Redirection of Cord Blood T Cells and Natural Killer Cells for Elimination of Autologous HIV-1-Infected Target Cells Using Bispecific DART® Molecules
Mother-to-child transmission of HIV-1 remains a major global health challenge. Currently, HIV-1-infected infants require strict lifelong adherence to antiretroviral therapy to prevent replication of virus from reservoirs of infected cells, and to halt progression of disease. There is a critical need...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.00713/full |
| _version_ | 1818985626055213056 |
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| author | Justin Pollara Justin Pollara R. Whitney Edwards Shalini Jha Shalini Jha Chia-Ying Kao Lam Liqin Liu Gundo Diedrich Jeffrey L. Nordstrom Tori Huffman Joy A. Pickeral Thomas N. Denny Sallie R. Permar Sallie R. Permar Guido Ferrari Guido Ferrari |
| author_facet | Justin Pollara Justin Pollara R. Whitney Edwards Shalini Jha Shalini Jha Chia-Ying Kao Lam Liqin Liu Gundo Diedrich Jeffrey L. Nordstrom Tori Huffman Joy A. Pickeral Thomas N. Denny Sallie R. Permar Sallie R. Permar Guido Ferrari Guido Ferrari |
| author_sort | Justin Pollara |
| collection | DOAJ |
| description | Mother-to-child transmission of HIV-1 remains a major global health challenge. Currently, HIV-1-infected infants require strict lifelong adherence to antiretroviral therapy to prevent replication of virus from reservoirs of infected cells, and to halt progression of disease. There is a critical need for immune interventions that can be deployed shortly after infection to eliminate HIV-1-infected cells in order to promote long-term remission of viremia, or to potentially cure pediatric HIV-1-infection. Bispecific HIV × CD3 DART® molecules able to co-engage the HIV-1 envelope protein on the surface of infected cells and CD3 on cytolytic T cells have been previously shown to eliminate HIV-1 infected cells in vitro and are candidates for passive immunotherapy to reduce the virus reservoir. However, their potential utility as therapy for infant HIV-1 infection is unclear as the ability of these novel antibody-based molecules to work in concert with cells of the infant immune system had not been assessed. Here, we use human umbilical cord blood as a model of the naïve neonatal immune system to evaluate the ability of HIV x CD3 DART molecules to recruit and redirect neonatal effector cells for elimination of autologous CD4+ T cells infected with HIV-1 encoding an envelope gene sequenced from a mother-to-child transmission event. We found that HIV × CD3 DART molecules can redirect T cells present in cord blood for elimination of HIV-infected CD4+ T cells. However, we observed reduced killing by T cells isolated from cord blood when compared to cells isolated from adult peripheral blood—likely due to the absence of the memory and effector CD8+ T cells that are most cytolytic when redirected by bispecific DART molecules. We also found that newly developed HIV × CD16 DART molecules were able to recruit CD16-expressing natural killer cells from cord blood to eliminate HIV-infected cells, and the activity of cord blood natural killer cells could be substantially increased by priming with IL-15. Our results support continued development of HIV-specific DART molecules using relevant preclinical animal models to optimize strategies for effective use of this immune therapy to reduce HIV-1 infection in pediatric populations. |
| first_indexed | 2024-12-20T18:37:53Z |
| format | Article |
| id | doaj.art-78fe6819d25a47b1a6f5da4ada1f0803 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-20T18:37:53Z |
| publishDate | 2020-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-78fe6819d25a47b1a6f5da4ada1f08032022-12-21T19:29:54ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-04-011110.3389/fimmu.2020.00713525312Redirection of Cord Blood T Cells and Natural Killer Cells for Elimination of Autologous HIV-1-Infected Target Cells Using Bispecific DART® MoleculesJustin Pollara0Justin Pollara1R. Whitney Edwards2Shalini Jha3Shalini Jha4Chia-Ying Kao Lam5Liqin Liu6Gundo Diedrich7Jeffrey L. Nordstrom8Tori Huffman9Joy A. Pickeral10Thomas N. Denny11Sallie R. Permar12Sallie R. Permar13Guido Ferrari14Guido Ferrari15Department of Surgery, Duke University School of Medicine, Durham, NC, United StatesHuman Vaccine Institute, Duke University School of Medicine, Durham, NC, United StatesHuman Vaccine Institute, Duke University School of Medicine, Durham, NC, United StatesDepartment of Surgery, Duke University School of Medicine, Durham, NC, United StatesHuman Vaccine Institute, Duke University School of Medicine, Durham, NC, United StatesMacrogenics, Inc., Rockville, MD, United StatesMacrogenics, Inc., Rockville, MD, United StatesMacrogenics, Inc., Rockville, MD, United StatesMacrogenics, Inc., Rockville, MD, United StatesDepartment of Surgery, Duke University School of Medicine, Durham, NC, United StatesDepartment of Surgery, Duke University School of Medicine, Durham, NC, United StatesHuman Vaccine Institute, Duke University School of Medicine, Durham, NC, United StatesHuman Vaccine Institute, Duke University School of Medicine, Durham, NC, United StatesDepartment of Pediatrics, Duke University School of Medicine, Durham, NC, United StatesDepartment of Surgery, Duke University School of Medicine, Durham, NC, United StatesHuman Vaccine Institute, Duke University School of Medicine, Durham, NC, United StatesMother-to-child transmission of HIV-1 remains a major global health challenge. Currently, HIV-1-infected infants require strict lifelong adherence to antiretroviral therapy to prevent replication of virus from reservoirs of infected cells, and to halt progression of disease. There is a critical need for immune interventions that can be deployed shortly after infection to eliminate HIV-1-infected cells in order to promote long-term remission of viremia, or to potentially cure pediatric HIV-1-infection. Bispecific HIV × CD3 DART® molecules able to co-engage the HIV-1 envelope protein on the surface of infected cells and CD3 on cytolytic T cells have been previously shown to eliminate HIV-1 infected cells in vitro and are candidates for passive immunotherapy to reduce the virus reservoir. However, their potential utility as therapy for infant HIV-1 infection is unclear as the ability of these novel antibody-based molecules to work in concert with cells of the infant immune system had not been assessed. Here, we use human umbilical cord blood as a model of the naïve neonatal immune system to evaluate the ability of HIV x CD3 DART molecules to recruit and redirect neonatal effector cells for elimination of autologous CD4+ T cells infected with HIV-1 encoding an envelope gene sequenced from a mother-to-child transmission event. We found that HIV × CD3 DART molecules can redirect T cells present in cord blood for elimination of HIV-infected CD4+ T cells. However, we observed reduced killing by T cells isolated from cord blood when compared to cells isolated from adult peripheral blood—likely due to the absence of the memory and effector CD8+ T cells that are most cytolytic when redirected by bispecific DART molecules. We also found that newly developed HIV × CD16 DART molecules were able to recruit CD16-expressing natural killer cells from cord blood to eliminate HIV-infected cells, and the activity of cord blood natural killer cells could be substantially increased by priming with IL-15. Our results support continued development of HIV-specific DART molecules using relevant preclinical animal models to optimize strategies for effective use of this immune therapy to reduce HIV-1 infection in pediatric populations.https://www.frontiersin.org/article/10.3389/fimmu.2020.00713/fullpediatric HIV-1umbilical cord bloodcytotoxic T cellsnatural killer cellsredirected cytotoxicitybispecific DART molecules |
| spellingShingle | Justin Pollara Justin Pollara R. Whitney Edwards Shalini Jha Shalini Jha Chia-Ying Kao Lam Liqin Liu Gundo Diedrich Jeffrey L. Nordstrom Tori Huffman Joy A. Pickeral Thomas N. Denny Sallie R. Permar Sallie R. Permar Guido Ferrari Guido Ferrari Redirection of Cord Blood T Cells and Natural Killer Cells for Elimination of Autologous HIV-1-Infected Target Cells Using Bispecific DART® Molecules Frontiers in Immunology pediatric HIV-1 umbilical cord blood cytotoxic T cells natural killer cells redirected cytotoxicity bispecific DART molecules |
| title | Redirection of Cord Blood T Cells and Natural Killer Cells for Elimination of Autologous HIV-1-Infected Target Cells Using Bispecific DART® Molecules |
| title_full | Redirection of Cord Blood T Cells and Natural Killer Cells for Elimination of Autologous HIV-1-Infected Target Cells Using Bispecific DART® Molecules |
| title_fullStr | Redirection of Cord Blood T Cells and Natural Killer Cells for Elimination of Autologous HIV-1-Infected Target Cells Using Bispecific DART® Molecules |
| title_full_unstemmed | Redirection of Cord Blood T Cells and Natural Killer Cells for Elimination of Autologous HIV-1-Infected Target Cells Using Bispecific DART® Molecules |
| title_short | Redirection of Cord Blood T Cells and Natural Killer Cells for Elimination of Autologous HIV-1-Infected Target Cells Using Bispecific DART® Molecules |
| title_sort | redirection of cord blood t cells and natural killer cells for elimination of autologous hiv 1 infected target cells using bispecific dart r molecules |
| topic | pediatric HIV-1 umbilical cord blood cytotoxic T cells natural killer cells redirected cytotoxicity bispecific DART molecules |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.00713/full |
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