylation and Complements Broadly Neutralizing Antibodies PGT121 and PGT126
| العنوان: | Griffithsin Retains Anti-HIV-1 Potency with Changes in gp120 Glycosylation and Complements Broadly Neutralizing Antibodies PGT121 and PGT126 |
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| المؤلفون: | Patricia J. LiWang, Kathryn Fischer, Kimberly Nguyen |
| المصدر: | Antimicrobial Agents and Chemotherapy Antimicrobial agents and chemotherapy, vol 64, iss 1 Antimicrob Agents Chemother |
| بيانات النشر: | American Society for Microbiology, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Models, Molecular, Glycosylation, Protein Conformation, Drug Resistance, HIV Infections, HIV Envelope Protein gp120, HIV Antibodies, medicine.disease_cause, chemistry.chemical_compound, Models, Site-Directed, Pharmacology (medical), Viral, Griffithsin, Mutation, high mannose, biology, Chemistry, Pharmacology and Pharmaceutical Sciences, Combined Modality Therapy, Cell biology, Infectious Diseases, Medical Microbiology, HIV/AIDS, Antibody, Plant Lectins, Glycan, Anti-HIV Agents, 030106 microbiology, In Vitro Techniques, Antiviral Agents, Microbiology, Vaccine Related, 03 medical and health sciences, Drug Resistance, Viral, medicine, Potency, Humans, Binding site, Vaccine Related (AIDS), Pharmacology, Binding Sites, griffithsin, Prevention, Lectin, Molecular, gp120 glycosylation, HIV inhibition, carbohydrates (lipids), 030104 developmental biology, Good Health and Well Being, Mutagenesis, biology.protein, Mutagenesis, Site-Directed, HIV-1, Immunization, Broadly Neutralizing Antibodies, microbicide |
| الوصف: | Griffithsin (Grft) is an antiviral lectin that has been shown to potently inhibit HIV-1 by binding high-mannose N-linked glycosylation sites on HIV-1 gp120. A key factor for Grft potency is glycosylation at N295 of gp120, which is directly adjacent to N332, a target glycan for an entire class of broadly neutralizing antibodies (bNAbs). Here, we unify previous work on the importance of other glycans to Grft potency against HIV-1 and Grft's role in mediating the conformational change of gp120 by mutating nearly every glycosylation site in gp120. In addition to a significant loss of Grft activity by the removal of glycosylation at N295, glycan absence at N332 or N448 was found to have moderate effects on Grft potency. Interestingly, in the absence of N295, Grft effectiveness could be improved by a mutation that results in the glycan at N448 shifting to N446, indicating that the importance of individual glycans may be related to their effect on glycosylation density. Grft's ability to alter the structure of gp120, exposing the CD4 binding site, correlated with the presence of glycosylation at N295 only in clade B strains, not clade C strains. We further demonstrate that Grft can rescue the activity of the bNAbs PGT121 and PGT126 in the event of a loss or a shift of glycosylation at N332, where the bNAbs suffer a drastic loss of potency. Despite targeting the same region, Grft in combination with PGT121 and PGT126 produced additive effects. This indicates that Grft could be an important combinational therapeutic. |
| وصف الملف: | application/pdf |
| تدمد: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.01084-19 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2cce4cccbb1433ecb0e990c7950209d6 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....2cce4cccbb1433ecb0e990c7950209d6 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10986596 00664804 |
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| DOI: | 10.1128/aac.01084-19 |