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| Status |
Public on Feb 24, 2022 |
| Title |
Pharmacological modulation of the Wnt/β-catenin pathway inhibits the proliferation of long-lived latently-infected memory CD4+ T-cells in ART-suppressed SIV-infected macaques |
| Organism |
Macaca mulatta |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The major obstacle to human immunodeficiency type 1 (HIV-1) eradication is a reservoir of latently-infected cells that persists despite long-term antiretroviral therapy (ART) and is maintained through cellular proliferation. Long-lived memory CD4+ T-cells with high self-renewal capacity such as central memory T-cells (CM) and T memory stem cells (SCM) are major contributors to the viral reservoir in HIV-infected individuals on ART. The Wnt/β-catenin signaling pathway regulates the balance between self-renewal and differentiation of SCM and CM T-cells and pharmacological manipulation of this pathway offers an opportunity to interfere with the proliferation of latently-infected cells. Here, we evaluated in vivo a novel approach to inhibit self-renewal of SCM and CM CD4+ T-cells in the rhesus macaque (RM) model of SIV infection. We used an inhibitor of the Wnt/β-catenin pathway, PRI-724, that blocks the interaction between the co-activator CREB binding protein (CBP) and β-catenin, resulting in the cell fate decision to differentiate rather than proliferate. Our study shows that PRI-724 treatment of ART-suppressed SIVmac251-infected RMs: (i) was well tolerated, with blood counts, liver enzymes, and renal function within normal limits and no alteration of tri-lineage hematopoiesis observed in bone marrow, (ii) resulted in decreased proliferation of SCM and CM T-cells, (iii) modified the SCM and CM CD4+ T-cell transcriptome towards a profile of more differentiated memory T-cells, and (iv) reduced SIV-DNA levels in CM and TFH CD4+ T-cells in the lymph nodes, but did not decrease the overall viral reservoir size. This work is the first demonstration in vivo that pharmacological modulation can effectively target T cell stemness in long-lived memory CD4+ T-cells, and represents a potential strategy to reduce HIV persistence.
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| Overall design |
Examination of CD4+ T-cell subsets under treatment with PRI-724, 8 macaques were treated and 4 were untreated as controls.
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| Contributor(s) |
Mavingner M, Zanoni M, Tharp GK, Habib J, Mattingly CR, Kouji H, Lawson BO, Vanderford TH, Silvestri G, Bosinger SE, Chahroudi A |
| Citation(s) |
31619550 |
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| Submission date |
Feb 27, 2019 |
| Last update date |
Feb 24, 2022 |
| Contact name |
Gregory K Tharp |
| E-mail(s) |
gktharp@emory.edu
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| Phone |
404-727-7797
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| Organization name |
Yerkes National Primate Research Center
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| Department |
Developmental and Cognitive Neuroscience
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| Lab |
Genomics Core
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| Street address |
954 Gatewood Dr
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| City |
Atlanta |
| State/province |
GA |
| ZIP/Postal code |
30329-4208 |
| Country |
USA |
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| Platforms (1) |
| GPL23804 |
Illumina HiSeq 3000 (Macaca mulatta) |
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| Samples (47)
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| Relations |
| BioProject |
PRJNA524692 |
| SRA |
SRP187057 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE127330_373_Maud_D1_DESeq2_NormCounts.txt.gz |
4.6 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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