HIV-1 Envelope Glycoproteins Proteolytic Cleavage Protects Infected Cells from ADCC Mediated by Plasma from Infected Individuals
The HIV-1 envelope glycoprotein (Env) is synthesized in the endoplasmic reticulum as a trimeric gp160 precursor, which requires proteolytic cleavage by a cellular furin protease to mediate virus-cell fusion. Env is conformationally flexible but controls its transition from the unbound “closed” confo...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-11-01
|
| Series: | Viruses |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4915/13/11/2236 |
| _version_ | 1797508239198257152 |
|---|---|
| author | Jérémie Prévost Halima Medjahed Dani Vézina Hung-Ching Chen Beatrice H. Hahn Amos B. Smith Andrés Finzi |
| author_facet | Jérémie Prévost Halima Medjahed Dani Vézina Hung-Ching Chen Beatrice H. Hahn Amos B. Smith Andrés Finzi |
| author_sort | Jérémie Prévost |
| collection | DOAJ |
| description | The HIV-1 envelope glycoprotein (Env) is synthesized in the endoplasmic reticulum as a trimeric gp160 precursor, which requires proteolytic cleavage by a cellular furin protease to mediate virus-cell fusion. Env is conformationally flexible but controls its transition from the unbound “closed” conformation (State 1) to downstream CD4-bound conformations (States 2/3), which are required for fusion. In particular, HIV-1 has evolved several mechanisms that reduce the premature “opening” of Env which exposes highly conserved epitopes recognized by non-neutralizing antibodies (nnAbs) capable of mediating antibody-dependent cellular cytotoxicity (ADCC). Env cleavage decreases its conformational transitions favoring the adoption of the “closed” conformation. Here we altered the gp160 furin cleavage site to impair Env cleavage and to examine its impact on ADCC responses mediated by plasma from HIV-1-infected individuals. We found that infected primary CD4+ T cells expressing uncleaved, but not wildtype, Env are efficiently recognized by nnAbs and become highly susceptible to ADCC responses mediated by plasma from HIV-1-infected individuals. Thus, HIV-1 limits the exposure of uncleaved Env at the surface of HIV-1-infected cells at least in part to escape ADCC responses. |
| first_indexed | 2024-03-10T04:59:44Z |
| format | Article |
| id | doaj.art-f9a7cfc38dc346768a1d29923cc3a948 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-10T04:59:44Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-f9a7cfc38dc346768a1d29923cc3a9482023-11-23T01:57:17ZengMDPI AGViruses1999-49152021-11-011311223610.3390/v13112236HIV-1 Envelope Glycoproteins Proteolytic Cleavage Protects Infected Cells from ADCC Mediated by Plasma from Infected IndividualsJérémie Prévost0Halima Medjahed1Dani Vézina2Hung-Ching Chen3Beatrice H. Hahn4Amos B. Smith5Andrés Finzi6Centre de Recherche du CHUM, Montreal, QC H2X 0A9, CanadaCentre de Recherche du CHUM, Montreal, QC H2X 0A9, CanadaCentre de Recherche du CHUM, Montreal, QC H2X 0A9, CanadaDepartment of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104-6323, USADepartments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6076, USADepartment of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104-6323, USACentre de Recherche du CHUM, Montreal, QC H2X 0A9, CanadaThe HIV-1 envelope glycoprotein (Env) is synthesized in the endoplasmic reticulum as a trimeric gp160 precursor, which requires proteolytic cleavage by a cellular furin protease to mediate virus-cell fusion. Env is conformationally flexible but controls its transition from the unbound “closed” conformation (State 1) to downstream CD4-bound conformations (States 2/3), which are required for fusion. In particular, HIV-1 has evolved several mechanisms that reduce the premature “opening” of Env which exposes highly conserved epitopes recognized by non-neutralizing antibodies (nnAbs) capable of mediating antibody-dependent cellular cytotoxicity (ADCC). Env cleavage decreases its conformational transitions favoring the adoption of the “closed” conformation. Here we altered the gp160 furin cleavage site to impair Env cleavage and to examine its impact on ADCC responses mediated by plasma from HIV-1-infected individuals. We found that infected primary CD4+ T cells expressing uncleaved, but not wildtype, Env are efficiently recognized by nnAbs and become highly susceptible to ADCC responses mediated by plasma from HIV-1-infected individuals. Thus, HIV-1 limits the exposure of uncleaved Env at the surface of HIV-1-infected cells at least in part to escape ADCC responses.https://www.mdpi.com/1999-4915/13/11/2236HIV-1Env glycoproteinfurin cleavage siteCD4 mimeticsTemsavirnnAbs |
| spellingShingle | Jérémie Prévost Halima Medjahed Dani Vézina Hung-Ching Chen Beatrice H. Hahn Amos B. Smith Andrés Finzi HIV-1 Envelope Glycoproteins Proteolytic Cleavage Protects Infected Cells from ADCC Mediated by Plasma from Infected Individuals Viruses HIV-1 Env glycoprotein furin cleavage site CD4 mimetics Temsavir nnAbs |
| title | HIV-1 Envelope Glycoproteins Proteolytic Cleavage Protects Infected Cells from ADCC Mediated by Plasma from Infected Individuals |
| title_full | HIV-1 Envelope Glycoproteins Proteolytic Cleavage Protects Infected Cells from ADCC Mediated by Plasma from Infected Individuals |
| title_fullStr | HIV-1 Envelope Glycoproteins Proteolytic Cleavage Protects Infected Cells from ADCC Mediated by Plasma from Infected Individuals |
| title_full_unstemmed | HIV-1 Envelope Glycoproteins Proteolytic Cleavage Protects Infected Cells from ADCC Mediated by Plasma from Infected Individuals |
| title_short | HIV-1 Envelope Glycoproteins Proteolytic Cleavage Protects Infected Cells from ADCC Mediated by Plasma from Infected Individuals |
| title_sort | hiv 1 envelope glycoproteins proteolytic cleavage protects infected cells from adcc mediated by plasma from infected individuals |
| topic | HIV-1 Env glycoprotein furin cleavage site CD4 mimetics Temsavir nnAbs |
| url | https://www.mdpi.com/1999-4915/13/11/2236 |
| work_keys_str_mv | AT jeremieprevost hiv1envelopeglycoproteinsproteolyticcleavageprotectsinfectedcellsfromadccmediatedbyplasmafrominfectedindividuals AT halimamedjahed hiv1envelopeglycoproteinsproteolyticcleavageprotectsinfectedcellsfromadccmediatedbyplasmafrominfectedindividuals AT danivezina hiv1envelopeglycoproteinsproteolyticcleavageprotectsinfectedcellsfromadccmediatedbyplasmafrominfectedindividuals AT hungchingchen hiv1envelopeglycoproteinsproteolyticcleavageprotectsinfectedcellsfromadccmediatedbyplasmafrominfectedindividuals AT beatricehhahn hiv1envelopeglycoproteinsproteolyticcleavageprotectsinfectedcellsfromadccmediatedbyplasmafrominfectedindividuals AT amosbsmith hiv1envelopeglycoproteinsproteolyticcleavageprotectsinfectedcellsfromadccmediatedbyplasmafrominfectedindividuals AT andresfinzi hiv1envelopeglycoproteinsproteolyticcleavageprotectsinfectedcellsfromadccmediatedbyplasmafrominfectedindividuals |