Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors.
Despite advances in the treatment of HIV infection with ART, elucidating strategies to overcome HIV persistence, including blockade of viral reservoir establishment, maintenance, and expansion, remains a challenge. T cell homeostasis is a major driver of HIV persistence. Cytokines involved in regula...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2017-12-01
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| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC5739511?pdf=render |
| _version_ | 1818335887879045120 |
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| author | Christina Gavegnano Jessica H Brehm Franck P Dupuy Aarthi Talla Susan Pereira Ribeiro Deanna A Kulpa Cheryl Cameron Stephanie Santos Selwyn J Hurwitz Vincent C Marconi Jean-Pierre Routy Laurent Sabbagh Raymond F Schinazi Rafick Pierre Sékaly |
| author_facet | Christina Gavegnano Jessica H Brehm Franck P Dupuy Aarthi Talla Susan Pereira Ribeiro Deanna A Kulpa Cheryl Cameron Stephanie Santos Selwyn J Hurwitz Vincent C Marconi Jean-Pierre Routy Laurent Sabbagh Raymond F Schinazi Rafick Pierre Sékaly |
| author_sort | Christina Gavegnano |
| collection | DOAJ |
| description | Despite advances in the treatment of HIV infection with ART, elucidating strategies to overcome HIV persistence, including blockade of viral reservoir establishment, maintenance, and expansion, remains a challenge. T cell homeostasis is a major driver of HIV persistence. Cytokines involved in regulating homeostasis of memory T cells, the major hub of the HIV reservoir, trigger the Jak-STAT pathway. We evaluated the ability of tofacitinib and ruxolitinib, two FDA-approved Jak inhibitors, to block seeding and maintenance of the HIV reservoir in vitro. We provide direct demonstration for involvement of the Jak-STAT pathway in HIV persistence in vivo, ex vivo, and in vitro; pSTAT5 strongly correlates with increased levels of integrated viral DNA in vivo, and in vitro Jak inhibitors reduce the frequency of CD4+ T cells harboring integrated HIV DNA. We show that Jak inhibitors block viral production from infected cells, inhibit γ-C receptor cytokine (IL-15)-induced viral reactivation from latent stores thereby preventing transmission of infectious particles to bystander activated T cells. These results show that dysregulation of the Jak-STAT pathway is associated with viral persistence in vivo, and that Jak inhibitors target key events downstream of γ-C cytokine (IL-2, IL-7 and IL-15) ligation to their receptors, impacting the magnitude of the HIV reservoir in all memory CD4 T cell subsets in vitro and ex vivo. Jak inhibitors represent a therapeutic modality to prevent key events of T cell activation that regulate HIV persistence and together, specific, potent blockade of these events may be integrated to future curative strategies. |
| first_indexed | 2024-12-13T14:30:34Z |
| format | Article |
| id | doaj.art-4317a5f5021746d493577bcfb4b68481 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-13T14:30:34Z |
| publishDate | 2017-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-4317a5f5021746d493577bcfb4b684812022-12-21T23:41:50ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742017-12-011312e100674010.1371/journal.ppat.1006740Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors.Christina GavegnanoJessica H BrehmFranck P DupuyAarthi TallaSusan Pereira RibeiroDeanna A KulpaCheryl CameronStephanie SantosSelwyn J HurwitzVincent C MarconiJean-Pierre RoutyLaurent SabbaghRaymond F SchinaziRafick Pierre SékalyDespite advances in the treatment of HIV infection with ART, elucidating strategies to overcome HIV persistence, including blockade of viral reservoir establishment, maintenance, and expansion, remains a challenge. T cell homeostasis is a major driver of HIV persistence. Cytokines involved in regulating homeostasis of memory T cells, the major hub of the HIV reservoir, trigger the Jak-STAT pathway. We evaluated the ability of tofacitinib and ruxolitinib, two FDA-approved Jak inhibitors, to block seeding and maintenance of the HIV reservoir in vitro. We provide direct demonstration for involvement of the Jak-STAT pathway in HIV persistence in vivo, ex vivo, and in vitro; pSTAT5 strongly correlates with increased levels of integrated viral DNA in vivo, and in vitro Jak inhibitors reduce the frequency of CD4+ T cells harboring integrated HIV DNA. We show that Jak inhibitors block viral production from infected cells, inhibit γ-C receptor cytokine (IL-15)-induced viral reactivation from latent stores thereby preventing transmission of infectious particles to bystander activated T cells. These results show that dysregulation of the Jak-STAT pathway is associated with viral persistence in vivo, and that Jak inhibitors target key events downstream of γ-C cytokine (IL-2, IL-7 and IL-15) ligation to their receptors, impacting the magnitude of the HIV reservoir in all memory CD4 T cell subsets in vitro and ex vivo. Jak inhibitors represent a therapeutic modality to prevent key events of T cell activation that regulate HIV persistence and together, specific, potent blockade of these events may be integrated to future curative strategies.http://europepmc.org/articles/PMC5739511?pdf=render |
| spellingShingle | Christina Gavegnano Jessica H Brehm Franck P Dupuy Aarthi Talla Susan Pereira Ribeiro Deanna A Kulpa Cheryl Cameron Stephanie Santos Selwyn J Hurwitz Vincent C Marconi Jean-Pierre Routy Laurent Sabbagh Raymond F Schinazi Rafick Pierre Sékaly Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors. PLoS Pathogens |
| title | Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors. |
| title_full | Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors. |
| title_fullStr | Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors. |
| title_full_unstemmed | Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors. |
| title_short | Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors. |
| title_sort | novel mechanisms to inhibit hiv reservoir seeding using jak inhibitors |
| url | http://europepmc.org/articles/PMC5739511?pdf=render |
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