HIV-1 exploits LBPA-dependent intraepithelial trafficking for productive infection of human intestinal mucosa.
The gastrointestinal tract is a prominent portal of entry for HIV-1 during sexual or perinatal transmission, as well as a major site of HIV-1 persistence and replication. Elucidation of underlying mechanisms of intestinal HIV-1 infection are thus needed for the advancement of HIV-1 curative therapie...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2024-12-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1012714 |
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| author | Anusca G Rader Alexandra P M Cloherty Kharishma S Patel Dima D A Almandawi Dasja Pajkrt Katja C Wolthers Adithya Sridhar Sterre van Piggelen Liselotte E Baaij Renée R C E Schreurs Carla M S Ribeiro |
| author_facet | Anusca G Rader Alexandra P M Cloherty Kharishma S Patel Dima D A Almandawi Dasja Pajkrt Katja C Wolthers Adithya Sridhar Sterre van Piggelen Liselotte E Baaij Renée R C E Schreurs Carla M S Ribeiro |
| author_sort | Anusca G Rader |
| collection | DOAJ |
| description | The gastrointestinal tract is a prominent portal of entry for HIV-1 during sexual or perinatal transmission, as well as a major site of HIV-1 persistence and replication. Elucidation of underlying mechanisms of intestinal HIV-1 infection are thus needed for the advancement of HIV-1 curative therapies. Here, we present a human 2D intestinal immuno-organoid system to model HIV-1 disease that recapitulates tissue compartmentalization and epithelial-immune cellular interactions. Our data demonstrate that apical exposure of intestinal epithelium to HIV-1 results in viral internalization, with subsequent basolateral shedding of replication-competent viruses, in a manner that is impervious to antiretroviral treatment. Incorporation of subepithelial dendritic cells resulted in HIV-1 luminal sampling and amplification of residual viral replication of lab-adapted and transmitted-founder (T/F) HIV-1 variants. Markedly, intraepithelial viral capture ensued an altered distribution of specialized endosomal pathways alongside durable sequestration of infectious HIV-1 within lysobisphosphatidic acid (LPBA)-rich vesicles. Therapeutic neutralization of LBPA-dependent trafficking limited productive HIV-1 infection, and thereby demonstrated the pivotal role of intraepithelial multivesicular endosomes as niches for virulent HIV-1 within the intestinal mucosa. Our study showcases the application of primary human 2D immune-competent organoid cultures in uncovering mechanisms of intestinal HIV-1 disease as well as a platform for preclinical antiviral drug discovery. |
| format | Article |
| id | doaj-art-c3eabf9638324a299f8b346ecaf98c7c |
| institution | DOAJ |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-c3eabf9638324a299f8b346ecaf98c7c2025-08-20T02:45:00ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742024-12-012012e101271410.1371/journal.ppat.1012714HIV-1 exploits LBPA-dependent intraepithelial trafficking for productive infection of human intestinal mucosa.Anusca G RaderAlexandra P M ClohertyKharishma S PatelDima D A AlmandawiDasja PajkrtKatja C WolthersAdithya SridharSterre van PiggelenLiselotte E BaaijRenée R C E SchreursCarla M S RibeiroThe gastrointestinal tract is a prominent portal of entry for HIV-1 during sexual or perinatal transmission, as well as a major site of HIV-1 persistence and replication. Elucidation of underlying mechanisms of intestinal HIV-1 infection are thus needed for the advancement of HIV-1 curative therapies. Here, we present a human 2D intestinal immuno-organoid system to model HIV-1 disease that recapitulates tissue compartmentalization and epithelial-immune cellular interactions. Our data demonstrate that apical exposure of intestinal epithelium to HIV-1 results in viral internalization, with subsequent basolateral shedding of replication-competent viruses, in a manner that is impervious to antiretroviral treatment. Incorporation of subepithelial dendritic cells resulted in HIV-1 luminal sampling and amplification of residual viral replication of lab-adapted and transmitted-founder (T/F) HIV-1 variants. Markedly, intraepithelial viral capture ensued an altered distribution of specialized endosomal pathways alongside durable sequestration of infectious HIV-1 within lysobisphosphatidic acid (LPBA)-rich vesicles. Therapeutic neutralization of LBPA-dependent trafficking limited productive HIV-1 infection, and thereby demonstrated the pivotal role of intraepithelial multivesicular endosomes as niches for virulent HIV-1 within the intestinal mucosa. Our study showcases the application of primary human 2D immune-competent organoid cultures in uncovering mechanisms of intestinal HIV-1 disease as well as a platform for preclinical antiviral drug discovery.https://doi.org/10.1371/journal.ppat.1012714 |
| spellingShingle | Anusca G Rader Alexandra P M Cloherty Kharishma S Patel Dima D A Almandawi Dasja Pajkrt Katja C Wolthers Adithya Sridhar Sterre van Piggelen Liselotte E Baaij Renée R C E Schreurs Carla M S Ribeiro HIV-1 exploits LBPA-dependent intraepithelial trafficking for productive infection of human intestinal mucosa. PLoS Pathogens |
| title | HIV-1 exploits LBPA-dependent intraepithelial trafficking for productive infection of human intestinal mucosa. |
| title_full | HIV-1 exploits LBPA-dependent intraepithelial trafficking for productive infection of human intestinal mucosa. |
| title_fullStr | HIV-1 exploits LBPA-dependent intraepithelial trafficking for productive infection of human intestinal mucosa. |
| title_full_unstemmed | HIV-1 exploits LBPA-dependent intraepithelial trafficking for productive infection of human intestinal mucosa. |
| title_short | HIV-1 exploits LBPA-dependent intraepithelial trafficking for productive infection of human intestinal mucosa. |
| title_sort | hiv 1 exploits lbpa dependent intraepithelial trafficking for productive infection of human intestinal mucosa |
| url | https://doi.org/10.1371/journal.ppat.1012714 |
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