Engineering HIV-resistant human CD4+ T cells with CXCR4-specific zinc-finger nucleases.
HIV-1 entry requires the cell surface expression of CD4 and either the CCR5 or CXCR4 coreceptors on host cells. Individuals homozygous for the ccr5Δ32 polymorphism do not express CCR5 and are protected from infection by CCR5-tropic (R5) virus strains. As an approach to inactivating CCR5, we introduc...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Public Library of Science (PLoS)
2011
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/186f7779921b432492a6f9af1a25f58c |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:186f7779921b432492a6f9af1a25f58c |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:186f7779921b432492a6f9af1a25f58c2021-11-18T06:03:27ZEngineering HIV-resistant human CD4+ T cells with CXCR4-specific zinc-finger nucleases.1553-73661553-737410.1371/journal.ppat.1002020https://doaj.org/article/186f7779921b432492a6f9af1a25f58c2011-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21533216/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374HIV-1 entry requires the cell surface expression of CD4 and either the CCR5 or CXCR4 coreceptors on host cells. Individuals homozygous for the ccr5Δ32 polymorphism do not express CCR5 and are protected from infection by CCR5-tropic (R5) virus strains. As an approach to inactivating CCR5, we introduced CCR5-specific zinc-finger nucleases into human CD4+ T cells prior to adoptive transfer, but the need to protect cells from virus strains that use CXCR4 (X4) in place of or in addition to CCR5 (R5X4) remains. Here we describe engineering a pair of zinc finger nucleases that, when introduced into human T cells, efficiently disrupt cxcr4 by cleavage and error-prone non-homologous DNA end-joining. The resulting cells proliferated normally and were resistant to infection by X4-tropic HIV-1 strains. CXCR4 could also be inactivated in ccr5Δ32 CD4+ T cells, and we show that such cells were resistant to all strains of HIV-1 tested. Loss of CXCR4 also provided protection from X4 HIV-1 in a humanized mouse model, though this protection was lost over time due to the emergence of R5-tropic viral mutants. These data suggest that CXCR4-specific ZFNs may prove useful in establishing resistance to CXCR4-tropic HIV for autologous transplant in HIV-infected individuals.Craig B WilenJianbin WangJohn C TiltonJeffrey C MillerKenneth A KimEdward J RebarScott A Sherrill-MixSean C PatroAnthony J SecretoAndrea P O JordanGary LeeJoshua KahnPyone P AyeBruce A BunnellAndrew A LacknerJames A HoxieGwenn A Danet-DesnoyersFrederic D BushmanJames L RileyPhilip D GregoryCarl H JuneMichael C HolmesRobert W DomsPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 7, Iss 4, p e1002020 (2011) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Craig B Wilen Jianbin Wang John C Tilton Jeffrey C Miller Kenneth A Kim Edward J Rebar Scott A Sherrill-Mix Sean C Patro Anthony J Secreto Andrea P O Jordan Gary Lee Joshua Kahn Pyone P Aye Bruce A Bunnell Andrew A Lackner James A Hoxie Gwenn A Danet-Desnoyers Frederic D Bushman James L Riley Philip D Gregory Carl H June Michael C Holmes Robert W Doms Engineering HIV-resistant human CD4+ T cells with CXCR4-specific zinc-finger nucleases. |
| description |
HIV-1 entry requires the cell surface expression of CD4 and either the CCR5 or CXCR4 coreceptors on host cells. Individuals homozygous for the ccr5Δ32 polymorphism do not express CCR5 and are protected from infection by CCR5-tropic (R5) virus strains. As an approach to inactivating CCR5, we introduced CCR5-specific zinc-finger nucleases into human CD4+ T cells prior to adoptive transfer, but the need to protect cells from virus strains that use CXCR4 (X4) in place of or in addition to CCR5 (R5X4) remains. Here we describe engineering a pair of zinc finger nucleases that, when introduced into human T cells, efficiently disrupt cxcr4 by cleavage and error-prone non-homologous DNA end-joining. The resulting cells proliferated normally and were resistant to infection by X4-tropic HIV-1 strains. CXCR4 could also be inactivated in ccr5Δ32 CD4+ T cells, and we show that such cells were resistant to all strains of HIV-1 tested. Loss of CXCR4 also provided protection from X4 HIV-1 in a humanized mouse model, though this protection was lost over time due to the emergence of R5-tropic viral mutants. These data suggest that CXCR4-specific ZFNs may prove useful in establishing resistance to CXCR4-tropic HIV for autologous transplant in HIV-infected individuals. |
| format |
article |
| author |
Craig B Wilen Jianbin Wang John C Tilton Jeffrey C Miller Kenneth A Kim Edward J Rebar Scott A Sherrill-Mix Sean C Patro Anthony J Secreto Andrea P O Jordan Gary Lee Joshua Kahn Pyone P Aye Bruce A Bunnell Andrew A Lackner James A Hoxie Gwenn A Danet-Desnoyers Frederic D Bushman James L Riley Philip D Gregory Carl H June Michael C Holmes Robert W Doms |
| author_facet |
Craig B Wilen Jianbin Wang John C Tilton Jeffrey C Miller Kenneth A Kim Edward J Rebar Scott A Sherrill-Mix Sean C Patro Anthony J Secreto Andrea P O Jordan Gary Lee Joshua Kahn Pyone P Aye Bruce A Bunnell Andrew A Lackner James A Hoxie Gwenn A Danet-Desnoyers Frederic D Bushman James L Riley Philip D Gregory Carl H June Michael C Holmes Robert W Doms |
| author_sort |
Craig B Wilen |
| title |
Engineering HIV-resistant human CD4+ T cells with CXCR4-specific zinc-finger nucleases. |
| title_short |
Engineering HIV-resistant human CD4+ T cells with CXCR4-specific zinc-finger nucleases. |
| title_full |
Engineering HIV-resistant human CD4+ T cells with CXCR4-specific zinc-finger nucleases. |
| title_fullStr |
Engineering HIV-resistant human CD4+ T cells with CXCR4-specific zinc-finger nucleases. |
| title_full_unstemmed |
Engineering HIV-resistant human CD4+ T cells with CXCR4-specific zinc-finger nucleases. |
| title_sort |
engineering hiv-resistant human cd4+ t cells with cxcr4-specific zinc-finger nucleases. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2011 |
| url |
https://doaj.org/article/186f7779921b432492a6f9af1a25f58c |
| work_keys_str_mv |
AT craigbwilen engineeringhivresistanthumancd4tcellswithcxcr4specificzincfingernucleases AT jianbinwang engineeringhivresistanthumancd4tcellswithcxcr4specificzincfingernucleases AT johnctilton engineeringhivresistanthumancd4tcellswithcxcr4specificzincfingernucleases AT jeffreycmiller engineeringhivresistanthumancd4tcellswithcxcr4specificzincfingernucleases AT kennethakim engineeringhivresistanthumancd4tcellswithcxcr4specificzincfingernucleases AT edwardjrebar engineeringhivresistanthumancd4tcellswithcxcr4specificzincfingernucleases AT scottasherrillmix engineeringhivresistanthumancd4tcellswithcxcr4specificzincfingernucleases AT seancpatro engineeringhivresistanthumancd4tcellswithcxcr4specificzincfingernucleases AT anthonyjsecreto engineeringhivresistanthumancd4tcellswithcxcr4specificzincfingernucleases AT andreapojordan engineeringhivresistanthumancd4tcellswithcxcr4specificzincfingernucleases AT garylee engineeringhivresistanthumancd4tcellswithcxcr4specificzincfingernucleases AT joshuakahn engineeringhivresistanthumancd4tcellswithcxcr4specificzincfingernucleases AT pyonepaye engineeringhivresistanthumancd4tcellswithcxcr4specificzincfingernucleases AT bruceabunnell engineeringhivresistanthumancd4tcellswithcxcr4specificzincfingernucleases AT andrewalackner engineeringhivresistanthumancd4tcellswithcxcr4specificzincfingernucleases AT jamesahoxie engineeringhivresistanthumancd4tcellswithcxcr4specificzincfingernucleases AT gwennadanetdesnoyers engineeringhivresistanthumancd4tcellswithcxcr4specificzincfingernucleases AT fredericdbushman engineeringhivresistanthumancd4tcellswithcxcr4specificzincfingernucleases AT jameslriley engineeringhivresistanthumancd4tcellswithcxcr4specificzincfingernucleases AT philipdgregory engineeringhivresistanthumancd4tcellswithcxcr4specificzincfingernucleases AT carlhjune engineeringhivresistanthumancd4tcellswithcxcr4specificzincfingernucleases AT michaelcholmes engineeringhivresistanthumancd4tcellswithcxcr4specificzincfingernucleases AT robertwdoms engineeringhivresistanthumancd4tcellswithcxcr4specificzincfingernucleases |
| _version_ |
1718424650768187392 |