TGF-β Signaling Supports HIV Latency in a Memory CD4+ T Cell Based In Vitro Model

Bergstresser, Sydney; Kulpa, Deanna A.

doi:10.1007/978-1-0716-1871-4_6

Cited by 9 publications

(9 citation statements)

References 46 publications

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“…Importantly, TGF-β inhibits TCR-induced T cell proliferation, CD28-mediated co-stimulation, and activation of T cells (47)(48)(49). Indeed, it has recently been used to promote latency in ex vivo models with primary polarized effector CD4 + T cells (50)(51)(52). Moreover, TGF-β was shown to induce latency in other cell types susceptible to HIV infection (53).…”

Section: Introductionmentioning

confidence: 99%

Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responsesin vivo

Samer

Thomas

Araínga

et al. 2022

Preprint

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Elevated levels of TGF-β, a potent immunosuppressive factor, are present in HIV-1 infected individuals even after years of antiretroviral therapy (ART). TGF-β plays a critical role in maintaining immune cells in a resting state by inhibiting cell activation and proliferation. Resting HIV-1 target cells represent one of the main cellular reservoirs after long term ART and the low inducibility of the latent provirus constitutes one of the major obstacles to “kick and kill” cure strategies. We hypothesized that releasing cells from TGF-β-driven signaling would promote latency reversal. To test our hypothesis, we compared ex vivo models of HIV-1 latency reactivation with and without TGF-β and a TGF-β type 1 receptor (TGFBR1) inhibitor, galunisertib. We also tested the effect of galunisertib in SIV infected, ART treated macaques by monitoring SIV envelope (env) protein expression via PET/CT using the Cu64-anti gp120 Fab (7D3) probe, along with plasma and tissue viral loads (VL). Exogenous TGF-1β reduced HIV-1 reactivation in U1 and ACH2 latency models. Galunisertib increased HIV-1 latency reversal both in ex vivo models and in PBMC from HIV-1 infected, cART treated aviremic donors. In vivo, oral galunisertib promoted increased SIV env protein total standardized uptake values (SUVtot) in PET/CT images of tissues (gut and lymph nodes) of 5 out of 7 aviremic, long-term ART-treated, SIV-infected, macaques. This increase correlated with an increase in SIV RNA in gut tissue. Two out of 7 animals also exhibited increases in plasma viral load. Higher anti-SIV T cell responses and anti-SIV env antibody titers were detected after galunisertib treatment in most animals. In summary, our data suggest that blocking TGF-β signaling simultaneously increases retroviral reactivation events and enhances anti-SIV immune responses.

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Section: Introductionmentioning

confidence: 99%

Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responsesin vivo

Samer

Thomas

Araínga

et al. 2022

Preprint

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“…In line with the promotion of HIV-1 latency, our transcriptional profile analysis showed that cellular pathways necessary for HIV-1 transcription and reactivation, such as NF-B and STAT (41,42,44), are downregulated by the TBassociated microenvironment. In addition, the TGF-SMAD pathway, reported to support HIV-1 latency (48,49), was upregulated. Importantly, a decrease in T cell activation, OXPHOS and glycolysis has also been associated with the establishment of HIV-1 latency (47,(74)(75)(76), supporting our hypothesis.…”

Section: Discussionmentioning

confidence: 99%

“…The NF-B and type I/II IFN pathways were also downmodulated by TB-PE in non-activated CD4+ T cells (Supplementary Figure 1). Furthermore, we observed upregulation of pathways associated with transforming growth factor beta (TGF)-SMAD response, which is known to support HIV-1 latency (47)(48)(49), in the cells exposed to TB-PE (Figure 4 A-B). Of note, regulation of the ERK cascade signaling did not show consistent modulation patterns (Figure 4A).…”

Section: Cellular Pathways Involved In Hiv-1 Latency Are Modulated By...mentioning

confidence: 94%

The immunosuppressive Tuberculosis-associated microenvironment inhibits viral replication and promotes HIV-1 latency in CD4+ T cells

Cronin,

de Vries-Egan,

Vahlas

et al. 2023

Preprint

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Author SummaryMycobacterium tuberculosis(Mtb), the causative agent of tuberculosis (TB), is the most common coinfection among people living with HIV-1. This coinfection alters the efficacy of the immune response against both HIV-1 andMtb, and is associated with accelerated HIV-1 disease progression and reduced survival. Enhanced HIV-1 replication in macrophages induced byMtbcoinfection may contribute to the worsened clinical outcomes observed in HIV-1/TB coinfected individuals. However, the impact of the HIV-1/TB coinfection on HIV-1 replication and latency in CD4+ T cells remains poorly studied.In this study, we used the acellular fraction of tuberculous pleural effusion (TB-PE) as a proxy for the microenvironment generated byMtbinfection. Using this physiologically relevant fluid, we investigated whether viral replication and HIV-1 latency in CD4+ T cells are affected by a TB-associated microenvironment. Interestingly, our results revealed that TB-PE shaped the transcriptional profile of CD4+ T cells impairing T cell receptor-dependent cell activation and decreased HIV-1 replication. Moreover, this immunosuppressive TB microenvironment promoted viral latency and inhibited HIV-1 reactivation in CD4+ T cells from people living with HIV-1. This study indicates that the immune response induced by TB may contribute to the persistence of the viral reservoir by silencing HIV-1 expression in individuals coinfected with both pathogens, allowing the virus to persist undetected by the immune system and increasing the size of the HIV-1 latent reservoir in cells at the site of the coinfection.

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“…Similar to the profile observed in cells from healthy individuals, CD101 + CD4 T cells expressed significantly more LAP (TGF-β) as compared to CD101cells, while producing similar levels of other effector cytokines (Fig 3K). This is particularly interesting, as TGF-β levels are known to be significantly elevated after HIV infection and remain elevated during suppressive ART and TGF-β has been demonstrated to play a role in potentiating T cell latency [52][53][54][55][56].…”

Section: Plos Pathogensmentioning

confidence: 99%

“…Second, CD101 + CD4 T cells, due to their highly functional regulatory potential, likely create an immunosuppressive environment that prevents HIV expression and CD8-mediated clearance of infected cells. The enriched production of LAP (TGFβ) by CD101 + CD4 T cells compared to CD101-cells in samples from PWH is likely to promote latency of these cells, as recent work has highlighted the important role of TGFβ in promoting reservoir persistence [53][54][55][56]74,75]. Additionally, the observation that CD101 + Tregs have higher expression of LGALS3 is particularly interesting in the context of previous findings that galectin-3 participates in N-glycan branching on CD8 T cells during chronic infection that increases the antigenic threshold for CD8 T cell activation and function [38].…”

Section: Plos Pathogensmentioning

confidence: 99%

The role of CD101-expressing CD4 T cells in HIV/SIV pathogenesis and persistence

Strongin

Hoang²,

Tharp³

et al. 2022

PLoS Pathog

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Despite the advent of effective antiretroviral therapy (ART), human immunodeficiency virus (HIV) continues to pose major challenges, with extensive pathogenesis during acute and chronic infection prior to ART initiation and continued persistence in a reservoir of infected CD4 T cells during long-term ART. CD101 has recently been characterized to play an important role in CD4 Treg potency. Using the simian immunodeficiency virus (SIV) model of HIV infection in rhesus macaques, we characterized the role and kinetics of CD101+ CD4 T cells in longitudinal SIV infection. Phenotypic analyses and single-cell RNAseq profiling revealed that CD101 marked CD4 Tregs with high immunosuppressive potential, distinct from CD101- Tregs, and these cells also were ideal target cells for HIV/SIV infection, with higher expression of CCR5 and α4β7 in the gut mucosa. Notably, during acute SIV infection, CD101+ CD4 T cells were preferentially depleted across all CD4 subsets when compared with their CD101- counterpart, with a pronounced reduction within the Treg compartment, as well as significant depletion in mucosal tissue. Depletion of CD101+ CD4 was associated with increased viral burden in plasma and gut and elevated levels of inflammatory cytokines. While restored during long-term ART, the reconstituted CD101+ CD4 T cells display a phenotypic profile with high expression of inhibitory receptors (including PD-1 and CTLA-4), immunsuppressive cytokine production, and high levels of Ki-67, consistent with potential for homeostatic proliferation. Both the depletion of CD101+ cells and phenotypic profile of these cells found in the SIV model were confirmed in people with HIV on ART. Overall, these data suggest an important role for CD101-expressing CD4 T cells at all stages of HIV/SIV infection and a potential rationale for targeting CD101 to limit HIV pathogenesis and persistence, particularly at mucosal sites.

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TGF-β Signaling Supports HIV Latency in a Memory CD4+ T Cell Based In Vitro Model

Cited by 9 publications

References 46 publications

Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responsesin vivo

Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responsesin vivo

The immunosuppressive Tuberculosis-associated microenvironment inhibits viral replication and promotes HIV-1 latency in CD4+ T cells

The role of CD101-expressing CD4 T cells in HIV/SIV pathogenesis and persistence

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