Temsavir Treatment of HIV-1-Infected Cells Decreases Envelope Glycoprotein Recognition by Broadly Neutralizing Antibodies
ABSTRACT The heavily glycosylated HIV-1 envelope glycoprotein (Env) is the sole viral antigen present at the surface of virions and infected cells, representing the main target for antibody responses. The FDA-approved small molecule temsavir acts as an HIV-1 attachment inhibitor by preventing Env-CD...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2022-06-01
|
| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.00577-22 |
| _version_ | 1828204482320662528 |
|---|---|
| author | Marianne Boutin Dani Vézina Shilei Ding Jérémie Prévost Annemarie Laumaea Lorie Marchitto Sai Priya Anand Halima Medjahed Gabrielle Gendron-Lepage Catherine Bourassa Guillaume Goyette Andrew Clark Jonathan Richard Andrés Finzi |
| author_facet | Marianne Boutin Dani Vézina Shilei Ding Jérémie Prévost Annemarie Laumaea Lorie Marchitto Sai Priya Anand Halima Medjahed Gabrielle Gendron-Lepage Catherine Bourassa Guillaume Goyette Andrew Clark Jonathan Richard Andrés Finzi |
| author_sort | Marianne Boutin |
| collection | DOAJ |
| description | ABSTRACT The heavily glycosylated HIV-1 envelope glycoprotein (Env) is the sole viral antigen present at the surface of virions and infected cells, representing the main target for antibody responses. The FDA-approved small molecule temsavir acts as an HIV-1 attachment inhibitor by preventing Env-CD4 interaction. This molecule also stabilizes Env in a prefusion “closed” conformation that is preferentially targeted by several broadly neutralizing antibodies (bNAbs). A recent study showed that an analog of temsavir (BMS-377806) affects the cleavage and addition of complex glycans on Env. In this study, we investigated the impact of temsavir on the overall glycosylation, proteolytic cleavage, cell surface expression, and antigenicity of Env. We found that temsavir impacts Env glycosylation and processing at physiological concentrations. This significantly alters the capacity of several bNAbs to recognize Env present on virions and HIV-1-infected cells. Temsavir treatment also reduces the capacity of bNAbs to eliminate HIV-1-infected cells by antibody-dependent cellular cytotoxicity (ADCC). Consequently, the impact of temsavir on Env glycosylation and antigenicity should be considered for the development of new antibody-based approaches in temsavir-treated individuals. IMPORTANCE FDA-approved fostemsavir, the prodrug for the active moiety small molecule temsavir (GSK 2616713 [formally BMS-626529]), acts as an attachment inhibitor by targeting the HIV-1 envelope (Env) and preventing CD4 interaction. Temsavir also stabilizes Env in its “closed,” functional state 1 conformation, which represents an ideal target for broadly neutralizing antibodies (bNAbs). Since these antibodies recognize conformation-dependent epitopes composed of or adjacent to glycans, we evaluated the impact of temsavir treatment on overall Env glycosylation and its influence on bNAb recognition. Our results showed an alteration of Env glycosylation and cleavage by temsavir at physiological concentrations. This significantly modifies the overall antigenicity of Env and therefore reduces the capacity of bNAbs to recognize and eliminate HIV-1-infected cells by ADCC. These findings provide important information for the design of immunotherapies aimed at targeting the viral reservoir in temsavir-treated individuals. |
| first_indexed | 2024-04-12T12:23:10Z |
| format | Article |
| id | doaj.art-5207e3e6036044ac9aab42d5b00816cb |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-04-12T12:23:10Z |
| publishDate | 2022-06-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-5207e3e6036044ac9aab42d5b00816cb2022-12-22T03:33:14ZengAmerican Society for MicrobiologymBio2150-75112022-06-0113310.1128/mbio.00577-22Temsavir Treatment of HIV-1-Infected Cells Decreases Envelope Glycoprotein Recognition by Broadly Neutralizing AntibodiesMarianne Boutin0Dani Vézina1Shilei Ding2Jérémie Prévost3Annemarie Laumaea4Lorie Marchitto5Sai Priya Anand6Halima Medjahed7Gabrielle Gendron-Lepage8Catherine Bourassa9Guillaume Goyette10Andrew Clark11Jonathan Richard12Andrés Finzi13Centre de Recherche du CHUM (CRCHUM), Montreal, Quebec, CanadaCentre de Recherche du CHUM (CRCHUM), Montreal, Quebec, CanadaCentre de Recherche du CHUM (CRCHUM), Montreal, Quebec, CanadaCentre de Recherche du CHUM (CRCHUM), Montreal, Quebec, CanadaCentre de Recherche du CHUM (CRCHUM), Montreal, Quebec, CanadaCentre de Recherche du CHUM (CRCHUM), Montreal, Quebec, CanadaDepartment of Microbiology and Immunology, McGill University, Montreal, Quebec, CanadaCentre de Recherche du CHUM (CRCHUM), Montreal, Quebec, CanadaCentre de Recherche du CHUM (CRCHUM), Montreal, Quebec, CanadaCentre de Recherche du CHUM (CRCHUM), Montreal, Quebec, CanadaCentre de Recherche du CHUM (CRCHUM), Montreal, Quebec, CanadaViiV Healthcare, Global Medical Affairs, Middlesex, United KingdomCentre de Recherche du CHUM (CRCHUM), Montreal, Quebec, CanadaCentre de Recherche du CHUM (CRCHUM), Montreal, Quebec, CanadaABSTRACT The heavily glycosylated HIV-1 envelope glycoprotein (Env) is the sole viral antigen present at the surface of virions and infected cells, representing the main target for antibody responses. The FDA-approved small molecule temsavir acts as an HIV-1 attachment inhibitor by preventing Env-CD4 interaction. This molecule also stabilizes Env in a prefusion “closed” conformation that is preferentially targeted by several broadly neutralizing antibodies (bNAbs). A recent study showed that an analog of temsavir (BMS-377806) affects the cleavage and addition of complex glycans on Env. In this study, we investigated the impact of temsavir on the overall glycosylation, proteolytic cleavage, cell surface expression, and antigenicity of Env. We found that temsavir impacts Env glycosylation and processing at physiological concentrations. This significantly alters the capacity of several bNAbs to recognize Env present on virions and HIV-1-infected cells. Temsavir treatment also reduces the capacity of bNAbs to eliminate HIV-1-infected cells by antibody-dependent cellular cytotoxicity (ADCC). Consequently, the impact of temsavir on Env glycosylation and antigenicity should be considered for the development of new antibody-based approaches in temsavir-treated individuals. IMPORTANCE FDA-approved fostemsavir, the prodrug for the active moiety small molecule temsavir (GSK 2616713 [formally BMS-626529]), acts as an attachment inhibitor by targeting the HIV-1 envelope (Env) and preventing CD4 interaction. Temsavir also stabilizes Env in its “closed,” functional state 1 conformation, which represents an ideal target for broadly neutralizing antibodies (bNAbs). Since these antibodies recognize conformation-dependent epitopes composed of or adjacent to glycans, we evaluated the impact of temsavir treatment on overall Env glycosylation and its influence on bNAb recognition. Our results showed an alteration of Env glycosylation and cleavage by temsavir at physiological concentrations. This significantly modifies the overall antigenicity of Env and therefore reduces the capacity of bNAbs to recognize and eliminate HIV-1-infected cells by ADCC. These findings provide important information for the design of immunotherapies aimed at targeting the viral reservoir in temsavir-treated individuals.https://journals.asm.org/doi/10.1128/mbio.00577-22HIV-1Env glycoproteinentry inhibitorsattachment inhibitorsfostemsavirBMS-663068 |
| spellingShingle | Marianne Boutin Dani Vézina Shilei Ding Jérémie Prévost Annemarie Laumaea Lorie Marchitto Sai Priya Anand Halima Medjahed Gabrielle Gendron-Lepage Catherine Bourassa Guillaume Goyette Andrew Clark Jonathan Richard Andrés Finzi Temsavir Treatment of HIV-1-Infected Cells Decreases Envelope Glycoprotein Recognition by Broadly Neutralizing Antibodies mBio HIV-1 Env glycoprotein entry inhibitors attachment inhibitors fostemsavir BMS-663068 |
| title | Temsavir Treatment of HIV-1-Infected Cells Decreases Envelope Glycoprotein Recognition by Broadly Neutralizing Antibodies |
| title_full | Temsavir Treatment of HIV-1-Infected Cells Decreases Envelope Glycoprotein Recognition by Broadly Neutralizing Antibodies |
| title_fullStr | Temsavir Treatment of HIV-1-Infected Cells Decreases Envelope Glycoprotein Recognition by Broadly Neutralizing Antibodies |
| title_full_unstemmed | Temsavir Treatment of HIV-1-Infected Cells Decreases Envelope Glycoprotein Recognition by Broadly Neutralizing Antibodies |
| title_short | Temsavir Treatment of HIV-1-Infected Cells Decreases Envelope Glycoprotein Recognition by Broadly Neutralizing Antibodies |
| title_sort | temsavir treatment of hiv 1 infected cells decreases envelope glycoprotein recognition by broadly neutralizing antibodies |
| topic | HIV-1 Env glycoprotein entry inhibitors attachment inhibitors fostemsavir BMS-663068 |
| url | https://journals.asm.org/doi/10.1128/mbio.00577-22 |
| work_keys_str_mv | AT marianneboutin temsavirtreatmentofhiv1infectedcellsdecreasesenvelopeglycoproteinrecognitionbybroadlyneutralizingantibodies AT danivezina temsavirtreatmentofhiv1infectedcellsdecreasesenvelopeglycoproteinrecognitionbybroadlyneutralizingantibodies AT shileiding temsavirtreatmentofhiv1infectedcellsdecreasesenvelopeglycoproteinrecognitionbybroadlyneutralizingantibodies AT jeremieprevost temsavirtreatmentofhiv1infectedcellsdecreasesenvelopeglycoproteinrecognitionbybroadlyneutralizingantibodies AT annemarielaumaea temsavirtreatmentofhiv1infectedcellsdecreasesenvelopeglycoproteinrecognitionbybroadlyneutralizingantibodies AT loriemarchitto temsavirtreatmentofhiv1infectedcellsdecreasesenvelopeglycoproteinrecognitionbybroadlyneutralizingantibodies AT saipriyaanand temsavirtreatmentofhiv1infectedcellsdecreasesenvelopeglycoproteinrecognitionbybroadlyneutralizingantibodies AT halimamedjahed temsavirtreatmentofhiv1infectedcellsdecreasesenvelopeglycoproteinrecognitionbybroadlyneutralizingantibodies AT gabriellegendronlepage temsavirtreatmentofhiv1infectedcellsdecreasesenvelopeglycoproteinrecognitionbybroadlyneutralizingantibodies AT catherinebourassa temsavirtreatmentofhiv1infectedcellsdecreasesenvelopeglycoproteinrecognitionbybroadlyneutralizingantibodies AT guillaumegoyette temsavirtreatmentofhiv1infectedcellsdecreasesenvelopeglycoproteinrecognitionbybroadlyneutralizingantibodies AT andrewclark temsavirtreatmentofhiv1infectedcellsdecreasesenvelopeglycoproteinrecognitionbybroadlyneutralizingantibodies AT jonathanrichard temsavirtreatmentofhiv1infectedcellsdecreasesenvelopeglycoproteinrecognitionbybroadlyneutralizingantibodies AT andresfinzi temsavirtreatmentofhiv1infectedcellsdecreasesenvelopeglycoproteinrecognitionbybroadlyneutralizingantibodies |