Diminished HIV Infection of Target CD4+ T Cells in a Toll-Like Receptor 4 Stimulated in vitro Model
Genital inflammation is associated with increased HIV acquisition risk. Induction of an inflammatory response can occur through the recognition of pathogenic or commensal microbes by Toll-like receptors (TLRs) on various immune cells. We used a in vitro peripheral blood mononuclear cell (PBMC) syste...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.01705/full |
| _version_ | 1818162517722005504 |
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| author | Ross Cromarty Alex Sigal Alex Sigal Lenine J. P. Liebenberg Lenine J. P. Liebenberg Lyle R. McKinnon Lyle R. McKinnon Salim S. Abdool Karim Salim S. Abdool Karim Jo-Ann S. Passmore Jo-Ann S. Passmore Jo-Ann S. Passmore Derseree Archary Derseree Archary |
| author_facet | Ross Cromarty Alex Sigal Alex Sigal Lenine J. P. Liebenberg Lenine J. P. Liebenberg Lyle R. McKinnon Lyle R. McKinnon Salim S. Abdool Karim Salim S. Abdool Karim Jo-Ann S. Passmore Jo-Ann S. Passmore Jo-Ann S. Passmore Derseree Archary Derseree Archary |
| author_sort | Ross Cromarty |
| collection | DOAJ |
| description | Genital inflammation is associated with increased HIV acquisition risk. Induction of an inflammatory response can occur through the recognition of pathogenic or commensal microbes by Toll-like receptors (TLRs) on various immune cells. We used a in vitro peripheral blood mononuclear cell (PBMC) system to understand the contribution of TLR stimulation in inducing inflammation and the activation of target T cells, and its effect on HIV susceptibility. PBMCs were stimulated with TLR agonists LPS (TLR4), R848 (TLR7/8), and Pam3CSK4 (TLR1/2), and then infected with HIV NL4-3 AD8. Multiplexed ELISA was used to measure 28 cytokines in cell culture supernatants. Flow cytometry was used to measure the activation state (CD38 and HLA-DR), and CCR5 expression on CD4+ and CD8+ T cells. Although TLR agonists induced higher cytokine and chemokine secretion, they did not significantly activate CD4+ and CD8+ T cells and showed decreased CCR5 expression relative to the unstimulated control. Despite several classes of inflammatory cytokines and chemokines being upregulated by TLR agonists, CD4+ T cells were significantly less infectable by HIV after TLR4-stimulation than the unstimulated control. These data demonstrate that the inflammatory effects that occur in the presence TLR agonist stimulations do not necessarily translate to the activation of T cells. Most importantly, the finding that TLR4-stimulation reduces rather than increases susceptibility of CD4+ T cells to HIV infection in this in vitro system strongly suggests that the increased chemokine and possible antiviral factor expression induced by these TLR agonists play a powerful although complex role in determining HIV infection risk. |
| first_indexed | 2024-12-11T16:34:56Z |
| format | Article |
| id | doaj.art-3d41fafdaefc40d495ee9ae2173c4677 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-11T16:34:56Z |
| publishDate | 2019-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-3d41fafdaefc40d495ee9ae2173c46772022-12-22T00:58:29ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-07-011010.3389/fimmu.2019.01705470436Diminished HIV Infection of Target CD4+ T Cells in a Toll-Like Receptor 4 Stimulated in vitro ModelRoss Cromarty0Alex Sigal1Alex Sigal2Lenine J. P. Liebenberg3Lenine J. P. Liebenberg4Lyle R. McKinnon5Lyle R. McKinnon6Salim S. Abdool Karim7Salim S. Abdool Karim8Jo-Ann S. Passmore9Jo-Ann S. Passmore10Jo-Ann S. Passmore11Derseree Archary12Derseree Archary13Centre for the AIDS Programme of Research in South Africa, Nelson Mandela School of Medicine, University of KwaZulu-Natal, Durban, South AfricaAfrica Health Research Institute, University of KwaZulu-Natal, Durban, South AfricaMax Planck Institute for Infection Biology, Berlin, GermanyCentre for the AIDS Programme of Research in South Africa, Nelson Mandela School of Medicine, University of KwaZulu-Natal, Durban, South AfricaDepartment of Medical Microbiology, University of KwaZulu-Natal, Durban, South AfricaCentre for the AIDS Programme of Research in South Africa, Nelson Mandela School of Medicine, University of KwaZulu-Natal, Durban, South AfricaDepartment of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, CanadaCentre for the AIDS Programme of Research in South Africa, Nelson Mandela School of Medicine, University of KwaZulu-Natal, Durban, South AfricaDepartment of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, United StatesCentre for the AIDS Programme of Research in South Africa, Nelson Mandela School of Medicine, University of KwaZulu-Natal, Durban, South AfricaMedical School, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South AfricaNational Health Laboratory Service, Cape Town, South AfricaCentre for the AIDS Programme of Research in South Africa, Nelson Mandela School of Medicine, University of KwaZulu-Natal, Durban, South AfricaDepartment of Medical Microbiology, University of KwaZulu-Natal, Durban, South AfricaGenital inflammation is associated with increased HIV acquisition risk. Induction of an inflammatory response can occur through the recognition of pathogenic or commensal microbes by Toll-like receptors (TLRs) on various immune cells. We used a in vitro peripheral blood mononuclear cell (PBMC) system to understand the contribution of TLR stimulation in inducing inflammation and the activation of target T cells, and its effect on HIV susceptibility. PBMCs were stimulated with TLR agonists LPS (TLR4), R848 (TLR7/8), and Pam3CSK4 (TLR1/2), and then infected with HIV NL4-3 AD8. Multiplexed ELISA was used to measure 28 cytokines in cell culture supernatants. Flow cytometry was used to measure the activation state (CD38 and HLA-DR), and CCR5 expression on CD4+ and CD8+ T cells. Although TLR agonists induced higher cytokine and chemokine secretion, they did not significantly activate CD4+ and CD8+ T cells and showed decreased CCR5 expression relative to the unstimulated control. Despite several classes of inflammatory cytokines and chemokines being upregulated by TLR agonists, CD4+ T cells were significantly less infectable by HIV after TLR4-stimulation than the unstimulated control. These data demonstrate that the inflammatory effects that occur in the presence TLR agonist stimulations do not necessarily translate to the activation of T cells. Most importantly, the finding that TLR4-stimulation reduces rather than increases susceptibility of CD4+ T cells to HIV infection in this in vitro system strongly suggests that the increased chemokine and possible antiviral factor expression induced by these TLR agonists play a powerful although complex role in determining HIV infection risk.https://www.frontiersin.org/article/10.3389/fimmu.2019.01705/fullToll-like receptorsinflammationimmune activationHIVcytokinesinnate antiviral immunity |
| spellingShingle | Ross Cromarty Alex Sigal Alex Sigal Lenine J. P. Liebenberg Lenine J. P. Liebenberg Lyle R. McKinnon Lyle R. McKinnon Salim S. Abdool Karim Salim S. Abdool Karim Jo-Ann S. Passmore Jo-Ann S. Passmore Jo-Ann S. Passmore Derseree Archary Derseree Archary Diminished HIV Infection of Target CD4+ T Cells in a Toll-Like Receptor 4 Stimulated in vitro Model Frontiers in Immunology Toll-like receptors inflammation immune activation HIV cytokines innate antiviral immunity |
| title | Diminished HIV Infection of Target CD4+ T Cells in a Toll-Like Receptor 4 Stimulated in vitro Model |
| title_full | Diminished HIV Infection of Target CD4+ T Cells in a Toll-Like Receptor 4 Stimulated in vitro Model |
| title_fullStr | Diminished HIV Infection of Target CD4+ T Cells in a Toll-Like Receptor 4 Stimulated in vitro Model |
| title_full_unstemmed | Diminished HIV Infection of Target CD4+ T Cells in a Toll-Like Receptor 4 Stimulated in vitro Model |
| title_short | Diminished HIV Infection of Target CD4+ T Cells in a Toll-Like Receptor 4 Stimulated in vitro Model |
| title_sort | diminished hiv infection of target cd4 t cells in a toll like receptor 4 stimulated in vitro model |
| topic | Toll-like receptors inflammation immune activation HIV cytokines innate antiviral immunity |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.01705/full |
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