{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T23:59:55Z","timestamp":1789430395061,"version":"build-2803163510"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T00:00:00Z","timestamp":1653004800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01 AI152655-01A1"],"award-info":[{"award-number":["R01 AI152655-01A1"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Gamma-delta (\u03b3\u03b4) T cells recognize antigens in a major histocompatibility complex (MHC) independent and have cytotoxic capability. Human immunodeficiency virus (HIV) infection reduces the proportion of the V\u03b42 cell subset compared to the V\u03b41 cell subset of \u03b3\u03b4 T cells in the blood in most infected individuals, except for elite controllers. The capacity of V\u03b42 T cells to kill HIV-infected targets has been demonstrated<jats:italic>in vitro<\/jats:italic>, albeit<jats:italic>in vivo<\/jats:italic>confirmatory studies are lacking. Here, we provide the first characterization of \u03b3\u03b4 T cell-HIV interactions in bone marrow-liver-thymus (BLT) humanized mice and examined the immunotherapeutic potential of V\u03b42 T cells in controlling HIV replication<jats:italic>in vivo<\/jats:italic>. We demonstrate a reduced proportion of V\u03b42 T cells and an increased proportion of V\u03b41 T cells in HIV-infected BLT humanized mice, like in HIV-positive individuals. HIV infection in BLT humanized mice also impaired the<jats:italic>ex vivo<\/jats:italic>expansion of V\u03b42 T cells, like in HIV-positive individuals. Adoptive transfer of activated V\u03b42 T cells did not control HIV replication during cell-associated HIV transmission in BLT humanized mice but instead exacerbated viremia, suggesting that V\u03b42 T cells may serve as early targets for HIV replication. Our findings demonstrate that BLT humanized mice can model \u03b3\u03b4 T cell-HIV interactions<jats:italic>in vivo<\/jats:italic>.<\/jats:p>","DOI":"10.3389\/fimmu.2022.881607","type":"journal-article","created":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T09:00:35Z","timestamp":1653037235000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["The BLT Humanized Mouse Model as a Tool for Studying Human Gamma Delta T Cell-HIV Interactions In Vivo"],"prefix":"10.3389","volume":"13","author":[{"given":"Shivkumar","family":"Biradar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yash","family":"Agarwal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T.","family":"Lotze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moses T.","family":"Bility","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robbie B.","family":"Mailliard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-07-4912","article-title":"Isopentenyl Pyrophosphate-Activated CD56+ {Gamma}{Delta} T Lymphocytes Display Potent Antitumor Activity Toward Human Squamous Cell Carcinoma","volume":"14","author":"Alexander","year":"2008","journal-title":"Clin Cancer Res"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1086\/314925","article-title":"Phosphoantigen-Reactive Vgamma9Vdelta2 T Lymphocytes Suppress In Vitro Human Immunodeficiency Virus Type 1 Replication by Cell-Released Antiviral Factors Including CC Chemokines","volume":"180","author":"Poccia","year":"1999","journal-title":"J Infect Dis"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00688","article-title":"Sensing of Pyrophosphate Metabolites by V\u03b39v\u03b42 T Cells","volume":"5","author":"Gu","year":"2014","journal-title":"Front Immunol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1016\/j.immuni.2018.01.009","article-title":"A Macrophage Colony-Stimulating-Factor-Producing \u03b3\u03b4 T Cell Subset Prevents Malarial Parasitemic Recurrence","volume":"48","author":"Mamedov","year":"2018","journal-title":"Immunity"},{"key":"B5","doi-asserted-by":"crossref","first-page":"998","DOI":"10.4049\/jimmunol.154.3.998","article-title":"V Gamma 2V Delta 2 TCR-Dependent Recognition of Non-Peptide Antigens and Daudi Cells Analyzed by TCR Gene Transfer","volume":"154","author":"Bukowski","year":"1995","journal-title":"J Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.19.10456-10467.2003","article-title":"Human Immunodeficiency Virus Type 1 Induces Persistent Changes in Mucosal and Blood Gammadelta T Cells Despite Suppressive Therapy","volume":"77","author":"Poles","year":"2003","journal-title":"J Virol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0b013e32832ff1ff","article-title":"Natural Viral Suppressors of HIV-1 Have a Unique Capacity to Maintain Gamma-Delta T Cells","volume":"23","author":"Riedel","year":"2009","journal-title":"Aids"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3109\/14653249.2011.623693","article-title":"Gamma Delta T Cells From HIV+ Donors can be Expanded In Vitro by Zoledronate\/Interleukin-2 to Become Cytotoxic Effectors for Antibody-Dependent Cellular Cytotoxicity","volume":"14","author":"Poonia","year":"2012","journal-title":"Cytotherapy"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.120121","article-title":"\u03b3\u03b4 T Cells: An Immunotherapeutic Approach for HIV Cure Strategies","volume":"3","author":"Garrido","year":"2018","journal-title":"JCI Insight"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.1995.tb03773.x","article-title":"Gamma Delta T Cells in Rhesus Monkeys and Their Response to Simian Immunodeficiency Virus (SIV) Infection","volume":"102","author":"Gan","year":"1995","journal-title":"Clin Exp Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1600579","article-title":"Mucosal and Systemic \u03b3\u03b4+ T Cells Associated With Control of Simian Immunodeficiency Virus Infection","volume":"197","author":"Tuero","year":"2016","journal-title":"J Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0050016","article-title":"Antiretroviral Pre-Exposure Prophylaxis Prevents Vaginal Transmission of HIV-1 in Humanized BLT Mice","volume":"5","author":"Denton","year":"2008","journal-title":"PloS Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiu537","article-title":"Modeling Mucosal Cell-Associated HIV Type 1 Transmission In Vitro","author":"Anderson","year":"2014","journal-title":"J Infect Dis"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0222574","article-title":"On the Efficiency of HIV Transmission: Insights Through Discrete Time HIV Models","volume":"14","author":"Showa","year":"2019","journal-title":"PloS One"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(98)80064-0","article-title":"Isolation From Human Fetal Liver of Cells Co-Expressing CD34 Haematopoietic Stem Cell and CAM 5.2 Pancytokeratin Markers","volume":"29","author":"Lemmer","year":"1998","journal-title":"J Hepatol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1186\/s40425-017-0209-6","article-title":"Enhancing Adoptive Cancer Immunotherapy With V\u03b32v\u03b42 T Cells Through Pulse Zoledronate Stimulation","volume":"5","author":"Nada","year":"2017","journal-title":"J Immunother Cancer"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2009.09.047","article-title":"HIV-1 Nef Dimerization Is Required for Nef-Mediated Receptor Downregulation and Viral Replication","volume":"394","author":"Poe","year":"2009","journal-title":"J Mol Biol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1021\/cb900195c","article-title":"Chemical Library Screens Targeting an HIV-1 Accessory Factor\/Host Cell Kinase Complex Identify Novel Antiretroviral Compounds","volume":"4","author":"Emert-Sedlak","year":"2009","journal-title":"ACS Chem Biol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA120.012536","article-title":"HIV-1 Nef Dimers Short-Circuit Immune Receptor Signaling by Activating Tec-Family Kinases at the Host Cell Membrane","volume":"295","author":"Li","year":"2020","journal-title":"J Biol Chem"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2011.10.024","article-title":"ADAR1 Is a Novel Multi Targeted Anti-HIV-1 Cellular Protein","volume":"422","author":"Biswas","year":"2012","journal-title":"Virology"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.120430","article-title":"Human Immunodeficiency Virus Infection Induces Lymphoid Fibrosis in the BM-Liver-Thymus-Spleen Humanized Mouse Model","author":"Samal","year":"2018","journal-title":"JCI Insight 3"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15193","article-title":"The ARRIVE Guidelines 2.0: Updated Guidelines for Reporting Animal Research","volume":"177","author":"Percie du Sert","year":"2020","journal-title":"Br J Pharmacol"},{"key":"B23","first-page":"373","article-title":"World Medical Association Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects","volume":"79","year":"2001","journal-title":"Bull World Health Org"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1084\/jem.169.5.1847","article-title":"CD8+ T Lymphocytes Recognize Tetanus Toxoid in an MHC-Restricted Fashion","volume":"169","author":"Kozbor","year":"1989","journal-title":"J Exp Med"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1007\/BF02935618","article-title":"TCR Gamma Delta Cells: Mysterious Cells of the Immune System","volume":"13","author":"Sciammas","year":"1994","journal-title":"Immunol Res"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.44.12.1012","article-title":"Tissue Distribution of Human Gamma Delta T Cells: No Evidence for General Epithelial Tropism","volume":"44","author":"Vroom","year":"1991","journal-title":"J Clin Pathol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/nri2781","article-title":"Gammadelta T Cell Effector Functions: A Blend of Innate Programming and Acquired Plasticity","volume":"10","author":"Bonneville","year":"2010","journal-title":"Nat Rev Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2007.11.020","article-title":"Mucosal Transmission of R5 and X4 Tropic HIV-1 via Vaginal and Rectal Routes in Humanized Rag2-\/- Gammac -\/- (RAG-Hu) Mice","volume":"373","author":"Berges","year":"2008","journal-title":"Virology"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01189","article-title":"Potential Role of V\u03b42(+) \u03b3\u03b4 T Cells in Regulation of Immune Activation in Primary HIV Infection","volume":"8","author":"Bhatnagar","year":"2017","journal-title":"Front Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2012.50","article-title":"Depletion and Dysfunction of V\u03b32v\u03b42 T Cells in HIV Disease: Mechanisms, Impacts and Therapeutic Implications","volume":"10","author":"Li","year":"2013","journal-title":"Cell Mol Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1089\/aid.2017.0254","article-title":"The Spleen Is an HIV-1 Sanctuary During Combined Antiretroviral Therapy","volume":"34","author":"Nolan","year":"2018","journal-title":"AIDS Res Hum Retroviruses"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.1996.d01-625.x","article-title":"Gamma Delta T Lymphocyte Responses to HIV","volume":"103","author":"Wallace","year":"1996","journal-title":"Clin Exp Immunol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1186\/1479-5876-12-45","article-title":"Successful Adoptive Transfer and In Vivo Expansion of Haploidentical \u03b3\u03b4 T Cells","volume":"12","author":"Wilhelm","year":"2014","journal-title":"J Transl Med"},{"key":"B34","doi-asserted-by":"publisher","first-page":"578741","DOI":"10.1155\/2014\/578741","article-title":"Alpha\/beta T-Cell Depleted Grafts as an Immunological Booster to Treat Graft Failure After Hematopoietic Stem Cell Transplantation With HLA-Matched Related and Unrelated Donors","volume":"2014","author":"R\u00e5destad","year":"2014","journal-title":"J Immunol Res"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005201","article-title":"Peripheral V\u03b39v\u03b42 T Cells Are a Novel Reservoir of Latent HIV Infection","volume":"11","author":"Soriano-Sarabia","year":"2015","journal-title":"PloS Pathog"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1089\/aid.2013.0111","article-title":"The Potential Role of CD16+ V\u03b32v\u03b42 T Cell-Mediated Antibody-Dependent Cell-Mediated Cytotoxicity in Control of HIV Type 1 Disease","volume":"29","author":"He","year":"2013","journal-title":"AIDS Res Hum Retroviruses"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nri2781","article-title":"\u03b3\u03b4 T Cell Effector Functions: A Blend of Innate Programming and Acquired Plasticity","volume":"10","author":"Bonneville","year":"2010","journal-title":"Nat Rev Immunol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00687","article-title":"\u03b3\u03b4 T Cells in HIV Disease: Past, Present, and Future","volume":"5","author":"Pauza","year":"2014","journal-title":"Front Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1002\/cti2.1069","article-title":"\u03b3\u03b4 T-Cell Responses During HIV Infection and Antiretroviral Therapy","volume":"8","author":"Juno","year":"2019","journal-title":"Clin Transl Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01452","article-title":"Diverse Impacts of HIV Latency-Reversing Agents on CD8+ T-Cell Function: Implications for HIV Cure","volume":"9","author":"Clutton","year":"2018","journal-title":"Front Immunol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1016\/j.immuni.2012.01.014","article-title":"Stimulation of HIV-1-Specific Cytolytic T Lymphocytes Facilitates Elimination of Latent Viral Reservoir After Virus Reactivation","volume":"36","author":"Shan","year":"2012","journal-title":"Immunity"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/nature14053","article-title":"Broad CTL Response Is Required to Clear Latent HIV-1 Due to Dominance of Escape Mutations","volume":"517","author":"Deng","year":"2015","journal-title":"Nature"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0b013e3283244619","article-title":"Zoledronic Acid and Interleukin-2 Treatment Improves Immunocompetence in HIV-Infected Persons by Activating Vgamma9Vdelta2 T Cells","volume":"23","author":"Poccia","year":"2009","journal-title":"Aids"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01401","article-title":"Current Advances in \u03b3\u03b4 T Cell-Based Tumor Immunotherapy","volume":"8","author":"Lo Presti","year":"2017","journal-title":"Front Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1602019","article-title":"Adoptive Transfer of Phosphoantigen-Specific \u03b3\u03b4 T Cell Subset Attenuates Mycobacterium Tuberculosis Infection in Nonhuman Primates","volume":"198","author":"Qaqish","year":"2017","journal-title":"J Immunol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.68.4.2570-2577.1994","article-title":"Differences in CD4 Dependence for Infectivity of Laboratory-Adapted and Primary Patient Isolates of Human Immunodeficiency Virus Type 1","volume":"68","author":"Kabat","year":"1994","journal-title":"J Virol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.15620","article-title":"The Phenotypic Changes of \u03b3\u03b4 T Cells in COVID-19 Patients","volume":"24","author":"Lei","year":"2020","journal-title":"J Cell Mol Med"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.881607\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,5]],"date-time":"2023-02-05T18:59:48Z","timestamp":1675623588000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.881607\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,20]]},"references-count":47,"alternative-id":["10.3389\/fimmu.2022.881607"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.881607","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,20]]},"article-number":"881607"}}