40 results on '"Rezek, Valerie"'
Search Results
2. Autophagy inducer rapamycin treatment reduces IFN-I–mediated Inflammation and improves anti–HIV-1 T cell response in vivo
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Mu, Wenli, Rezek, Valerie, Martin, Heather, Carrillo, Mayra A, Tomer, Shallu, Hamid, Philip, Lizarraga, Miguel A, Tibbe, Tristan D, Yang, Otto O, Jamieson, Beth D, Kitchen, Scott G, and Zhen, Anjie
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Infectious Diseases ,HIV/AIDS ,2.1 Biological and endogenous factors ,Aetiology ,Infection ,Inflammatory and immune system ,Good Health and Well Being ,Mice ,Animals ,HIV Infections ,Sirolimus ,HIV-1 ,Interferon Type I ,Autophagy ,AIDS/HIV ,Cellular immune response ,Inflammation ,Innate immunity ,Biomedical and clinical sciences ,Health sciences - Abstract
A hallmark of HIV-1 infection is chronic inflammation, even in patients treated with antiretroviral therapy (ART). Chronic inflammation drives HIV-1 pathogenesis, leading to loss of CD4+ T cells and exhaustion of antiviral immunity. Therefore, strategies to safely reduce systematic inflammation are needed to halt disease progression and restore defective immune responses. Autophagy is a cellular mechanism for disposal of damaged organelles and elimination of intracellular pathogens. Autophagy is pivotal for energy homeostasis and plays critical roles in regulating immunity. However, how it regulates inflammation and antiviral T cell responses during HIV infection is unclear. Here, we demonstrate that autophagy is directly linked to IFN-I signaling, which is a key driver of immune activation and T cell exhaustion during chronic HIV infection. Impairment of autophagy leads to spontaneous IFN-I signaling, and autophagy induction reduces IFN-I signaling in monocytic cells. Importantly, in HIV-1-infected humanized mice, autophagy inducer rapamycin treatment significantly reduced persistent IFN-I-mediated inflammation and improved antiviral T cell responses. Cotreatment of rapamycin with ART led to significantly reduced viral rebound after ART withdrawal. Taken together, our data suggest that therapeutically targeting autophagy is a promising approach to treat persistent inflammation and improve immune control of HIV replication.
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- 2022
3. Purine nucleoside phosphorylase enables dual metabolic checkpoints that prevent T cell immunodeficiency and TLR7-dependent autoimmunity
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Abt, Evan R, Rashid, Khalid, Le, Thuc M, Li, Suwen, Lee, Hailey R, Lok, Vincent, Li, Luyi, Creech, Amanda L, Labora, Amanda N, Mandl, Hanna K, Lam, Alex K, Cho, Arthur, Rezek, Valerie, Wu, Nanping, Abril-Rodriguez, Gabriel, Rosser, Ethan W, Mittelman, Steven D, Hugo, Willy, Mehrling, Thomas, Bantia, Shanta, Ribas, Antoni, Donahue, Timothy R, Crooks, Gay M, Wu, Ting-Ting, and Radu, Caius G
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Immunology ,Autoimmune Disease ,1.1 Normal biological development and functioning ,Underpinning research ,Inflammatory and immune system ,Animals ,Autoimmunity ,Humans ,Immunologic Deficiency Syndromes ,Mice ,Purine Nucleosides ,Purine-Nucleoside Phosphorylase ,T-Lymphocytes ,Toll-Like Receptor 7 ,Autoimmune diseases ,Immunotherapy ,Metabolism ,T cell development ,Medical and Health Sciences ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Purine nucleoside phosphorylase (PNP) enables the breakdown and recycling of guanine nucleosides. PNP insufficiency in humans is paradoxically associated with both immunodeficiency and autoimmunity, but the mechanistic basis for these outcomes is incompletely understood. Here, we identify two immune lineage-dependent consequences of PNP inactivation dictated by distinct gene interactions. During T cell development, PNP inactivation is synthetically lethal with downregulation of the dNTP triphosphohydrolase SAMHD1. This interaction requires deoxycytidine kinase activity and is antagonized by microenvironmental deoxycytidine. In B lymphocytes and macrophages, PNP regulates Toll-like receptor 7 signaling by controlling the levels of its (deoxy)guanosine nucleoside ligands. Overriding this regulatory mechanism promotes germinal center formation in the absence of exogenous antigen and accelerates disease in a mouse model of autoimmunity. This work reveals that one purine metabolism gene protects against immunodeficiency and autoimmunity via independent mechanisms operating in distinct immune lineages and identifies PNP as a potentially novel metabolic immune checkpoint.
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- 2022
4. Stem cell-derived CAR T cells show greater persistence, trafficking, and viral control compared to ex vivo transduced CAR T cells
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Carrillo, Mayra A., Zhen, Anjie, Mu, Wenli, Rezek, Valerie, Martin, Heather, Peterson, Christopher W., Kiem, Hans-Peter, and Kitchen, Scott G.
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- 2024
- Full Text
- View/download PDF
5. ApoA-I mimetics reduce systemic and gut inflammation in chronic treated HIV
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Daskou, Maria, Mu, William, Sharma, Madhav, Vasilopoulos, Hariclea, Heymans, Rachel, Ritou, Eleni, Rezek, Valerie, Hamid, Philip, Kossyvakis, Athanasios, Roy, Shubhendu Sen, Grijalva, Victor, Chattopadhyay, Arnab, Kitchen, Scott G, Fogelman, Alan M, Reddy, Srinivasa T, and Kelesidis, Theodoros
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Digestive Diseases ,HIV/AIDS ,Biotechnology ,Autoimmune Disease ,Infectious Diseases ,Sexually Transmitted Infections ,5.1 Pharmaceuticals ,2.1 Biological and endogenous factors ,Infection ,ADAM17 Protein ,Animals ,Anti-HIV Agents ,Apolipoprotein A-I ,HIV Infections ,Humans ,Inflammation ,Intestines ,Mice ,Peptides ,Microbiology ,Virology ,Medical microbiology - Abstract
Novel therapeutic strategies are needed to attenuate increased systemic and gut inflammation that contribute to morbidity and mortality in chronic HIV infection despite potent antiretroviral therapy (ART). The goal of this study is to use preclinical models of chronic treated HIV to determine whether the antioxidant and anti-inflammatory apoA-I mimetic peptides 6F and 4F attenuate systemic and gut inflammation in chronic HIV. We used two humanized murine models of HIV infection and gut explants from 10 uninfected and 10 HIV infected persons on potent ART, to determine the in vivo and ex vivo impact of apoA-I mimetics on systemic and intestinal inflammation in HIV. When compared to HIV infected humanized mice treated with ART alone, mice on oral apoA-I mimetic peptide 6F with ART had consistently reduced plasma and gut tissue cytokines (TNF-α, IL-6) and chemokines (CX3CL1) that are products of ADAM17 sheddase activity. Oral 6F attenuated gut protein levels of ADAM17 that were increased in HIV-1 infected mice on potent ART compared to uninfected mice. Adding oxidized lipoproteins and endotoxin (LPS) ex vivo to gut explants from HIV infected persons increased levels of ADAM17 in myeloid and intestinal cells, which increased TNF-α and CX3CL1. Both 4F and 6F attenuated these changes. Our preclinical data suggest that apoA-I mimetic peptides provide a novel therapeutic strategy that can target increased protein levels of ADAM17 and its sheddase activity that contribute to intestinal and systemic inflammation in treated HIV. The large repertoire of inflammatory mediators involved in ADAM17 sheddase activity places it as a pivotal orchestrator of several inflammatory pathways associated with morbidity in chronic treated HIV that make it an attractive therapeutic target.
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- 2022
6. Cannabidiol modulates expression of type I IFN response genes and HIV infection in macrophages
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Tomer, Shallu, Mu, Wenli, Suryawanshi, Gajendra, Ng, Hwee, Wang, Li, Wennerberg, Wally, Rezek, Valerie, Martin, Heather, Chen, Irvin, Kitchen, Scott, and Zhen, Anjie
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Pharmacology and Pharmaceutical Sciences ,Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,HIV/AIDS ,Infectious Diseases ,Genetics ,Therapeutic Cannabinoid Research ,Clinical Research ,Substance Misuse ,Cannabinoid Research ,Sexually Transmitted Infections ,Cannabidiol Research ,2.1 Biological and endogenous factors ,Aetiology ,Infection ,Inflammatory and immune system ,Good Health and Well Being ,Anti-Inflammatory Agents ,Cannabidiol ,HIV Infections ,Humans ,Interferon Type I ,Macrophages ,Nucleotidyltransferases ,RNA ,Sequestosome-1 Protein ,HIV ,human immunodeficiency virus ,CBD ,cannabidiol ,ISG ,type I interferons ,macrophage ,CBD - cannabidiol ,HIV - human immunodeficiency virus ,Biochemistry and cell biology - Abstract
Cannabis (Cannabis sativa) is a widely used drug in the United States and the frequency of cannabis use is particularly high among people living with HIV (PLWH). One key component of cannabis, the non-psychotropic (-)-cannabidiol (CBD) exerts a wide variety of biological actions, including anticonvulsive, analgesic, and anti-inflammatory effects. However, the exact mechanism of action through which CBD affects the immune cell signaling remains poorly understood. Here we report that CBD modulates type I interferon responses in human macrophages. Transcriptomics analysis shows that CBD treatment significantly attenuates cGAS-STING-mediated activation of type I Interferon response genes (ISGs) in monocytic THP-1 cells. We further showed that CBD treatment effectively attenuates 2'3-cGAMP stimulation of ISGs in both THP-1 cells and primary human macrophages. Interestingly, CBD significantly upregulates expression of autophagy receptor p62/SQSTM1. p62 is critical for autophagy-mediated degradation of stimulated STING. We observed that CBD treated THP-1 cells have elevated autophagy activity. Upon 2'3'-cGAMP stimulation, CBD treated cells have rapid downregulation of phosphorylated-STING, leading to attenuated expression of ISGs. The CBD attenuation of ISGs is reduced in autophagy deficient THP-1 cells, suggesting that the effects of CBD on ISGs is partially mediated by autophagy induction. Lastly, CBD decreases ISGs expression upon HIV infection in THP-1 cells and human primary macrophages, leading to increased HIV RNA expression 24 hours after infection. However, long term culture with CBD in infected primary macrophages reduced HIV viral spread, suggesting potential dichotomous roles of CBD in HIV replication. Our study highlights the immune modulatory effects of CBD and the needs for additional studies on its effect on viral infection and inflammation.
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- 2022
7. Correction: Robust CAR-T memory formation and function via hematopoietic stem cell delivery.
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Zhen, Anjie, Carrillo, Mayra A, Mu, Wenli, Rezek, Valerie, Martin, Heather, Hamid, Philip, Chen, Irvin SY, Yang, Otto O, Zack, Jerome A, and Kitchen, Scott G
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Virology ,Microbiology ,Immunology ,Medical Microbiology - Abstract
[This corrects the article DOI: 10.1371/journal.ppat.1009404.].
- Published
- 2021
8. Robust CAR-T memory formation and function via hematopoietic stem cell delivery.
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Zhen, Anjie, Carrillo, Mayra A, Mu, Wenli, Rezek, Valerie, Martin, Heather, Hamid, Philip, Chen, Irvin SY, Yang, Otto O, Zack, Jerome A, and Kitchen, Scott G
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Hematopoietic Stem Cells ,Animals ,Humans ,Mice ,HIV-1 ,HIV Infections ,Receptors ,Antigen ,T-Cell ,Lymphocyte Activation ,Receptors ,Chimeric Antigen ,Genetics ,Immunization ,Transplantation ,HIV/AIDS ,Infectious Diseases ,Gene Therapy ,Stem Cell Research ,Biotechnology ,Regenerative Medicine ,Vaccine Related ,5.2 Cellular and gene therapies ,Infection ,Virology ,Microbiology ,Immunology ,Medical Microbiology - Abstract
Due to the durability and persistence of reservoirs of HIV-1-infected cells, combination antiretroviral therapy (ART) is insufficient in eradicating infection. Achieving HIV-1 cure or sustained remission without ART treatment will require the enhanced and persistent effective antiviral immune responses. Chimeric Antigen Receptor (CAR) T-cells have emerged as a powerful immunotherapy and show promise in treating HIV-1 infection. Persistence, trafficking, and maintenance of function remain to be a challenge in many of these approaches, which are based on peripheral T cell modification. To overcome many of these issues, we have previously demonstrated successful long-term engraftment and production of anti-HIV CAR T cells in modified hematopoietic stem cells (HSCs) in vivo. Here we report the development and in vivo testing of second generation CD4-based CARs (CD4CAR) against HIV-1 infection using a HSCs-based approach. We found that a modified, truncated CD4-based CAR (D1D2CAR) allows better CAR-T cell differentiation from gene modified HSCs, and maintains similar CTL activity as compared to the full length CD4-based CAR. In addition, D1D2CAR does not mediate HIV infection or stimulation mediated by IL-16, suggesting lower risk of off-target effects. Interestingly, stimulatory domains of 4-1BB but not CD28 allowed successful hematopoietic differentiation and improved anti-viral function of CAR T cells from CAR modified HSCs. Addition of 4-1BB to CD4 based CARs led to faster suppression of viremia during early untreated HIV-1 infection. D1D2CAR 4-1BB mice had faster viral suppression in combination with ART and better persistence of CAR T cells during ART. In summary, our data indicate that the D1D2CAR-41BB is a superior CAR, showing better HSC differentiation, viral suppression and persistence, and less deleterious functions compared to the original CD4CAR, and should continue to be pursued as a candidate for clinical study.
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- 2021
9. Apolipoprotein A-I mimetics attenuate macrophage activation in chronic treated HIV.
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Mu, William, Sharma, Madhav, Heymans, Rachel, Ritou, Eleni, Rezek, Valerie, Hamid, Philip, Kossyvakis, Athanasios, Sen Roy, Shubhendu, Grijalva, Victor, Chattopadhyay, Arnab, Papesh, Jeremy, Meriwether, David, Kitchen, Scott G, Fogelman, Alan M, Reddy, Srinivasa T, and Kelesidis, Theodoros
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Clinical Research ,Infectious Diseases ,HIV/AIDS ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Infection ,Animals ,Apolipoprotein A-I ,Biomarkers ,HIV Infections ,Lipopolysaccharide Receptors ,Macrophage Activation ,Mice ,apolipoprotein A-I mimetic peptides ,chronic treated HIV ,immune activation ,Biological Sciences ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Virology ,Biomedical and clinical sciences ,Health sciences - Abstract
ObjectivesDespite antiretroviral therapy (ART), there is an unmet need for therapies to mitigate immune activation in HIV infection. The goal of this study is to determine whether the apoA-I mimetics 6F and 4F attenuate macrophage activation in chronic HIV.DesignPreclinical assessment of the in-vivo impact of Tg6F and the ex-vivo impact of apoA-I mimetics on biomarkers of immune activation and gut barrier dysfunction in treated HIV.MethodsWe used two humanized murine models of HIV infection to determine the impact of oral Tg6F with ART (HIV+ART+Tg6F+) on innate immune activation (plasma human sCD14, sCD163) and gut barrier dysfunction [murine I-FABP, endotoxin (LPS), LPS-binding protein (LBP), murine sCD14]. We also used gut explants from 10 uninfected and 10 HIV-infected men on potent ART and no morbidity, to determine the impact of ex-vivo treatment with 4F for 72 h on secretion of sCD14, sCD163, and I-FABP from gut explants.ResultsWhen compared with mice treated with ART alone (HIV+ART+), HIV+ART+Tg6F+ mice attenuated macrophage activation (h-sCD14, h-sCD163), gut barrier dysfunction (m-IFABP, LPS, LBP, and m-sCD14), plasma and gut tissue oxidized lipoproteins. The results were consistent with independent mouse models and ART regimens. Both 4F and 6F attenuated shedding of I-FABP and sCD14 from gut explants from HIV-infected and uninfected participants.ConclusionGiven that gut barrier dysfunction and macrophage activation are contributors to comorbidities like cardiovascular disease in HIV, apoA-I mimetics should be tested as therapy for morbidity in chronic treated HIV.
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- 2021
10. Development of Hematopoietic Stem Cell-Engineered Invariant Natural Killer T Cell Therapy for Cancer
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Zhu, Yanni, Smith, Drake J, Zhou, Yang, Li, Yan-Ruide, Yu, Jiaji, Lee, Derek, Wang, Yu-Chen, Di Biase, Stefano, Wang, Xi, Hardoy, Christian, Ku, Josh, Tsao, Tasha, Lin, Levina J, Pham, Alexander T, Moon, Heesung, McLaughlin, Jami, Cheng, Donghui, Hollis, Roger P, Campo-Fernandez, Beatriz, Urbinati, Fabrizia, Wei, Liu, Pang, Larry, Rezek, Valerie, Berent-Maoz, Beata, Macabali, Mignonette H, Gjertson, David, Wang, Xiaoyan, Galic, Zoran, Kitchen, Scott G, An, Dong Sung, Hu-Lieskovan, Siwen, Kaplan-Lefko, Paula J, De Oliveira, Satiro N, Seet, Christopher S, Larson, Sarah M, Forman, Stephen J, Heath, James R, Zack, Jerome A, Crooks, Gay M, Radu, Caius G, Ribas, Antoni, Kohn, Donald B, Witte, Owen N, and Yang, Lili
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Immunology ,Medical Biotechnology ,Oncology and Carcinogenesis ,Stem Cell Research - Nonembryonic - Human ,Regenerative Medicine ,Genetics ,Biotechnology ,Cancer ,Stem Cell Research ,Stem Cell Research - Nonembryonic - Non-Human ,Hematology ,Gene Therapy ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,5.2 Cellular and gene therapies ,Animals ,Cells ,Cultured ,Genetic Engineering ,Hematopoietic Stem Cells ,Humans ,Immunotherapy ,Adoptive ,Mice ,Mice ,SCID ,Natural Killer T-Cells ,Neoplasms ,Receptors ,Antigen ,T-Cell ,Xenograft Model Antitumor Assays ,HSC ,HSC transfer ,HSCT ,T cell receptor ,TCR ,cancer immunotherapy ,cell therapy ,gene therapy ,hematopoietic stem cell ,iNKT ,invariant natural killer T cell ,preclinical development ,sr39TK suicide gene ,stem cell therapy ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
Invariant natural killer T (iNKT) cells are potent immune cells for targeting cancer; however, their clinical application has been hindered by their low numbers in cancer patients. Here, we developed a proof-of-concept for hematopoietic stem cell-engineered iNKT (HSC-iNKT) cell therapy with the potential to provide therapeutic levels of iNKT cells for a patient's lifetime. Using a human HSC engrafted mouse model and a human iNKT TCR gene engineering approach, we demonstrated the efficient and long-term generation of HSC-iNKT cells in vivo. These HSC-iNKT cells closely resembled endogenous human iNKT cells, could deploy multiple mechanisms to attack tumor cells, and effectively suppressed tumor growth in vivo in multiple human tumor xenograft mouse models. Preclinical safety studies showed no toxicity or tumorigenicity of the HSC-iNKT cell therapy. Collectively, these results demonstrated the feasibility, safety, and cancer therapy potential of the proposed HSC-iNKT cell therapy and laid a foundation for future clinical development.
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- 2019
11. Correction: Long-term persistence and function of hematopoietic stem cell-derived chimeric antigen receptor T cells in a nonhuman primate model of HIV/AIDS.
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Zhen, Anjie, Peterson, Christopher W, Carrillo, Mayra A, Reddy, Sowmya Somashekar, Youn, Cindy S, Lam, Brianna B, Chang, Nelson Y, Martin, Heather A, Rick, Jonathan W, Kim, Jennifer, Neel, Nick C, Rezek, Valerie K, Kamata, Masakazu, Chen, Irvin SY, Zack, Jerome A, Kiem, Hans-Peter, and Kitchen, Scott G
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Virology ,Microbiology ,Immunology ,Medical Microbiology - Abstract
[This corrects the article DOI: 10.1371/journal.ppat.1006753.].
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- 2018
12. Long-term persistence and function of hematopoietic stem cell-derived chimeric antigen receptor T cells in a nonhuman primate model of HIV/AIDS.
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Zhen, Anjie, Peterson, Christopher W, Carrillo, Mayra A, Reddy, Sowmya Somashekar, Youn, Cindy S, Lam, Brianna B, Chang, Nelson Y, Martin, Heather A, Rick, Jonathan W, Kim, Jennifer, Neel, Nick C, Rezek, Valerie K, Kamata, Masakazu, Chen, Irvin SY, Zack, Jerome A, Kiem, Hans-Peter, and Kitchen, Scott G
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CD4-Positive T-Lymphocytes ,Hematopoietic Stem Cells ,Animals ,Macaca nemestrina ,HIV Infections ,Simian Acquired Immunodeficiency Syndrome ,Disease Models ,Animal ,Receptors ,Antigen ,T-Cell ,Recombinant Fusion Proteins ,Immunotherapy ,Hematopoietic Stem Cell Transplantation ,Cell Differentiation ,Cell Lineage ,Male ,Genetic Therapy ,Immunization ,Vaccine Related ,Regenerative Medicine ,Genetics ,Stem Cell Research ,Stem Cell Research - Nonembryonic - Non-Human ,Gene Therapy ,Biotechnology ,Stem Cell Research - Nonembryonic - Human ,HIV/AIDS ,Cancer ,Infectious Diseases ,Transplantation ,5.2 Cellular and gene therapies ,Infection ,Virology ,Microbiology ,Immunology ,Medical Microbiology - Abstract
Chimeric Antigen Receptor (CAR) T-cells have emerged as a powerful immunotherapy for various forms of cancer and show promise in treating HIV-1 infection. However, significant limitations are persistence and whether peripheral T cell-based products can respond to malignant or infected cells that may reappear months or years after treatment remains unclear. Hematopoietic Stem/Progenitor Cells (HSPCs) are capable of long-term engraftment and have the potential to overcome these limitations. Here, we report the use of a protective CD4 chimeric antigen receptor (C46CD4CAR) to redirect HSPC-derived T-cells against simian/human immunodeficiency virus (SHIV) infection in pigtail macaques. CAR-containing cells persisted for more than 2 years without any measurable toxicity and were capable of multilineage engraftment. Combination antiretroviral therapy (cART) treatment followed by cART withdrawal resulted in lower viral rebound in CAR animals relative to controls, and demonstrated an immune memory-like response. We found CAR-expressing cells in multiple lymphoid tissues, decreased tissue-associated SHIV RNA levels, and substantially higher CD4/CD8 ratios in the gut as compared to controls. These results show that HSPC-derived CAR T-cells are capable of long-term engraftment and immune surveillance. This study demonstrates for the first time the safety and feasibility of HSPC-based CAR therapy in a large animal preclinical model.
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- 2017
13. Stem cell-derived CAR T cells show greater persistence, trafficking, and plasma viral control compared to ex vivo transduced CAR T cells in vivo
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Carrillo, Mayra A., primary, Zhen, Anjie, additional, Mu, Wenli, additional, Rezek, Valerie, additional, Martin, Heather, additional, Peterson, Christopher W., additional, Kiem, Hans-Peter, additional, and Kitchen, Scott G., additional
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- 2024
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14. Targeting type I interferon–mediated activation restores immune function in chronic HIV infection
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Zhen, Anjie, Rezek, Valerie, Youn, Cindy, Lam, Brianna, Chang, Nelson, Rick, Jonathan, Carrillo, Mayra, Martin, Heather, Kasparian, Saro, Syed, Philip, Rice, Nicholas, Brooks, David G, and Kitchen, Scott G
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Clinical Research ,Immunotherapy ,Infectious Diseases ,Sexually Transmitted Infections ,HIV/AIDS ,5.1 Pharmaceuticals ,2.1 Biological and endogenous factors ,Infection ,Good Health and Well Being ,Animals ,Anti-Retroviral Agents ,CD8-Positive T-Lymphocytes ,Chronic Disease ,Disease Models ,Animal ,HIV Infections ,HIV-1 ,Humans ,Interferon Type I ,Mice ,Mice ,Knockout ,Medical and Health Sciences ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Chronic immune activation, immunosuppression, and T cell exhaustion are hallmarks of HIV infection, yet the mechanisms driving these processes are unclear. Chronic activation can be a driving force in immune exhaustion, and type I interferons (IFN-I) are emerging as critical components underlying ongoing activation in HIV infection. Here, we have tested the effect of blocking IFN-I signaling on T cell responses and virus replication in a murine model of chronic HIV infection. Using HIV-infected humanized mice, we demonstrated that in vivo blockade of IFN-I signaling during chronic HIV infection diminished HIV-driven immune activation, decreased T cell exhaustion marker expression, restored HIV-specific CD8 T cell function, and led to decreased viral replication. Antiretroviral therapy (ART) in combination with IFN-I blockade accelerated viral suppression, further decreased viral loads, and reduced the persistently infected HIV reservoir compared with ART treatment alone. Our data suggest that blocking IFN-I signaling in conjunction with ART treatment can restore immune function and may reduce viral reservoirs during chronic HIV infection, providing validation for IFN-I blockade as a potential therapy for HIV infection.
- Published
- 2017
15. Propagating Humanized BLT Mice for the Study of Human Immunology and Immunotherapy
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Smith, Drake J, Lin, Levina J, Moon, Heesung, Pham, Alexander T, Wang, Xi, Liu, Siyuan, Ji, Sunjong, Rezek, Valerie, Shimizu, Saki, Ruiz, Marlene, Lam, Jennifer, Janzen, Deanna M, Memarzadeh, Sanaz, Kohn, Donald B, Zack, Jerome A, Kitchen, Scott G, An, Dong Sung, and Yang, Lili
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Biological Sciences ,Stem Cell Research ,Human Fetal Tissue ,Genetics ,Stem Cell Research - Nonembryonic - Human ,5.2 Cellular and gene therapies ,Development of treatments and therapeutic interventions ,2.1 Biological and endogenous factors ,Aetiology ,Inflammatory and immune system ,Allergy and Immunology ,Animals ,Bone Marrow ,Cell Lineage ,Humans ,Immunotherapy ,Inheritance Patterns ,Liver ,Mice ,Mice ,Inbred NOD ,Mice ,SCID ,T-Lymphocytes ,Thymus Gland ,humanized BLT mice ,human immunology ,human immunotherapy ,propagating ,CD34 ,HSC ,Technology ,Medical and Health Sciences ,Developmental Biology ,Immunology ,Biological sciences - Abstract
The humanized bone marrow-liver-thymus (BLT) mouse model harbors a nearly complete human immune system, therefore providing a powerful tool to study human immunology and immunotherapy. However, its application is greatly limited by the restricted supply of human CD34+ hematopoietic stem cells and fetal thymus tissues that are needed to generate these mice. The restriction is especially significant for the study of human immune systems with special genetic traits, such as certain human leukocyte antigen (HLA) haplotypes or monogene deficiencies. To circumvent this critical limitation, we have developed a method to quickly propagate established BLT mice. Through secondary transfer of bone marrow cells and human thymus implants from BLT mice into NSG (NOD/SCID/IL-2Rγ-/-) recipient mice, we were able to expand one primary BLT mouse into a colony of 4-5 proBLT (propagated BLT) mice in 6-8 weeks. These proBLT mice reconstituted human immune cells, including T cells, at levels comparable to those of their primary BLT donor mouse. They also faithfully inherited the human immune cell genetic traits from their donor BLT mouse, such as the HLA-A2 haplotype that is of special interest for studying HLA-A2-restricted human T cell immunotherapies. Moreover, an EGFP reporter gene engineered into the human immune system was stably passed from BLT to proBLT mice, making proBLT mice suitable for studying human immune cell gene therapy. This method provides an opportunity to overcome a critical hurdle to utilizing the BLT humanized mouse model and enables its more widespread use as a valuable preclinical research tool.
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- 2016
16. Mitoquinone mesylate attenuates brain inflammation in humanized mouse model of chronic HIV infection
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Satta, Sandro, Hugo, Cristelle, Sharma, Madhav, Rezek, Valerie, Kossyvakis, Athanassios, Roy, Shubhendu Sen, Kitchen, Scott, and Kelesidis, Theodoros
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- 2022
- Full Text
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17. Stem-cell Based Engineered Immunity Against HIV Infection in the Humanized Mouse Model.
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Zhen, Anjie, Rezek, Valerie, Youn, Cindy, Rick, Jonathan, Lam, Brianna, Chang, Nelson, Zack, Jerome, Kamata, Masakazu, and Kitchen, Scott
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Biochemistry and Cell Biology ,Biological Sciences ,Human Fetal Tissue ,Stem Cell Research - Nonembryonic - Human ,Transplantation ,Infectious Diseases ,Stem Cell Research ,Biotechnology ,HIV/AIDS ,Regenerative Medicine ,5.2 Cellular and gene therapies ,Development of treatments and therapeutic interventions ,2.1 Biological and endogenous factors ,Aetiology ,Infection ,Inflammatory and immune system ,Animals ,Disease Models ,Animal ,HIV Infections ,Hematopoietic Stem Cell Transplantation ,Hematopoietic Stem Cells ,Humans ,Mice ,Mice ,Inbred NOD ,Mice ,SCID ,Medicine ,Issue 113 ,Humanized BLT mouse ,chimeric antigen receptor ,HIV ,non-obese diabetic ,human leukocyte antigen ,hematopoietic stem cells ,Psychology ,Cognitive Sciences ,Biochemistry and cell biology - Abstract
With the rapid development of stem cell-based gene therapies against HIV, there is pressing requirement for an animal model to study the hematopoietic differentiation and immune function of the genetically modified cells. The humanized Bone-marrow/Liver/Thymus (BLT) mouse model allows for full reconstitution of a human immune system in the periphery, which includes T cells, B cells, NK cells and monocytes. The human thymic implant also allows for thymic selection of T cells in autologous thymic tissue. In addition to the study of HIV infection, the model stands as a powerful tool to study differentiation, development and functionality of cells derived from hematopoietic stem cells (HSCs). Here we outline the construction of humanized non-obese diabetic (NOD)-severe combined immunodeficient (SCID)-common gamma chain knockout (cγ(-/-))-Bone-marrow/Liver/Thymus (NSG-BLT) mice with HSCs transduced with CD4 chimeric antigen receptor (CD4CAR) lentivirus vector. We show that the CD4CAR HSCs can successfully differentiate into multiple lineages and have anti-HIV activity. The goal of the study is to demonstrate the use of NSG-BLT mouse model as an in vivo model for engineered immunity against HIV. It is worth noting that, because lentivirus and human tissue is used, experiments and surgeries should be performed in a Class II biosafety cabinet in a Biosafety Level 2 (BSL2) with special precautions (BSL2+) facility.
- Published
- 2016
18. Behavioral and histological assessment of a novel treatment of neuroHIV in humanized mice
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Levine, Andrew J., primary, Thadani, Chirag, additional, Soontornniyomkij, Virawudh, additional, Lopez-Aranda, Manuel F., additional, Mesa, Yoelvis Garcia, additional, Kitchen, Scott, additional, Rezek, Valerie, additional, Silva, Alcino, additional, and Kolson, Dennis L., additional
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- 2023
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19. Purine nucleoside phosphorylase enables dual metabolic checkpoints that prevent T cell immunodeficiency and TLR7-associated autoimmunity
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Abt, Evan R., Rashid, Khalid, Le, Thuc M., Li, Suwen, Lee, Hailey R., Lok, Vincent, Li, Luyi, Creech, Amanda L., Labora, Amanda N., Mandl, Hanna K., Lam, Alex K., Cho, Arthur, Rezek, Valerie, Wu, Nanping, Abril-Rodriguez, Gabriel, Rosser, Ethan W., Mittelman, Steven D., Hugo, Willy, Mehrling, Thomas, Bantia, Shanta, Ribas, Antoni, Donahue, Timothy R., Crooks, Gay M., Wu, Ting-Ting, and Radu, Caius G.
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Purine nucleotides -- Physiological aspects -- Health aspects ,Immunological deficiency syndromes -- Genetic aspects -- Prevention ,Phosphorylase -- Physiological aspects -- Health aspects ,TLR7 -- Health aspects -- Physiological aspects ,Autoimmune diseases -- Genetic aspects -- Prevention ,Health care industry - Abstract
Purine nucleoside phosphorylase (PNP) enables the breakdown and recycling of guanine nucleosides. PNP insufficiency in humans is paradoxically associated with both immunodeficiency and autoimmunity, but the mechanistic basis for these outcomes is incompletely understood. Here, we identify two immune lineage-dependent consequences of PNP inactivation dictated by distinct gene interactions. During T cell development, PNP inactivation is synthetically lethal with downregulation of the dNTP triphosphohydrolase SAMHD1. This interaction requires deoxycytidine kinase activity and is antagonized by microenvironmental deoxycytidine. In B lymphocytes and macrophages, PNP regulates Toll-like receptor 7 signaling by controlling the levels of its (deoxy)guanosine nucleoside ligands. Overriding this regulatory mechanism promotes germinal center formation in the absence of exogenous antigen and accelerates disease in a mouse model of autoimmunity. This work reveals that one purine metabolism gene protects against immunodeficiency and autoimmunity via independent mechanisms operating in distinct immune lineages and identifies PNP as a potentially novel metabolic immune checkpoint., Introduction Nucleotide metabolism controls immune cell development and function through diverse mechanisms (1). The purine nucleoside adenosine is sensed by A2a/b receptors, which mediate immunosuppressive effects in various immune cell [...]
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- 2022
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20. HIV-specific Immunity Derived From Chimeric Antigen Receptor-engineered Stem Cells.
- Author
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Zhen, Anjie, Kamata, Masakazu, Rezek, Valerie, Rick, Jonathan, Levin, Bernard, Kasparian, Saro, Chen, Irvin Sy, Yang, Otto O, Zack, Jerome A, and Kitchen, Scott G
- Abstract
The human immunodeficiency virus (HIV)-specific cytotoxic T lymphocyte (CTL) response is critical in controlling HIV infection. Since the immune response does not eliminate HIV, it would be beneficial to develop ways to enhance the HIV-specific CTL response to allow long-term viral suppression or clearance. Here, we report the use of a protective chimeric antigen receptor (CAR) in a hematopoietic stem/progenitor cell (HSPC)-based approach to engineer HIV immunity. We determined that CAR-modified HSPCs differentiate into functional T cells as well as natural killer (NK) cells in vivo in humanized mice and these cells are resistant to HIV infection and suppress HIV replication. These results strongly suggest that stem cell-based gene therapy with a CAR may be feasible and effective in treating chronic HIV infection and other morbidities.
- Published
- 2015
21. Engineering Cellular Resistance to HIV-1 Infection In Vivo Using a Dual Therapeutic Lentiviral Vector.
- Author
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Burke, Bryan P, Levin, Bernard R, Zhang, Jane, Sahakyan, Anna, Boyer, Joshua, Carroll, Maria V, Colón, Joanna Camba, Keech, Naomi, Rezek, Valerie, Bristol, Gregory, Eggers, Erica, Cortado, Ruth, Boyd, Maureen P, Impey, Helen, Shimizu, Saki, Lowe, Emily L, Ringpis, Gene-Errol E, Kim, Sohn G, Vatakis, Dimitrios N, Breton, Louis R, Bartlett, Jeffrey S, Chen, Irvin SY, Kitchen, Scott G, An, Dong Sung, and Symonds, Geoff P
- Subjects
siRNAs ,shRNAs ,miRNAs ,Therapeutic Proof-of-Concept ,Biochemistry and Cell Biology ,Clinical Sciences - Abstract
We described earlier a dual-combination anti-HIV type 1 (HIV-1) lentiviral vector (LVsh5/C46) that downregulates CCR5 expression of transduced cells via RNAi and inhibits HIV-1 fusion via cell surface expression of cell membrane-anchored C46 antiviral peptide. This combinatorial approach has two points of inhibition for R5-tropic HIV-1 and is also active against X4-tropic HIV-1. Here, we utilize the humanized bone marrow, liver, thymus (BLT) mouse model to characterize the in vivo efficacy of LVsh5/C46 (Cal-1) vector to engineer cellular resistance to HIV-1 pathogenesis. Human CD34+ hematopoietic stem/progenitor cells (HSPC) either nonmodified or transduced with LVsh5/C46 vector were transplanted to generate control and treatment groups, respectively. Control and experimental groups displayed similar engraftment and multilineage hematopoietic differentiation that included robust CD4+ T-cell development. Splenocytes isolated from the treatment group were resistant to both R5- and X4-tropic HIV-1 during ex vivo challenge experiments. Treatment group animals challenged with R5-tropic HIV-1 displayed significant protection of CD4+ T-cells and reduced viral load within peripheral blood and lymphoid tissues up to 14 weeks postinfection. Gene-marking and transgene expression were confirmed stable at 26 weeks post-transplantation. These data strongly support the use of LVsh5/C46 lentiviral vector in gene and cell therapeutic applications for inhibition of HIV-1 infection.
- Published
- 2015
22. In Vivo Suppression of HIV by Antigen Specific T Cells Derived from Engineered Hematopoietic Stem Cells
- Author
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Kitchen, Scott G, Levin, Bernard R, Bristol, Gregory, Rezek, Valerie, Kim, Sohn, Aguilera-Sandoval, Christian, Balamurugan, Arumugam, Yang, Otto O, and Zack, Jerome A
- Subjects
Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Stem Cell Research - Nonembryonic - Human ,Biotechnology ,Stem Cell Research ,Infectious Diseases ,Gene Therapy ,Human Fetal Tissue ,HIV/AIDS ,Regenerative Medicine ,Genetics ,5.2 Cellular and gene therapies ,Development of treatments and therapeutic interventions ,Inflammatory and immune system ,Infection ,Animals ,CD8-Positive T-Lymphocytes ,Cell Engineering ,Female ,Genetic Therapy ,HIV Core Protein p24 ,HIV Infections ,HIV-1 ,Hematopoietic Stem Cell Transplantation ,Hematopoietic Stem Cells ,Humans ,Male ,Mice ,Mice ,Transgenic ,Receptors ,Antigen ,T-Cell ,Transplantation ,Heterologous ,Virus Replication ,Microbiology ,Virology ,Medical microbiology - Abstract
The HIV-specific cytotoxic T lymphocyte (CTL) response is a critical component in controlling viral replication in vivo, but ultimately fails in its ability to eradicate the virus. Our intent in these studies is to develop ways to enhance and restore the HIV-specific CTL response to allow long-term viral suppression or viral clearance. In our approach, we sought to genetically manipulate human hematopoietic stem cells (HSCs) such that they differentiate into mature CTL that will kill HIV infected cells. To perform this, we molecularly cloned an HIV-specific T cell receptor (TCR) from CD8+ T cells that specifically targets an epitope of the HIV-1 Gag protein. This TCR was then used to genetically transduce HSCs. These HSCs were then introduced into a humanized mouse containing human fetal liver, fetal thymus, and hematopoietic progenitor cells, and were allowed to differentiate into mature human CD8+ CTL. We found human, HIV-specific CTL in multiple tissues in the mouse. Thus, genetic modification of human HSCs with a cloned TCR allows proper differentiation of the cells to occur in vivo, and these cells migrate to multiple anatomic sites, mimicking what is seen in humans. To determine if the presence of the transgenic, HIV-specific TCR has an effect on suppressing HIV replication, we infected with HIV-1 mice expressing the transgenic HIV-specific TCR and, separately, mice expressing a non-specific control TCR. We observed significant suppression of HIV replication in multiple organs in the mice expressing the HIV-specific TCR as compared to control, indicating that the presence of genetically modified HIV-specific CTL can form a functional antiviral response in vivo. These results strongly suggest that stem cell based gene therapy may be a feasible approach in the treatment of chronic viral infections and provide a foundation towards the development of this type of strategy.
- Published
- 2012
23. 3016 – MYCT1 CONTROLS HUMAN HEMATOPOIETIC STEM CELL FUNCTION BY MODERATING ENDOCYTOSIS AND ENVIRONMENTAL SENSING
- Author
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Aguadé-Gorgorió, Júlia, primary, Jami-alahmadi, Yasaman, additional, Kardouh, Maya, additional, Fares, Iman, additional, Calvanese, Vincenzo, additional, Johnson, Haley, additional, Rezek, Valerie, additional, Magnusson, Mattias, additional, Shin, Juliana, additional, Nance, Karina, additional, Goodridge, Helen, additional, Crooks, Gay, additional, Wohlschlegel, James, additional, and Mikkola, Hanna, additional
- Published
- 2023
- Full Text
- View/download PDF
24. Oral Combinational Antiretroviral Treatment in HIV-1 Infected Humanized Mice
- Author
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Mu, Wenli, primary, Zhen, Anjie, primary, Carrillo, Mayra A., primary, Rezek, Valerie, primary, Martin, Heather, primary, Lizarraga, Miguel, primary, and Kitchen, Scott, primary
- Published
- 2022
- Full Text
- View/download PDF
25. Cannabidiol modulates expression of type I IFN response genes and HIV infection in macrophages
- Author
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Tomer, Shallu, primary, Mu, Wenli, additional, Suryawanshi, Gajendra, additional, Ng, Hwee, additional, Wang, Li, additional, Wennerberg, Wally, additional, Rezek, Valerie, additional, Martin, Heather, additional, Chen, Irvin, additional, Kitchen, Scott, additional, and Zhen, Anjie, additional
- Published
- 2022
- Full Text
- View/download PDF
26. Induction of Autophagy reduces IFN-I mediated Inflammation and restores anti-HIV-1 T Cell response in vivo
- Author
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Zhen, Anjie, primary, Mu, Wenli, additional, Rezek, Valerie, additional, Martin, Heather, additional, Carrillo, Mayra, additional, Hamid, Philip, additional, Lizarraga, Miguel, additional, Yang, Otto, additional, Jamieson, Beth, additional, and Kitchen, Scott, additional
- Published
- 2022
- Full Text
- View/download PDF
27. Purine nucleoside phosphorylase enables dual metabolic checkpoints that prevent T cell immunodeficiency and TLR7-associated autoimmunity.
- Author
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Abt, Evan R, Abt, Evan R, Rashid, Khalid, Le, Thuc M, Li, Suwen, Lee, Hailey R, Lok, Vincent, Li, Luyi, Creech, Amanda L, Labora, Amanda N, Mandl, Hanna K, Lam, Alex K, Cho, Arthur, Rezek, Valerie, Wu, Nanping, Abril-Rodriguez, Gabriel, Rosser, Ethan W, Mittelman, Steven D, Hugo, Willy, Mehrling, Thomas, Bantia, Shanta, Ribas, Antoni, Donahue, Timothy R, Crooks, Gay M, Wu, Ting-Ting, Radu, Caius G, Abt, Evan R, Abt, Evan R, Rashid, Khalid, Le, Thuc M, Li, Suwen, Lee, Hailey R, Lok, Vincent, Li, Luyi, Creech, Amanda L, Labora, Amanda N, Mandl, Hanna K, Lam, Alex K, Cho, Arthur, Rezek, Valerie, Wu, Nanping, Abril-Rodriguez, Gabriel, Rosser, Ethan W, Mittelman, Steven D, Hugo, Willy, Mehrling, Thomas, Bantia, Shanta, Ribas, Antoni, Donahue, Timothy R, Crooks, Gay M, Wu, Ting-Ting, and Radu, Caius G
- Abstract
Purine nucleoside phosphorylase (PNP) enables the breakdown and recycling of guanine nucleosides. PNP insufficiency in humans is paradoxically associated with both immunodeficiency and autoimmunity, but the mechanistic basis for these outcomes is incompletely understood. Here, we identify two immune lineage-dependent consequences of PNP inactivation dictated by distinct gene interactions. During T cell development, PNP inactivation is synthetically lethal with downregulation of the dNTP triphosphohydrolase SAMHD1. This interaction requires deoxycytidine kinase activity and is antagonized by microenvironmental deoxycytidine. In B lymphocytes and macrophages, PNP regulates Toll-like receptor 7 signaling by controlling the levels of its (deoxy)guanosine nucleoside ligands. Overriding this regulatory mechanism promotes germinal center formation in the absence of exogenous antigen and accelerates disease in a mouse model of autoimmunity. This work reveals that one purine metabolism gene protects against immunodeficiency and autoimmunity via independent mechanisms operating in distinct immune lineages and identifies PNP as a potentially novel metabolic immune checkpoint.
- Published
- 2022
28. Induction of Autophagy Reduces IFN-I Mediated Inflammation and Restores Anti-HIV-1 T Cell Response in vivo
- Author
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Mu, Wenli, primary, Rezek, Valerie, additional, Martin, Heather, additional, Carrillo, Mayra, additional, Hamid, Philip, additional, Lizarraga, Miguel, additional, Yang, Otto O., additional, Jamieson, Beth, additional, Kitchen, Scott G., additional, and Zhen, Anjie, additional
- Published
- 2021
- Full Text
- View/download PDF
29. Apolipoprotein A-I mimetics attenuate macrophage activation in chronic treated HIV
- Author
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Mu, William, primary, Sharma, Madhav, additional, Heymans, Rachel, additional, Ritou, Eleni, additional, Rezek, Valerie, additional, Hamid, Philip, additional, Kossyvakis, Athanasios, additional, Sen Roy, Shubhendu, additional, Grijalva, Victor, additional, Chattopadhyay, Arnab, additional, Papesh, Jeremy, additional, Meriwether, David, additional, Kitchen, Scott G., additional, Fogelman, Alan M., additional, Reddy, Srinivasa T., additional, and Kelesidis, Theodoros, additional
- Published
- 2020
- Full Text
- View/download PDF
30. Abstract 5640: Targeting tumor-promoting inflammation (TPI) via the IL-1βpathway for cancer immunotherapy
- Author
-
Jayaraman, Pushpa, primary, Rodrik-Outmezguine, Vanessa, additional, Millholland, John, additional, O'Brien, Neil, additional, Wong, Connie, additional, Diwanji, Rohan, additional, Wang, Muchun, additional, Choi, Elizabeth, additional, Linnartz, Ronald, additional, Rose, Kristine, additional, Pelletier, Marc, additional, Savchenko, Alexander, additional, Luo, Tong, additional, Rezek, Valerie, additional, Kitchen, Scott, additional, Baum, Jason, additional, Sabatos-Peyton, Catherine, additional, Martin, Anne-Marie, additional, and Dranoff, Glenn, additional
- Published
- 2020
- Full Text
- View/download PDF
31. Abstract C103: Targeting IL-1β pathway for cancer immunotherapy
- Author
-
Jayaraman, Pushpa, primary, Millholland, John, additional, O’Brien, Neil, additional, Wong, Connie, additional, Diwanji, Rohan, additional, Wang, Muchun, additional, Choi, Elizabeth, additional, Linnartz, Ronald, additional, Rose, Kristine, additional, Rodrik-Outmezguine, Vanessa, additional, Pelletier, Marc, additional, Savchenko, Alexander, additional, Luo, Tong, additional, Rezek, Valerie, additional, Kitchen, Scott, additional, Baum, Jason, additional, Sabatos-Peyton, Catherine, additional, Martin, Anne-Marie, additional, and Dranoff, Glenn, additional
- Published
- 2019
- Full Text
- View/download PDF
32. Propagating Humanized BLT Mice for the Study of Human Immunology and Immunotherapy
- Author
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Yang, Lili, primary, Smith, Drake J., additional, Lin, Levina J., additional, Moon, Heesung, additional, Pham, Alexander T., additional, Wang, Xi, additional, Liu, Siyuan, additional, Ji, Sunjong, additional, Rezek, Valerie, additional, Shimizu, Saki, additional, Ruiz, Marlene, additional, Lam, Jennifer, additional, Janzen, Deanna M., additional, Memarzadeh, Sanaz, additional, Kohn, Donald B., additional, Zack, Jerome A., additional, Kitchen, Scott G., additional, and An, Dong Sung, additional
- Published
- 2017
- Full Text
- View/download PDF
33. Targeting type I interferon–mediated activation restores immune function in chronic HIV infection
- Author
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Zhen, Anjie, primary, Rezek, Valerie, additional, Youn, Cindy, additional, Lam, Brianna, additional, Chang, Nelson, additional, Rick, Jonathan, additional, Carrillo, Mayra, additional, Martin, Heather, additional, Kasparian, Saro, additional, Syed, Philip, additional, Rice, Nicholas, additional, Brooks, David G., additional, and Kitchen, Scott G., additional
- Published
- 2016
- Full Text
- View/download PDF
34. Stem-cell Based Engineered Immunity Against HIV Infection in the Humanized Mouse Model
- Author
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Zhen, Anjie, primary, Rezek, Valerie, primary, Youn, Cindy, primary, Rick, Jonathan, primary, Lam, Brianna, primary, Chang, Nelson, primary, Zack, Jerome, primary, Kamata, Masakazu, primary, and Kitchen, Scott, primary
- Published
- 2016
- Full Text
- View/download PDF
35. A novel in vivo chemoselection strategy for genetically modified hematopoietic stem cells
- Author
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Hacke, Katrin, primary, Treger, Janet, additional, Bogan, Brooke, additional, Rezek, Valerie, additional, Narukawa, Munetoshi, additional, Shimizu, Saki, additional, Liu, Pei-Qi, additional, Reik, Andreas, additional, Lieber, André, additional, Crooks, Gay, additional, Kohn, Donald, additional, An, Dong Sung, additional, Kitchen, Scott, additional, Gregory, Philip, additional, Cost, Gregory, additional, Holmes, Michael, additional, and Kasahara, Noriyuki, additional
- Published
- 2015
- Full Text
- View/download PDF
36. Engineering Cellular Resistance to HIV-1 Infection In Vivo Using a Dual Therapeutic Lentiviral Vector
- Author
-
Burke, Bryan P, primary, Levin, Bernard R, additional, Zhang, Jane, additional, Sahakyan, Anna, additional, Boyer, Joshua, additional, Carroll, Maria V, additional, Colón, Joanna Camba, additional, Keech, Naomi, additional, Rezek, Valerie, additional, Bristol, Gregory, additional, Eggers, Erica, additional, Cortado, Ruth, additional, Boyd, Maureen P, additional, Impey, Helen, additional, Shimizu, Saki, additional, Lowe, Emily L, additional, Ringpis, Gene-Errol E, additional, Kim, Sohn G, additional, Vatakis, Dimitrios N, additional, Breton, Louis R, additional, Bartlett, Jeffrey S, additional, Chen, Irvin S Y, additional, Kitchen, Scott G, additional, An, Dong Sung, additional, and Symonds, Geoff P, additional
- Published
- 2015
- Full Text
- View/download PDF
37. Targeting type I interferon-mediated activation restores immune function in chronic HIV infection.
- Author
-
Anjie Zhen, Rezek, Valerie, Youn, Cindy, Lam, Brianna, Chang, Nelson, Rick, Jonathan, Carrillo, Mayra, Martin, Heather, Kasparian, Saro, Syed, Philip, Rice, Nicholas, Brooks, David C., Kitchen, Scott C., Zhen, Anjie, Brooks, David G, and Kitchen, Scott G
- Subjects
- *
TYPE I interferons , *THERAPEUTICS , *HIV infections , *IMMUNOSUPPRESSION , *T cells , *CELLULAR signal transduction , *ANIMALS , *BIOLOGICAL models , *CHRONIC diseases , *HIV , *INTERFERONS , *MICE , *ANTIRETROVIRAL agents , *CHEMICAL inhibitors , *PHARMACODYNAMICS - Abstract
Chronic immune activation, immunosuppression, and T cell exhaustion are hallmarks of HIV infection, yet the mechanisms driving these processes are unclear. Chronic activation can be a driving force in immune exhaustion, and type I interferons (IFN-I) are emerging as critical components underlying ongoing activation in HIV infection. Here, we have tested the effect of blocking IFN-I signaling on T cell responses and virus replication in a murine model of chronic HIV infection. Using HIV-infected humanized mice, we demonstrated that in vivo blockade of IFN-I signaling during chronic HIV infection diminished HIV-driven immune activation, decreased T cell exhaustion marker expression, restored HIV-specific CD8 T cell function, and led to decreased viral replication. Antiretroviral therapy (ART) in combination with IFN-I blockade accelerated viral suppression, further decreased viral loads, and reduced the persistently infected HIV reservoir compared with ART treatment alone. Our data suggest that blocking IFN-I signaling in conjunction with ART treatment can restore immune function and may reduce viral reservoirs during chronic HIV infection, providing validation for IFN-I blockade as a potential therapy for HIV infection. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
38. Ligation of CD4 on human blood monocytes triggers macrophage differentiation (158.8)
- Author
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Kitchen, Scott, primary, Krutzik, Stephan, additional, Levin, Bernard, additional, Rezek, Valerie, additional, Kitchen, Christina, additional, and Zack, Jerome, additional
- Published
- 2011
- Full Text
- View/download PDF
39. Behavioral and histological assessment of a novel treatment of neuroHIV in humanized mice.
- Author
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Levine AJ, Thadani C, Soontornniyomkij V, Lopez-Aranda MF, Mesa YG, Kitchen S, Rezek V, Silva A, and Kolson DL
- Abstract
Neurocognitive deficits are prevalent among people living with HIV, likely due to chronic inflammation and oxidative stress in the brain. To date, no pharmaceutical treatments beyond antiretroviral therapy (ARV) has been shown to reduce risk for, or severity of, HIV-associated neurocognitive disorder. Here we investigate a novel compound, CDDO-Me, with documented neuroprotective effects via activation of the nrf2 and inhibition of the NFkB pathways., Methods: We conducted three studies to assess the efficacy of CDDO-Me alone or in combination with antiretroviral therapy in humanized mice infected with HIV; behavioral, histopathological, and immunohistochemical., Results: CDDO-Me in combination with ARV rescued social interaction deficits; however, only ARV was associated with preserved functioning in other behaviors, and CDDO-Me may have attenuated those benefits. A modest neuroprotective effect was found for CDDO-Me when administered with ARV, via preservation of PSD-95 expression; however, ARV alone had a more consistent protective effect. No significant changes in antioxidant enzyme expression levels were observed in CDDO-Me-treated animals. Only ARV use seemed to affect some antioxidant levels, indicating that it is ARV rather than CDDO-Me that is the major factor providing neuroprotection in this animal model. Finally, immunohistochemical analysis found that several cellular markers in various brain regions varied due to ARV rather than CDDO-Me., Conclusion: Limited benefit of CDDO-Me on behavior and neuroprotection were observed. Instead, ARV was shown to be the more beneficial treatment. These experiments support the future use of this chimeric mouse for behavioral experiments in neuroHIV research., Competing Interests: Additional Declarations: No competing interests reported.
- Published
- 2023
- Full Text
- View/download PDF
40. Engineering Cellular Resistance to HIV-1 Infection In Vivo Using a Dual Therapeutic Lentiviral Vector.
- Author
-
Burke BP, Levin BR, Zhang J, Sahakyan A, Boyer J, Carroll MV, Colón JC, Keech N, Rezek V, Bristol G, Eggers E, Cortado R, Boyd MP, Impey H, Shimizu S, Lowe EL, Ringpis GE, Kim SG, Vatakis DN, Breton LR, Bartlett JS, Chen IS, Kitchen SG, An DS, and Symonds GP
- Abstract
We described earlier a dual-combination anti-HIV type 1 (HIV-1) lentiviral vector (LVsh5/C46) that downregulates CCR5 expression of transduced cells via RNAi and inhibits HIV-1 fusion via cell surface expression of cell membrane-anchored C46 antiviral peptide. This combinatorial approach has two points of inhibition for R5-tropic HIV-1 and is also active against X4-tropic HIV-1. Here, we utilize the humanized bone marrow, liver, thymus (BLT) mouse model to characterize the in vivo efficacy of LVsh5/C46 (Cal-1) vector to engineer cellular resistance to HIV-1 pathogenesis. Human CD34+ hematopoietic stem/progenitor cells (HSPC) either nonmodified or transduced with LVsh5/C46 vector were transplanted to generate control and treatment groups, respectively. Control and experimental groups displayed similar engraftment and multilineage hematopoietic differentiation that included robust CD4+ T-cell development. Splenocytes isolated from the treatment group were resistant to both R5- and X4-tropic HIV-1 during ex vivo challenge experiments. Treatment group animals challenged with R5-tropic HIV-1 displayed significant protection of CD4+ T-cells and reduced viral load within peripheral blood and lymphoid tissues up to 14 weeks postinfection. Gene-marking and transgene expression were confirmed stable at 26 weeks post-transplantation. These data strongly support the use of LVsh5/C46 lentiviral vector in gene and cell therapeutic applications for inhibition of HIV-1 infection.
- Published
- 2015
- Full Text
- View/download PDF
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