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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

ABSTRACT: 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.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE127330 | GEO | 2022/02/24

REPOSITORIES: GEO

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Project description:HIV-1 infection of resting memory CD4+ T cells forms a barrier to curing HIV-1. Identification of immune biomarkers that correlate with HIV-1 reservoir size could aid with assessing efficacy of HIV-1 eradication strategies, especially in pediatric infections where blood sampling is limited. In adults, the immune exhaustion marker PD-1 on central memory CD4+ T cells (Tcm) correlates with HIV-1 reservoir size. Immune correlates of HIV-1 reservoir size are less defined in perinatal infection. Using multi-parameter flow cytometry, we examined immune activation (CD69, CD25, HLA-DR), and exhaustion (PD-1, TIGIT, LAG-3 and TIM-3) markers on CD4+ T cell subsets (naïve (Tn), central memory (Tcm), and a combination (Ttem) of transitional (Ttm) and effector memory (Tem) in 10 children living with HIV-1 (median age 15.9 years; median duration of virologic suppression 7.0 years), in whom HIV-1 reservoir size was determined with both the Intact Proviral HIV-1 DNA assay (IPDA) and the Tat/Rev limiting dilution assay (TILDA). Total HIV-1 DNA in CD4+ T cells was also measured. Correlations between immune activation, and exhaustion markers on T cell subsets with the various markers of proviral reservoir size, and baseline CD4+ T cell transcriptomes were examined. The median total HIV-1 DNA concentration was 211.9 copies per million CD4+ T cells, with a median intact proviral load in individuals with HIV-1 subtype B of 8.0 copies per million CD4+ T cells. Levels of HLA-DR and TIGIT on Ttem were strongly correlated with total HIV-1 DNA (r=0.758, p=0.015) and (r=0.721, p=0.023), respectively, but not with intact proviral load or inducible reservoir size. HIV-1 DNA load was also positively correlated with transcriptional clusters associated with HLA-DR. In contrast, PD-1 expression on Tcm was inversely correlated with both total HIV-1 DNA (r=-0.67, p=0.039) and HLA-DR in Ttem (r=-0.89, p=0.060). Gene expression profiles for HLA-DR and PD-1 were also inversely correlated. In conclusion, with virologically suppressed perinatal HIV-1 infection, HLA-DR and TIGIT on Ttem CD4+ T cells correlate with total HIV-1 DNA, and may serve as immune biomarkers for transcriptionally active proviruses, including defectives persisting on ART.

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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

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