المؤلفون: Freeman, Tracey L., Zhao, Connie, Schrode, Nadine, Fortune, Trinisia, Shroff, Sanjana, Tweel, Benjamin, Beaumont, Kristin G., Swartz, Talia H.

المساهمون: National Institutes of Health

المصدر: Frontiers in Immunology ; volume 14 ; ISSN 1664-3224

مصطلحات موضوعية: Immunology, Immunology and Allergy

الوصف: Introduction Human immunodeficiency virus type 1 (HIV-1) causes a chronic, incurable infection leading to immune activation and chronic inflammation in people with HIV-1 (PWH), even with virologic suppression on antiretroviral therapy (ART). The role of lymphoid structures as reservoirs for viral latency and immune activation has been implicated in chronic inflammation mechanisms. Still, the specific transcriptomic changes induced by HIV-1 infection in different cell types within lymphoid tissue remain unexplored. Methods In this study, we utilized human tonsil explants from healthy human donors and infected them with HIV-1 ex vivo . We performed single-cell RNA sequencing (scRNA-seq) to analyze the cell types represented in the tissue and to investigate the impact of infection on gene expression profiles and inflammatory signaling pathways. Results Our analysis revealed that infected CD4 + T cells exhibited upregulation of genes associated with oxidative phosphorylation. Furthermore, macrophages exposed to the virus but uninfected showed increased expression of genes associated with the NLRP3 inflammasome pathway. Discussion These findings provide valuable insights into the specific transcriptomic changes induced by HIV-1 infection in different cell types within lymphoid tissue. The activation of oxidative phosphorylation in infected CD4 + T cells and the proinflammatory response in macrophages may contribute to the chronic inflammation observed in PWH despite ART. Understanding these mechanisms is crucial for developing targeted therapeutic strategies to eradicate HIV-1 infection in PWH.

الإتاحة: https://doi.org/10.3389/fimmu.2023.1172938Test

المؤلفون: Tavazoie, Masoud F, Pollack, Ilana, Tanqueco, Raissa, Ostendorf, Benjamin N, Reis, Bernardo S, Gonsalves, Foster C, Kurth, Isabel, Andreu-Agullo, Celia, Derbyshire, Mark L, Posada, Jessica, Takeda, Shugaku, Tafreshian, Kimia N, Rowinsky, Eric, Szarek, Michael, Waltzman, Roger J, Mcmillan, Elizabeth A, Zhao, Connie, Mita, Monica, Mita, Alain, Chmielowski, Bartosz, Postow, Michael A, Ribas, Antoni, Mucida, Daniel, Tavazoie, Sohail F

المصدر: Cell. 172(4)

مصطلحات موضوعية: Immunization, Digestive Diseases, Cancer, Liver Disease, Clinical Research, Vaccine Related, Development of treatments and therapeutic interventions, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, Aetiology, Inflammatory and immune system, Animals, Apolipoproteins E, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Female, Immunity, Innate, Liver X Receptors, Male, Mice, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Myeloid-Derived Suppressor Cells, Neoplasms, Experimental, Xenograft Model Antitumor Assays, ApoE, LRP8, LXR, MDSC, cancer, clinical trial, immune therapy, myeloid, nuclear hormone receptor, tumor immunology, Biological Sciences, Medical and Health Sciences, Developmental Biology

الوصف: Therapeutic harnessing of adaptive immunity via checkpoint inhibition has transformed the treatment of many cancers. Despite unprecedented long-term responses, most patients do not respond to these therapies. Immunotherapy non-responders often harbor high levels of circulating myeloid-derived suppressor cells (MDSCs)-an immunosuppressive innate cell population. Through genetic and pharmacological approaches, we uncovered a pathway governing MDSC abundance in multiple cancer types. Therapeutic liver-X nuclear receptor (LXR) agonism reduced MDSC abundance in murine models and in patients treated in a first-in-human dose escalation phase 1 trial. MDSC depletion was associated with activation of cytotoxic T lymphocyte (CTL) responses in mice and patients. The LXR transcriptional target ApoE mediated these effects in mice, where LXR/ApoE activation therapy elicited robust anti-tumor responses and also enhanced T cell activation during various immune-based therapies. We implicate the LXR/ApoE axis in the regulation of innate immune suppression and as a target for enhancing the efficacy of cancer immunotherapy in patients.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/9zd8p0v2Test

المؤلفون: Tsurumi, Amy, Zhao, Connie, Li, Willis X

المصدر: BMC Genomics. 18(1)

مصطلحات موضوعية: Biochemistry and Cell Biology, Biological Sciences, Genetics, Biotechnology, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Aetiology, Underpinning research, Generic health relevance, Genomics, Heterochromatin, Janus Kinases, Mutation, STAT Transcription Factors, Transcription, Genetic, Transcriptome, JAK, STAT, Non-canonical JAK/STAT signaling, Drosophila, Development, Signal transduction, Epigenetics, Information and Computing Sciences, Medical and Health Sciences, Bioinformatics, Biological sciences, Biomedical and clinical sciences

الوصف: BackgroundThe Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway has been well-characterized as a crucial signal transduction cascade that regulates vital biological responses including development, immunity and oncogenesis. Additionally to its canonical pathway that uses the phosphorylated form of the STAT transcription factor, recently the non-canonical pathway involving heterochromatin formation by unphosphorylated STAT was recently uncovered. Considering the significant role of the JAK/STAT pathway, we used the simple Drosophila system in which the non-canonical pathway was initially characterized, to compare putative canonical versus non-canonical transcriptional targets across the genome. We analyzed microarray expression patterns of wildtype, Jak gain- and loss-of-function mutants, as well as the Stat loss-of-function mutant during embryogenesis, since the contribution of the canonical signal transduction pathway has been well-characterized in these contexts. Previous studies have also demonstrated that Jak gain-of-function and Stat mutants counter heterochromatin silencing to de-repress target genes by the non-canonical pathway.ResultsCompared to canonical target genomic loci, non-canonical targets were significantly more associated with sites enriched with heterochromatin-related factors (p = 0.004). Furthermore, putative canonical and non-canonical transcriptional targets identified displayed some differences in biological pathways they regulate, as determined by Gene Ontology (GO) enrichment analyses. Canonical targets were enriched mainly with genes relevant to development and immunity, as expected, whereas the non-canonical target gene set mainly showed enrichment of genes for various metabolic responses and stress response, highlighting the possibility that some differences may exist between the two loci.ConclusionsCanonical and non-canonical JAK/STAT genes may regulate distinct and overlapping sets of genes and may perform specific overall functions in physiology. Further studies at different developmental stages, or using distinct tissues may identify additional targets and provide insight into which gene targets are unique to the canonical or non-canonical pathway.

الوصول الحر: https://escholarship.org/uc/item/4mr8m3h9Test

المؤلفون: Zhao, Connie, Li, Hongru, Swartz, Talia H., Chen, Benjamin K.

المساهمون: Wu, Li, Prasad, Vinayaka R., Division of Intramural Research, National Institute of Allergy and Infectious Diseases, HHS | NIH | National Institute of General Medical Sciences, HHS | NIH | National Institute on Drug Abuse

المصدر: mBio ; volume 13, issue 2 ; ISSN 2150-7511

الوصف: The HIV Env glycoprotein is the surface glycoprotein responsible for viral entry into CD4 + immune cells. During infection, Env also serves as a primary target for antibody responses, which are robust but unable to control virus replication.

الإتاحة: https://doi.org/10.1128/mbio.01825-21Test

المؤلفون: Min, Alice K., Evans, Michelle, Vo, Christopher, Chaudhuri, Shaoli, Zhao, Connie, Frere, Justin, Serafini, Randal, Liu, Sean T.H., Swartz, Talia H.

المصدر: COVID-19 Viral Sepsis ; page 223-249 ; ISBN 9780323918121

الإتاحة: https://doi.org/10.1016/b978-0-323-91812-1.00014-7Test
https://api.elsevier.com/content/article/PII:B9780323918121000147?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:B9780323918121000147?httpAccept=text/plainTest

المؤلفون: Abdul-Mutakabbir, Jacinda C., Bora, Yasmeen D., Boyland, Ryan F., Calac, Alec J., Carvalho, Agostinho, Cawcutt, Kelly, Chaudhuri, Shaoli, Chopra, Teena, Condoluci, Mark, Dhagat, Priya, Egger, Matthias, Evans, Michelle, Fadul, Nada, Flores, Laura E., Frere, Justin, Fussa, Mark, Glowacki, Joseph B., Goldman, Gustavo H., Hoenigl, Martin, Hou, Cindy, Ibrahim, Ashraf S., Johnson, Dan, Kissinger, Patricia, Lang, Lucjan, Levin, Todd P., Liu, Sean T.H., Madad, Syra S., Marcelin, Jasmine R., McDougal, April, Min, Alice K., Nasir, Seif L., Popescu, Saskia, Ratnayake, Aneeka, Serafini, Randal, Sokol, Theresa, Swartz, Talia H., Syed, Uzma, Tan, Karen K., Thompson, Shaun, Touleyrou, Lauren, Truong, Tiffany B., Vo, Christopher, Vyas, Nikunj, Woc-Colburn, Laila, Wong Murray, Victoria, Zhao, Connie, Zheng, Crystal

المصدر: COVID-19 Viral Sepsis ; page xv-xvii ; ISBN 9780323918121

الإتاحة: https://doi.org/10.1016/b978-0-323-91812-1.00022-6Test
https://api.elsevier.com/content/article/PII:B9780323918121000226?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:B9780323918121000226?httpAccept=text/plainTest

المؤلفون: DeFalco, Jeff, Tomishima, Mark, Liu, Hongyan, Zhao, Connie, Cai, XiaoLi, Marth, Jamey D., Enquist, Lynn, Friedman, Jeffrey M.

المصدر: Science, 2001 Mar . 291(5513), 2608-2613.

الوصول الحر: https://www.jstor.org/stable/3082841Test

المؤلفون: Fei, Hong, Okano, Hirotaka J., Li, Cai, Lee, Gwo-Hwa, Zhao, Connie, Darnell, Robert, Friedman, Jeffrey M.

المصدر: Proceedings of the National Academy of Sciences of the United States of America, 1997 Jun . 94(13), 7001-7005.

الوصول الحر: https://www.jstor.org/stable/42268Test

المؤلفون: Zhao, Connie, Princiotto, Amy M., Nguyen, Hanh T., Zou, Shitao, Zhao, Meiqing Lily, Zhang, Shijian, Herschhorn, Alon, Farrell, Mark, Pahil, Karanbir, Melillo, Bruno, Sambasivarao, Somisetti V., Abrams, Cameron, Smith, Amos B., Madani, Navid, Sodroski, Joseph

المساهمون: Simon, Viviana, HHS | National Institutes of Health, amfAR, The Foundation for AIDS Research, Ragon Institute of MGH, MIT and Harvard

المصدر: Journal of Virology ; volume 93, issue 21 ; ISSN 0022-538X 1098-5514

الوصف: Envelope glycoprotein (Env) spikes on the surface of human immunodeficiency virus (HIV-1) bind target cell receptors, triggering changes in the shape of Env. We studied a small molecule, MF275, that also induced shape changes in Env. The consequences of MF275 interaction with Env depended on the HIV-1 strain, with infection by some viruses inhibited and infection by other viruses enhanced. These studies reveal the strain-dependent diversity of HIV-1 Envs as they undergo shape changes in proceeding down the entry pathway. Appreciation of this diversity will assist attempts to develop broadly active inhibitors of HIV-1 entry.

الإتاحة: https://doi.org/10.1128/jvi.01197-19Test

المؤلفون: Madani, Navid, Princiotto, Amy M., Mach, Linh, Ding, Shilei, Prevost, Jérémie, Richard, Jonathan, Hora, Bhavna, Sutherland, Laura, Zhao, Connie A., Conn, Brandon P., Bradley, Todd, Moody, M. Anthony, Melillo, Bruno, Finzi, Andrés, Haynes, Barton F., Smith III, Amos B., Santra, Sampa, Sodroski, Joseph

المصدر: Nature Communications ; volume 9, issue 1 ; ISSN 2041-1723

مصطلحات موضوعية: General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Multidisciplinary

الوصف: The envelope glycoprotein (Env) trimer ((gp120/gp41) 3 ) mediates human immunodeficiency virus (HIV-1) entry into cells. The “closed,” antibody-resistant Env trimer is driven to more open conformations by binding the host receptor, CD4. Broadly neutralizing antibodies that recognize conserved elements of the closed Env are potentially protective, but are elicited inefficiently. HIV-1 has evolved multiple mechanisms to evade readily elicited antibodies against more open Env conformations. Small-molecule CD4-mimetic compounds (CD4mc) bind the HIV-1 gp120 Env and promote conformational changes similar to those induced by CD4, exposing conserved Env elements to antibodies. Here, we show that a CD4mc synergizes with antibodies elicited by monomeric HIV-1 gp120 to protect monkeys from multiple high-dose intrarectal challenges with a heterologous simian-human immunodeficiency virus (SHIV). The protective immune response persists for at least six months after vaccination. CD4mc should increase the protective efficacy of any HIV-1 Env vaccine that elicits antibodies against CD4-induced conformations of Env.

الإتاحة: https://doi.org/10.1038/s41467-018-04758-9Test
https://www.nature.com/articles/s41467-018-04758-9Test
https://www.nature.com/articles/s41467-018-04758-9.pdfTest