Shift of HIV Tropism in Stem-Cell Transplantation with <i>CCR5</i> Delta32 Mutation

Kordelas, Lambros; Verheyen, Jens; Eßer, Stefan

doi:10.1056/nejmc1405805

Cited by 151 publications

(117 citation statements)

References 3 publications

Supporting

Mentioning

116

Contrasting

Order By: Relevance

“…While the driving force and molecular mechanism of coreceptor switch remain elusive, antiretroviral treatments with CCR5 antagonists tend to select for R5X4 or X4-tropic variants (Fätkenheuer et al, 2008;Moncunill et al, 2008;Mosier, 2009). A recent study has reported that a shift from R5-tropic to X4-tropic HIV-1 variants occurred in a patient following transplantation of stem cells with the CCR5 D32 mutation (Kordelas et al, 2014), further highlighting the importance of coreceptor switch or adaptation in gene therapy targeting CCR5. Nevertheless, by delivery of CRISPR/Cas9 with two sgRNAs simultaneously targeting CCR5 and CXCR4, or CCR5 and viral genes essential for HIV-1 infection, it is theoretically applicable in preventing coreceptor adaptation and virus infection more effectively.…”

Section: Ccr5 Editing By Adenovirus-delivered Crispr/cas9mentioning

confidence: 99%

Inhibition of HIV-1 infection of primary CD4+ T-cells by gene editing of CCR5 using adenovirus-delivered CRISPR/Cas9

Guan

et al. 2015

Journal of General Virology

189

139

View full text Add to dashboard Cite

CCR5 serves as an essential coreceptor for human immunodeficiency virus type 1 (HIV-1) entry, and individuals with a CCR5 D32 variant appear to be healthy, making CCR5 an attractive target for control of HIV-1 infection. The CRISPR/Cas9, which functions as a naturally existing adaptive immune system in prokaryotes, has been recently harnessed as a novel nuclease system for genome editing in mammalian cells. Although CRISPR/Cas9 can be readily delivered into cell lines, due to the large size of the Cas9 protein, efficient delivery of CCR5-targeting CRISPR/Cas9 components into primary cells, including CD4 + T-cells, the primary target for HIV-1 infection in vivo, remains a challenge. In the current study, following design of a panel of top-ranked single-guided RNAs (sgRNAs) targeting the ORF of CCR5, we demonstrate that CRISPR/Cas9 can efficiently mediate the editing of the CCR5 locus in cell lines, resulting in the knockout of CCR5 expression on the cell surface. Next-generation sequencing revealed that various mutations were introduced around the predicted cleavage site of CCR5. For each of the three most effective sgRNAs that we analysed, no significant off-target effects were detected at the 15 top-scoring potential sites. More importantly, by constructing chimeric Ad5F35 adenoviruses carrying CRISPR/Cas9 components, we efficiently transduced primary CD4 + Tlymphocytes and disrupted CCR5 expression, and the positively transduced cells were conferred with HIV-1 resistance. To our knowledge, this is the first study establishing HIV-1 resistance in primary CD4 + T-cells utilizing adenovirus-delivered CRISPR/Cas9.

show abstract

Section: Ccr5 Editing By Adenovirus-delivered Crispr/cas9mentioning

confidence: 99%

Inhibition of HIV-1 infection of primary CD4+ T-cells by gene editing of CCR5 using adenovirus-delivered CRISPR/Cas9

Guan

et al. 2015

Journal of General Virology

189

139

View full text Add to dashboard Cite

show abstract

“…This potential need to maintain the natural function of the receptor is one reason that we may wish to have inducible gene expression of the MTA so as to allow restoration of the receptor in certain clinical situations. Also, in some cases, chronically infected patients who received CCR5 Δ32 stem cell transplants suffered virus outbreak because of selection in vivo of CXCR4-tropic viruses (13). Again, this need for the receptor is why we may wish to use more than one MTA, particularly inclusive of an antibody against CXCR4 that allows retention of its critical physiological function.…”

Section: Discussionmentioning

confidence: 99%

Immunochemical engineering of cell surfaces to generate virus resistance

Xie

Sok

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Modern immunochemical engineering allows the creation of cells that either secrete antibodies or incorporate them into various cellular compartments, including the plasma membrane. Because the receptors for most viruses are known, if one can achieve the proper stoichiometry and geometry, plasma membrane-associated antibodies to these receptors should block viral infection. In this report, we test this concept for two different viruses, human rhinovirus and HIV. Plasma membrane-tethered antibodies efficiently rendered cells permanently nonpermissive for infection by both these viruses. Membrane-bound antibodies were much more efficient than free antibody in preventing infection, likely because of the effective molarity of membrane bound antibodies. Such resistant cells may restore immune-competence to otherwise compromised HIV patients.

show abstract

“…Unfortunately, the virus rebounded after transplantation as the type of HIV-1 changed into CXCR4 tropic. The inducement of the virus variation were not explicit, but it suggested the importance of CXCR4 mutant in HIV resistance [9]. Anyway, it has provided reference for a promising therapeutics to disrupt CCR5 or/and CXCR4 gene of healthy cells, then to transfuse them back to patients.…”

Section: From "Berlin Patients" To the Therapy Within Gene Editingmentioning

confidence: 99%

“…In the above curing process, there are periods that patients should always yield to the treatment of HAART [9] When they are under severe side effects of HAART, the method of restricting the replication of HIV-1 by CRISPR can be considered to share responsibility for the drug therapy. The construction of AAV containing split dCas9-SAM (or VP64)-sgRNAs can activate the expression of restriction factors.…”

Section: A Comprehensive Vista: Molecular Cocktailmentioning

confidence: 99%

“…The strategy of "shock and kill" in vivo also depends on efficient transporting system and the strategy may be harmful to the patients with an exactly opposite effect. Furthermore, in the therapy process, the time of stopping HAART can influence the result of therapy totally in view of the sharp contrast between "Berlin patient" and the "Essen Patient" [9], which should be considered seriously. Finally, the ethical problems are also unneglectable.…”

Section: The Challenges and Opportunitiesmentioning

confidence: 99%

See 1 more Smart Citation

CRISPRs encounter Cocktail: a dawn for curing HIV/AIDS

Li¹,

Zhang²,

Feng³

et al. 2017

Virol Res Rev

View full text Add to dashboard Cite

a These authors contributed equally to this work. AbstractThe acquired immunodeficiency syndrome (AIDS) patients can scarcely be cured completely because of the Human Immunodeficiency Virus (HIV) provirus existence post-infection in body, though cocktail of the highly active antiretroviral therapy (HAART) has achieved great effects on controlling and decreasing HIV clinically. Recently, the genome editing strategies are developing by leaps and bounds. Among three generation of technologies, the clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated protein 9 (Cas9) is a newborn to former zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) but grows fast into the most popular at present, because of its advantages in less time-and cost-consuming. Eradicating HIV by disrupting the viral co-receptor C-C chemokine receptor type five (CCR5) or C-X-C chemokine receptor type four (CXCR4) gene, excising the provirus segments integrated into human genome, or activating/inactivating the replication of the virus genome by using these technologies are several current strategies to reach the goal of AIDS prevention and treatment. It seems hard, however, to arrive the keen anticipation exactly by using them respectively. After a comprehensive literature review, it concluded that the combination of those interventions, as together co-receptor with provirus genome interference as a cocktail edition, may lead us to an eventual cure for the horrible disease.

show abstract

Shift of HIV Tropism in Stem-Cell Transplantation with CCR5 Delta32 Mutation

Cited by 151 publications

References 3 publications

Inhibition of HIV-1 infection of primary CD4+ T-cells by gene editing of CCR5 using adenovirus-delivered CRISPR/Cas9

Inhibition of HIV-1 infection of primary CD4+ T-cells by gene editing of CCR5 using adenovirus-delivered CRISPR/Cas9

Immunochemical engineering of cell surfaces to generate virus resistance

CRISPRs encounter Cocktail: a dawn for curing HIV/AIDS

Contact Info

Product

Resources

About