Lentivirus-mediated Gene Transfer in Hematopoietic Stem Cells Is Impaired in SHIV-infected, ART-treated Nonhuman Primates
Recent studies have demonstrated that genetically modified hematopoietic stem cells (HSCs) can reduce HIV viremia. We have developed an HIV/AIDS-patient model in Simian/human immunodeficiency virus (SHIV)-infected pigtailed macaques that are stably suppressed on antiretroviral therapy (ART: raltegra...
Gespeichert in:
| Veröffentlicht in: | Molecular therapy 2015-05, Vol.23 (5), p.943-951 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 951 |
|---|---|
| container_issue | 5 |
| container_start_page | 943 |
| container_title | Molecular therapy |
| container_volume | 23 |
| creator | Younan, Patrick M Peterson, Christopher W Polacino, Patricia Kowalski, John P Obenza, Willimark Miller, Hannah W Milless, Brian P Gafken, Phil DeRosa, Stephen C Hu, Shiu-Lok Kiem, Hans-Peter |
| description | Recent studies have demonstrated that genetically modified hematopoietic stem cells (HSCs) can reduce HIV viremia. We have developed an HIV/AIDS-patient model in Simian/human immunodeficiency virus (SHIV)-infected pigtailed macaques that are stably suppressed on antiretroviral therapy (ART: raltegravir, emtricitabine and tenofovir). Following SHIV infection and ART, animals undergo autologous HSC transplantation (HSCT) with lentivirally transduced cluster of differentiation (CD)34+ cells expressing the mC46 anti-HIV fusion protein. We show that SHIV+, ART-treated animals had very low gene marking levels after HSCT. Pretransduction CD34+ cells contained detectable levels of all three ART drugs, likely contributing to the low gene transfer efficiency. Following HSCT recovery and the cessation of ART, plasma viremia rebounded, indicating that myeloablative total body irradiation cannot completely eliminate viral reservoirs after autologous HSCT. The kinetics of recovery following autologous HSCT in SHIV+, ART-treated macaques paralleled those observed following transplantation of control animals. However, T-cell subset analyses demonstrated a high percentage of C-C chemokine receptor 5 (CCR5)-expressing CD4+ T-cells after HSCT. These data suggest that an extended ART interruption time may be required for more efficient lentiviral transduction. To avoid complications associated with ART interruption in the context of high percentages of CD4+CCR5+T-cells after HSCT, the use of vector systems not impaired by the presence of residual ART may also be beneficial. |
| doi_str_mv | 10.1038/mt.2015.19 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4427875</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S1525001616301186</els_id><sourcerecordid>1680186531</sourcerecordid><originalsourceid>FETCH-LOGICAL-c554t-a5b6e9e71b34190160214362eda4e8ff99461ade626e1804e6863a8610625beb3</originalsourceid><addsrcrecordid>eNqFkV2LEzEUhoMo7ofe-ANkwBsRpyaZJJO5EZai20JRcau3ITNzxs3SSbpJprD_fk_tWlQEIZBAnjycNy8hLxidMVrpd2OeccrkjDWPyCmTXJaUcvH4eGbqhJyldIMnJhv1lJxwqYTmSpySuxX47HYuTqkcoXc2Q19cgodiHa1PA8TC-WIBo81hGxxk1xVXGcZiDptNKpa4xq11EV8hd7VYfi-dH6BDzdvi4uu6zBF-Oj8Ffz2N1hdfokMZpGfkyWA3CZ4_7Ofk28cP6_miXH2-XM4vVmUnpcilla2CBmrWVoI1mIVyJirFobcC9DA0jVDM9qC4AqapAKVVZbViVHHZQludk_cH73ZqMWGHeaPdmO1-jHhngnXmzxvvrs2PsDNC8FrXEgWvHwQx3E6Qshld6jC-9RCmZFhdV5oLzqv_o0pTppWsGKKv_kJvwhQ9_gQKG1Zp3XCN1JsD1cWQUoThODejZl--GbPZl29Yg_DL35Me0V9tIyAOAOB_7xxEkzoHvsPeI1Zm-uD-5b0H0om7cw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1791388928</pqid></control><display><type>article</type><title>Lentivirus-mediated Gene Transfer in Hematopoietic Stem Cells Is Impaired in SHIV-infected, ART-treated Nonhuman Primates</title><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>ProQuest Central UK/Ireland</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>Younan, Patrick M ; Peterson, Christopher W ; Polacino, Patricia ; Kowalski, John P ; Obenza, Willimark ; Miller, Hannah W ; Milless, Brian P ; Gafken, Phil ; DeRosa, Stephen C ; Hu, Shiu-Lok ; Kiem, Hans-Peter</creator><creatorcontrib>Younan, Patrick M ; Peterson, Christopher W ; Polacino, Patricia ; Kowalski, John P ; Obenza, Willimark ; Miller, Hannah W ; Milless, Brian P ; Gafken, Phil ; DeRosa, Stephen C ; Hu, Shiu-Lok ; Kiem, Hans-Peter</creatorcontrib><description>Recent studies have demonstrated that genetically modified hematopoietic stem cells (HSCs) can reduce HIV viremia. We have developed an HIV/AIDS-patient model in Simian/human immunodeficiency virus (SHIV)-infected pigtailed macaques that are stably suppressed on antiretroviral therapy (ART: raltegravir, emtricitabine and tenofovir). Following SHIV infection and ART, animals undergo autologous HSC transplantation (HSCT) with lentivirally transduced cluster of differentiation (CD)34+ cells expressing the mC46 anti-HIV fusion protein. We show that SHIV+, ART-treated animals had very low gene marking levels after HSCT. Pretransduction CD34+ cells contained detectable levels of all three ART drugs, likely contributing to the low gene transfer efficiency. Following HSCT recovery and the cessation of ART, plasma viremia rebounded, indicating that myeloablative total body irradiation cannot completely eliminate viral reservoirs after autologous HSCT. The kinetics of recovery following autologous HSCT in SHIV+, ART-treated macaques paralleled those observed following transplantation of control animals. However, T-cell subset analyses demonstrated a high percentage of C-C chemokine receptor 5 (CCR5)-expressing CD4+ T-cells after HSCT. These data suggest that an extended ART interruption time may be required for more efficient lentiviral transduction. To avoid complications associated with ART interruption in the context of high percentages of CD4+CCR5+T-cells after HSCT, the use of vector systems not impaired by the presence of residual ART may also be beneficial.</description><identifier>ISSN: 1525-0016</identifier><identifier>EISSN: 1525-0024</identifier><identifier>DOI: 10.1038/mt.2015.19</identifier><identifier>PMID: 25648264</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Acquired immune deficiency syndrome ; AIDS ; Animals ; Antiretroviral Therapy, Highly Active ; Cancer research ; Chemokines ; Drug therapy ; Gene Expression ; Gene therapy ; Genetic Therapy ; Genetic Vectors - genetics ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells - metabolism ; HIV ; Human immunodeficiency virus ; Immunophenotyping ; Infections ; Lentivirus - genetics ; Leukemia ; Lymphocyte Count ; Lymphoma ; Macaca ; Macaca nemestrina ; Medical research ; Original ; Patients ; Plasma ; Research centers ; Simian Acquired Immunodeficiency Syndrome - immunology ; Simian Acquired Immunodeficiency Syndrome - therapy ; Simian Acquired Immunodeficiency Syndrome - virology ; Simian Immunodeficiency Virus - immunology ; Simian/human immunodeficiency virus ; Stem cells ; T-Lymphocyte Subsets - immunology ; T-Lymphocyte Subsets - radiation effects ; T-Lymphocyte Subsets - virology ; Transduction, Genetic ; Transgenes ; Transplantation Conditioning ; Transplants & implants ; Vectors (Biology) ; Viral Load</subject><ispartof>Molecular therapy, 2015-05, Vol.23 (5), p.943-951</ispartof><rights>2015 American Society of Gene & Cell Therapy</rights><rights>Copyright Nature Publishing Group May 2015</rights><rights>Copyright © 2015 American Society of Gene & Cell Therapy 2015 American Society of Gene & Cell Therapy</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c554t-a5b6e9e71b34190160214362eda4e8ff99461ade626e1804e6863a8610625beb3</citedby><cites>FETCH-LOGICAL-c554t-a5b6e9e71b34190160214362eda4e8ff99461ade626e1804e6863a8610625beb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427875/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1791388928?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793,64385,64387,64389,72469</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25648264$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Younan, Patrick M</creatorcontrib><creatorcontrib>Peterson, Christopher W</creatorcontrib><creatorcontrib>Polacino, Patricia</creatorcontrib><creatorcontrib>Kowalski, John P</creatorcontrib><creatorcontrib>Obenza, Willimark</creatorcontrib><creatorcontrib>Miller, Hannah W</creatorcontrib><creatorcontrib>Milless, Brian P</creatorcontrib><creatorcontrib>Gafken, Phil</creatorcontrib><creatorcontrib>DeRosa, Stephen C</creatorcontrib><creatorcontrib>Hu, Shiu-Lok</creatorcontrib><creatorcontrib>Kiem, Hans-Peter</creatorcontrib><title>Lentivirus-mediated Gene Transfer in Hematopoietic Stem Cells Is Impaired in SHIV-infected, ART-treated Nonhuman Primates</title><title>Molecular therapy</title><addtitle>Mol Ther</addtitle><description>Recent studies have demonstrated that genetically modified hematopoietic stem cells (HSCs) can reduce HIV viremia. We have developed an HIV/AIDS-patient model in Simian/human immunodeficiency virus (SHIV)-infected pigtailed macaques that are stably suppressed on antiretroviral therapy (ART: raltegravir, emtricitabine and tenofovir). Following SHIV infection and ART, animals undergo autologous HSC transplantation (HSCT) with lentivirally transduced cluster of differentiation (CD)34+ cells expressing the mC46 anti-HIV fusion protein. We show that SHIV+, ART-treated animals had very low gene marking levels after HSCT. Pretransduction CD34+ cells contained detectable levels of all three ART drugs, likely contributing to the low gene transfer efficiency. Following HSCT recovery and the cessation of ART, plasma viremia rebounded, indicating that myeloablative total body irradiation cannot completely eliminate viral reservoirs after autologous HSCT. The kinetics of recovery following autologous HSCT in SHIV+, ART-treated macaques paralleled those observed following transplantation of control animals. However, T-cell subset analyses demonstrated a high percentage of C-C chemokine receptor 5 (CCR5)-expressing CD4+ T-cells after HSCT. These data suggest that an extended ART interruption time may be required for more efficient lentiviral transduction. To avoid complications associated with ART interruption in the context of high percentages of CD4+CCR5+T-cells after HSCT, the use of vector systems not impaired by the presence of residual ART may also be beneficial.</description><subject>Acquired immune deficiency syndrome</subject><subject>AIDS</subject><subject>Animals</subject><subject>Antiretroviral Therapy, Highly Active</subject><subject>Cancer research</subject><subject>Chemokines</subject><subject>Drug therapy</subject><subject>Gene Expression</subject><subject>Gene therapy</subject><subject>Genetic Therapy</subject><subject>Genetic Vectors - genetics</subject><subject>Hematopoietic Stem Cell Transplantation</subject><subject>Hematopoietic Stem Cells - metabolism</subject><subject>HIV</subject><subject>Human immunodeficiency virus</subject><subject>Immunophenotyping</subject><subject>Infections</subject><subject>Lentivirus - genetics</subject><subject>Leukemia</subject><subject>Lymphocyte Count</subject><subject>Lymphoma</subject><subject>Macaca</subject><subject>Macaca nemestrina</subject><subject>Medical research</subject><subject>Original</subject><subject>Patients</subject><subject>Plasma</subject><subject>Research centers</subject><subject>Simian Acquired Immunodeficiency Syndrome - immunology</subject><subject>Simian Acquired Immunodeficiency Syndrome - therapy</subject><subject>Simian Acquired Immunodeficiency Syndrome - virology</subject><subject>Simian Immunodeficiency Virus - immunology</subject><subject>Simian/human immunodeficiency virus</subject><subject>Stem cells</subject><subject>T-Lymphocyte Subsets - immunology</subject><subject>T-Lymphocyte Subsets - radiation effects</subject><subject>T-Lymphocyte Subsets - virology</subject><subject>Transduction, Genetic</subject><subject>Transgenes</subject><subject>Transplantation Conditioning</subject><subject>Transplants & implants</subject><subject>Vectors (Biology)</subject><subject>Viral Load</subject><issn>1525-0016</issn><issn>1525-0024</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqFkV2LEzEUhoMo7ofe-ANkwBsRpyaZJJO5EZai20JRcau3ITNzxs3SSbpJprD_fk_tWlQEIZBAnjycNy8hLxidMVrpd2OeccrkjDWPyCmTXJaUcvH4eGbqhJyldIMnJhv1lJxwqYTmSpySuxX47HYuTqkcoXc2Q19cgodiHa1PA8TC-WIBo81hGxxk1xVXGcZiDptNKpa4xq11EV8hd7VYfi-dH6BDzdvi4uu6zBF-Oj8Ffz2N1hdfokMZpGfkyWA3CZ4_7Ofk28cP6_miXH2-XM4vVmUnpcilla2CBmrWVoI1mIVyJirFobcC9DA0jVDM9qC4AqapAKVVZbViVHHZQludk_cH73ZqMWGHeaPdmO1-jHhngnXmzxvvrs2PsDNC8FrXEgWvHwQx3E6Qshld6jC-9RCmZFhdV5oLzqv_o0pTppWsGKKv_kJvwhQ9_gQKG1Zp3XCN1JsD1cWQUoThODejZl--GbPZl29Yg_DL35Me0V9tIyAOAOB_7xxEkzoHvsPeI1Zm-uD-5b0H0om7cw</recordid><startdate>20150501</startdate><enddate>20150501</enddate><creator>Younan, Patrick M</creator><creator>Peterson, Christopher W</creator><creator>Polacino, Patricia</creator><creator>Kowalski, John P</creator><creator>Obenza, Willimark</creator><creator>Miller, Hannah W</creator><creator>Milless, Brian P</creator><creator>Gafken, Phil</creator><creator>DeRosa, Stephen C</creator><creator>Hu, Shiu-Lok</creator><creator>Kiem, Hans-Peter</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><general>Nature Publishing Group</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>7QO</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20150501</creationdate><title>Lentivirus-mediated Gene Transfer in Hematopoietic Stem Cells Is Impaired in SHIV-infected, ART-treated Nonhuman Primates</title><author>Younan, Patrick M ; Peterson, Christopher W ; Polacino, Patricia ; Kowalski, John P ; Obenza, Willimark ; Miller, Hannah W ; Milless, Brian P ; Gafken, Phil ; DeRosa, Stephen C ; Hu, Shiu-Lok ; Kiem, Hans-Peter</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c554t-a5b6e9e71b34190160214362eda4e8ff99461ade626e1804e6863a8610625beb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Acquired immune deficiency syndrome</topic><topic>AIDS</topic><topic>Animals</topic><topic>Antiretroviral Therapy, Highly Active</topic><topic>Cancer research</topic><topic>Chemokines</topic><topic>Drug therapy</topic><topic>Gene Expression</topic><topic>Gene therapy</topic><topic>Genetic Therapy</topic><topic>Genetic Vectors - genetics</topic><topic>Hematopoietic Stem Cell Transplantation</topic><topic>Hematopoietic Stem Cells - metabolism</topic><topic>HIV</topic><topic>Human immunodeficiency virus</topic><topic>Immunophenotyping</topic><topic>Infections</topic><topic>Lentivirus - genetics</topic><topic>Leukemia</topic><topic>Lymphocyte Count</topic><topic>Lymphoma</topic><topic>Macaca</topic><topic>Macaca nemestrina</topic><topic>Medical research</topic><topic>Original</topic><topic>Patients</topic><topic>Plasma</topic><topic>Research centers</topic><topic>Simian Acquired Immunodeficiency Syndrome - immunology</topic><topic>Simian Acquired Immunodeficiency Syndrome - therapy</topic><topic>Simian Acquired Immunodeficiency Syndrome - virology</topic><topic>Simian Immunodeficiency Virus - immunology</topic><topic>Simian/human immunodeficiency virus</topic><topic>Stem cells</topic><topic>T-Lymphocyte Subsets - immunology</topic><topic>T-Lymphocyte Subsets - radiation effects</topic><topic>T-Lymphocyte Subsets - virology</topic><topic>Transduction, Genetic</topic><topic>Transgenes</topic><topic>Transplantation Conditioning</topic><topic>Transplants & implants</topic><topic>Vectors (Biology)</topic><topic>Viral Load</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Younan, Patrick M</creatorcontrib><creatorcontrib>Peterson, Christopher W</creatorcontrib><creatorcontrib>Polacino, Patricia</creatorcontrib><creatorcontrib>Kowalski, John P</creatorcontrib><creatorcontrib>Obenza, Willimark</creatorcontrib><creatorcontrib>Miller, Hannah W</creatorcontrib><creatorcontrib>Milless, Brian P</creatorcontrib><creatorcontrib>Gafken, Phil</creatorcontrib><creatorcontrib>DeRosa, Stephen C</creatorcontrib><creatorcontrib>Hu, Shiu-Lok</creatorcontrib><creatorcontrib>Kiem, Hans-Peter</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>Biotechnology Research Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Younan, Patrick M</au><au>Peterson, Christopher W</au><au>Polacino, Patricia</au><au>Kowalski, John P</au><au>Obenza, Willimark</au><au>Miller, Hannah W</au><au>Milless, Brian P</au><au>Gafken, Phil</au><au>DeRosa, Stephen C</au><au>Hu, Shiu-Lok</au><au>Kiem, Hans-Peter</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Lentivirus-mediated Gene Transfer in Hematopoietic Stem Cells Is Impaired in SHIV-infected, ART-treated Nonhuman Primates</atitle><jtitle>Molecular therapy</jtitle><addtitle>Mol Ther</addtitle><date>2015-05-01</date><risdate>2015</risdate><volume>23</volume><issue>5</issue><spage>943</spage><epage>951</epage><pages>943-951</pages><issn>1525-0016</issn><eissn>1525-0024</eissn><abstract>Recent studies have demonstrated that genetically modified hematopoietic stem cells (HSCs) can reduce HIV viremia. We have developed an HIV/AIDS-patient model in Simian/human immunodeficiency virus (SHIV)-infected pigtailed macaques that are stably suppressed on antiretroviral therapy (ART: raltegravir, emtricitabine and tenofovir). Following SHIV infection and ART, animals undergo autologous HSC transplantation (HSCT) with lentivirally transduced cluster of differentiation (CD)34+ cells expressing the mC46 anti-HIV fusion protein. We show that SHIV+, ART-treated animals had very low gene marking levels after HSCT. Pretransduction CD34+ cells contained detectable levels of all three ART drugs, likely contributing to the low gene transfer efficiency. Following HSCT recovery and the cessation of ART, plasma viremia rebounded, indicating that myeloablative total body irradiation cannot completely eliminate viral reservoirs after autologous HSCT. The kinetics of recovery following autologous HSCT in SHIV+, ART-treated macaques paralleled those observed following transplantation of control animals. However, T-cell subset analyses demonstrated a high percentage of C-C chemokine receptor 5 (CCR5)-expressing CD4+ T-cells after HSCT. These data suggest that an extended ART interruption time may be required for more efficient lentiviral transduction. To avoid complications associated with ART interruption in the context of high percentages of CD4+CCR5+T-cells after HSCT, the use of vector systems not impaired by the presence of residual ART may also be beneficial.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>25648264</pmid><doi>10.1038/mt.2015.19</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1525-0016 |
| ispartof | Molecular therapy, 2015-05, Vol.23 (5), p.943-951 |
| issn | 1525-0016 1525-0024 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4427875 |
| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; ProQuest Central UK/Ireland; PubMed Central; Alma/SFX Local Collection |
| subjects | Acquired immune deficiency syndrome AIDS Animals Antiretroviral Therapy, Highly Active Cancer research Chemokines Drug therapy Gene Expression Gene therapy Genetic Therapy Genetic Vectors - genetics Hematopoietic Stem Cell Transplantation Hematopoietic Stem Cells - metabolism HIV Human immunodeficiency virus Immunophenotyping Infections Lentivirus - genetics Leukemia Lymphocyte Count Lymphoma Macaca Macaca nemestrina Medical research Original Patients Plasma Research centers Simian Acquired Immunodeficiency Syndrome - immunology Simian Acquired Immunodeficiency Syndrome - therapy Simian Acquired Immunodeficiency Syndrome - virology Simian Immunodeficiency Virus - immunology Simian/human immunodeficiency virus Stem cells T-Lymphocyte Subsets - immunology T-Lymphocyte Subsets - radiation effects T-Lymphocyte Subsets - virology Transduction, Genetic Transgenes Transplantation Conditioning Transplants & implants Vectors (Biology) Viral Load |
| title | Lentivirus-mediated Gene Transfer in Hematopoietic Stem Cells Is Impaired in SHIV-infected, ART-treated Nonhuman Primates |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-18T20%3A58%3A14IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Lentivirus-mediated%20Gene%20Transfer%20in%20Hematopoietic%20Stem%20Cells%20Is%20Impaired%20in%20SHIV-infected,%20ART-treated%20Nonhuman%20Primates&rft.jtitle=Molecular%20therapy&rft.au=Younan,%20Patrick%20M&rft.date=2015-05-01&rft.volume=23&rft.issue=5&rft.spage=943&rft.epage=951&rft.pages=943-951&rft.issn=1525-0016&rft.eissn=1525-0024&rft_id=info:doi/10.1038/mt.2015.19&rft_dat=%3Cproquest_pubme%3E1680186531%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1791388928&rft_id=info:pmid/25648264&rft_els_id=S1525001616301186&rfr_iscdi=true |