Targeted Immuno-Antiretroviral to Promote Dual Protection against HIV: A Proof-of-Concept Study
The C–C motif chemokine receptor-5 (CCR5) expression on the T-cell surface is the prime barrier to HIV/AIDS eradication, as it promotes both active human immunodeficiency virus (HIV)-infection and latency; however, antiretrovirals (ARVs) suppress plasma viral loads to non-detectable levels. Keeping...
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MDPI AG
2022-06-01
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| Series: | Nanomaterials |
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| Online Access: | https://www.mdpi.com/2079-4991/12/11/1942 |
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| author | Subhra Mandal Shawnalyn W. Sunagawa Pavan Kumar Prathipati Michael Belshan Annemarie Shibata Christopher J. Destache |
| author_facet | Subhra Mandal Shawnalyn W. Sunagawa Pavan Kumar Prathipati Michael Belshan Annemarie Shibata Christopher J. Destache |
| author_sort | Subhra Mandal |
| collection | DOAJ |
| description | The C–C motif chemokine receptor-5 (CCR5) expression on the T-cell surface is the prime barrier to HIV/AIDS eradication, as it promotes both active human immunodeficiency virus (HIV)-infection and latency; however, antiretrovirals (ARVs) suppress plasma viral loads to non-detectable levels. Keeping this in mind, we strategically designed a targeted ARVs-loaded nanoformulation that targets CCR5 expressing T-cells (e.g., CD4+ cells). Conceptually, CCR5-blocking and targeted ARV delivery would be a dual protection strategy to prevent HIV infection. For targeting CCR5+ T-cells, the nanoformulation was surface conjugated with anti-CCR5 monoclonal antibodies (CCR5 mAb) and loaded with dolutegravir+tenofovir alafenamide (D+T) ARVs to block HIV replication. The result demonstrated that the targeted-ARV nanoparticle’s multimeric CCR5 binding property improved its antigen-binding affinity, prolonged receptor binding, and ARV intracellular retention. Further, nanoformulation demonstrated high binding affinity to CCR5 expressing CD4+ cells, monocytes, and other CCR5+ T-cells. Finally, the short-term pre-exposure prophylaxis study demonstrated that prolonged CCR5 blockage and ARV presence further induced a “protective immune phenotype” with a boosted T-helper (Th), temporary memory (TM), and effector (E) sub-population. The proof-of-concept study that the targeted-ARV nanoformulation dual-action mechanism could provide a multifactorial solution toward achieving HIV “functional cure.” |
| first_indexed | 2024-03-10T01:00:22Z |
| format | Article |
| id | doaj.art-2123b81dcfc846a2ae7edb0954ff24ed |
| institution | Directory Open Access Journal |
| issn | 2079-4991 |
| language | English |
| last_indexed | 2024-03-10T01:00:22Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Nanomaterials |
| spelling | doaj.art-2123b81dcfc846a2ae7edb0954ff24ed2023-11-23T14:34:42ZengMDPI AGNanomaterials2079-49912022-06-011211194210.3390/nano12111942Targeted Immuno-Antiretroviral to Promote Dual Protection against HIV: A Proof-of-Concept StudySubhra Mandal0Shawnalyn W. Sunagawa1Pavan Kumar Prathipati2Michael Belshan3Annemarie Shibata4Christopher J. Destache5School of Pharmacy & Health Professions, Creighton University, Omaha, NE 68178, USASchool of Pharmacy & Health Professions, Creighton University, Omaha, NE 68178, USASchool of Pharmacy & Health Professions, Creighton University, Omaha, NE 68178, USADepartment of Medical Microbiology & Immunology, Creighton University School of Medicine, Creighton University, Omaha, NE 68178, USADepartment of Biology, College of Arts and Sciences, Creighton University, Omaha, NE 68178, USASchool of Pharmacy & Health Professions, Creighton University, Omaha, NE 68178, USAThe C–C motif chemokine receptor-5 (CCR5) expression on the T-cell surface is the prime barrier to HIV/AIDS eradication, as it promotes both active human immunodeficiency virus (HIV)-infection and latency; however, antiretrovirals (ARVs) suppress plasma viral loads to non-detectable levels. Keeping this in mind, we strategically designed a targeted ARVs-loaded nanoformulation that targets CCR5 expressing T-cells (e.g., CD4+ cells). Conceptually, CCR5-blocking and targeted ARV delivery would be a dual protection strategy to prevent HIV infection. For targeting CCR5+ T-cells, the nanoformulation was surface conjugated with anti-CCR5 monoclonal antibodies (CCR5 mAb) and loaded with dolutegravir+tenofovir alafenamide (D+T) ARVs to block HIV replication. The result demonstrated that the targeted-ARV nanoparticle’s multimeric CCR5 binding property improved its antigen-binding affinity, prolonged receptor binding, and ARV intracellular retention. Further, nanoformulation demonstrated high binding affinity to CCR5 expressing CD4+ cells, monocytes, and other CCR5+ T-cells. Finally, the short-term pre-exposure prophylaxis study demonstrated that prolonged CCR5 blockage and ARV presence further induced a “protective immune phenotype” with a boosted T-helper (Th), temporary memory (TM), and effector (E) sub-population. The proof-of-concept study that the targeted-ARV nanoformulation dual-action mechanism could provide a multifactorial solution toward achieving HIV “functional cure.”https://www.mdpi.com/2079-4991/12/11/1942dolutegravirtenofovirCCR5 monoclonal antibodynanoformulationtargetingfunctional HIV cure |
| spellingShingle | Subhra Mandal Shawnalyn W. Sunagawa Pavan Kumar Prathipati Michael Belshan Annemarie Shibata Christopher J. Destache Targeted Immuno-Antiretroviral to Promote Dual Protection against HIV: A Proof-of-Concept Study Nanomaterials dolutegravir tenofovir CCR5 monoclonal antibody nanoformulation targeting functional HIV cure |
| title | Targeted Immuno-Antiretroviral to Promote Dual Protection against HIV: A Proof-of-Concept Study |
| title_full | Targeted Immuno-Antiretroviral to Promote Dual Protection against HIV: A Proof-of-Concept Study |
| title_fullStr | Targeted Immuno-Antiretroviral to Promote Dual Protection against HIV: A Proof-of-Concept Study |
| title_full_unstemmed | Targeted Immuno-Antiretroviral to Promote Dual Protection against HIV: A Proof-of-Concept Study |
| title_short | Targeted Immuno-Antiretroviral to Promote Dual Protection against HIV: A Proof-of-Concept Study |
| title_sort | targeted immuno antiretroviral to promote dual protection against hiv a proof of concept study |
| topic | dolutegravir tenofovir CCR5 monoclonal antibody nanoformulation targeting functional HIV cure |
| url | https://www.mdpi.com/2079-4991/12/11/1942 |
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