The Role of the BCL-2 Family of Proteins in HIV-1 Pathogenesis and Persistence

Chandrasekar, Aswath P.; Cummins, Nathan W.; Badley, Andrew D.

doi:10.1128/cmr.00107-19

Cited by 42 publications

(36 citation statements)

References 181 publications

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“…Since the ICD strategy does not depend on other components of the host immune system such as CD8+ T cells or NK cells, this system can be used to measure pro-apoptotic compounds that have previously been studied to selectively eliminate HIV-1-expressing cells. Some examples of compounds that can be tested include Bcl2 agonists such as venetoclax 69, 70 ; SMAC mimetics like birinipant, GDC-0152, and embelin 71 ; Benzolactam derivatives such as BL-V8-310 65 ; p38/JNK pathways activator anisomycin 18 , specific autophagy-inducing peptides Tat-Beclin 1 and Tat-vFLIP-α2 72 ; PI3K/Akt inhibitors 73 ; or synthesized compounds such as L-HIPPO that inhibit viral trafficking and budding of Gag 74 that have all been implicated in killing of HIV-1 infected cells. Pharmacological inhibition of BIRC5, also one of the genes downregulated by DDX3 expression, has been demonstrated to target HIV-1-infected cells and reduce the frequency of proviral containing cells in vitro 54 .…”

Section: Discussionmentioning

confidence: 99%

Induction of selective cell death in HIV-1-infected cells by DDX3 inhibitors leads to depletion of the inducible reservoir

Rao

Lungu

Steijaert

et al. 2020

Preprint

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An innovative approach to eliminate HIV-1-infected cells emerging out of latency, the major hurdle to HIV-1 cure, is to pharmacologically reactivate viral expression and concomitantly trigger intracellular pro-apoptotic pathways in order to selectively induce cell death (ICD) of infected cells, without reliance on the extracellular immune system. In this work we demonstrate the effect of DEAD-box polypeptide 3, X-Linked (DDX3) inhibitors on selectively inducing cell death in latent HIV-1-infected cell lines, primary CD4+ T cells and in CD4+ T cells from cART-suppressed people living with HIV-1 (PLWHIV). We used single-cell FISH-Flow technology to characterise the contribution of viral RNA to inducing cell death; pharmacological targeting of DDX3 reversed HIV-1 latency and selectively induced apoptosis in viral RNA-expressing CD4+ T cells from PLWHIV but not bystander cells. DDX3 inhibitor treatment of CD4+ T cells from PLWHIV in an in vitro culture model over five days resulted in an approximately 30% reduction of the inducible latent HIV-1 reservoir as determined by quantitation of CA HIV-1 RNA, by TILDA, as well as by FISH-Flow technology. RNA sequencing analysis revealed that while overall gene expression was minimally dysregulated, treatment of independent donor CD4+ T cells with DDX3 inhibitors led to significant downregulation of BIRC5 and HSPB1A, genes critical to cell survival during HIV-1 infection, providing mechanism for the observed selective cell death. Our data support the translation of DDX3 inhibitor class compounds into HIV-1 curative strategies and provide proof of concept for pharmacological reversal of latency coupled to induction of apoptosis towards elimination of the inducible reservoir.

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Section: Discussionmentioning

confidence: 99%

Induction of selective cell death in HIV-1-infected cells by DDX3 inhibitors leads to depletion of the inducible reservoir

Rao

Lungu

Steijaert

et al. 2020

Preprint

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“…We speculate that these anergic B-cells eventually undergo apoptosis and lead to the maintenance of viremia. Interestingly, previous studies have shown that up-regulated of programmed cell death protein 1 (PD-1) or down-regulated of anti apoptotic molecule Bcl-2 in immature B-cells in the peripheral blood of HIV patients finally made B-cells prone to apoptosis by endogenous apoptotic pathway [44,45], which was the important pathological process of immune tolerance induced by HIV-1.Therefore, we hypothesized that ALV-J, as a chronic stimulant antigen, activated the negative regulation role of Lyn in B-cell signal transduction.…”

Section: Discussionmentioning

confidence: 99%

Lyn inhibited BCR signal pathway mediates B-cell anergy induced by avian leukosis virus subgroup J

Zheng

Yang

et al. 2020

Preprint

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Background: Immune tolerance induced by retrovirus is a prerequisite for tumorigeness. We had reported that B-cell anergy was the main reason for immune tolerance induced by avian leukosis virus subgroup J (ALV-J). However, the molecular mechanism remains unclear. Results: Initially, we found that Lyn showed down-regulation in chick embryo fibroblasts (CEF) and up-regulation in B-cells infected by ALV-J. So, we speculated that tyrosine kinase Lyn plays a key role in B-cell anergy induced by ALV-J. Confocal laser scanning microscopy (CLSM) and co-immunoprecipitation (Co-IP) results demonstrated that ALV-J indirectly regulated the expression of Lyn. To further investigate the role and regulatory mechanism of Lyn in B-cell anergy induced by ALV-J, the expression levels of Lyn and Syk at different phosphorylation site, the Ca 2+ mobilization, and the expression levels of NF-κB p65 protein in vitro and vivo were detected in B-cells. The result showed that Ca 2+ mobilization was delayed and p65 expression level was decreased in B-cells after ALV-J infection. Consistently, the retrieve of Ca 2+ mobilization, expression levels of NF-κB p65 were found after RNA interference of Lyn. Subsequently, we demonstrated that the activation of phosphorylated Lyn protein at Tyr507 site played a critical role in B-cells anergy, which were verified by the fact of the significantly up-regulation of the expression levels of phosphorylated Syk protein at Tyr525/526 site when RNA interference for Lyn were performed in B-cells. Furthermore, immunohistochemical (IHC) staining results confirmed that the expression levels of Lyn phosphorylated protein at Tyr507 site in bursal cells were increased, while the expression levels of Syk phosphorylated protein at Tyr525/526 sites were decreased. Conclusions: These findings suggested that Lyn inhibited BCR signal pathway mediates B-cell anergy under ALV-J infection，which will provide a new insight for revealing the molecular mechanism of immune tolerance induced by ALV-J. Keywords: avian leukosis virus subgroup J , B-cell anergy, immune tolerance, Lyn, Syk

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“…Thus, these signaling components can promote latent cell survival and HIV reservoir establishment. Interactions between HIV-1 and the Bcl-2 protein family, as well as possible therapeutics, have been reviewed elsewhere [ 156 ]. A detailed investigation of these pro- and anti-apoptotic proteins in latency establishment and maintenance is essential to develop novel reversal approaches [ 63 ].…”

Section: Hiv Latency and Potential Agents For Reversalmentioning

confidence: 99%

HIV-1 Latency and Viral Reservoirs: Existing Reversal Approaches and Potential Technologies, Targets, and Pathways Involved in HIV Latency Studies

Khanal

Schank

Gazzar

et al. 2021

Cells

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Eradication of latent human immunodeficiency virus (HIV) infection is a global health challenge. Reactivation of HIV latency and killing of virus-infected cells, the so-called “kick and kill” or “shock and kill” approaches, are a popular strategy for HIV cure. While antiretroviral therapy (ART) halts HIV replication by targeting multiple steps in the HIV life cycle, including viral entry, integration, replication, and production, it cannot get rid of the occult provirus incorporated into the host-cell genome. These latent proviruses are replication-competent and can rebound in cases of ART interruption or cessation. In general, a very small population of cells harbor provirus, serve as reservoirs in ART-controlled HIV subjects, and are capable of expressing little to no HIV RNA or proteins. Beyond the canonical resting memory CD4+ T cells, HIV reservoirs also exist within tissue macrophages, myeloid cells, brain microglial cells, gut epithelial cells, and hematopoietic stem cells (HSCs). Despite a lack of active viral production, latently HIV-infected subjects continue to exhibit aberrant cellular signaling and metabolic dysfunction, leading to minor to major cellular and systemic complications or comorbidities. These include genomic DNA damage; telomere attrition; mitochondrial dysfunction; premature aging; and lymphocytic, cardiac, renal, hepatic, or pulmonary dysfunctions. Therefore, the arcane machineries involved in HIV latency and its reversal warrant further studies to identify the cryptic mechanisms of HIV reservoir formation and clearance. In this review, we discuss several molecules and signaling pathways, some of which have dual roles in maintaining or reversing HIV latency and reservoirs, and describe some evolving strategies and possible approaches to eliminate viral reservoirs and, ultimately, cure/eradicate HIV infection.

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The Role of the BCL-2 Family of Proteins in HIV-1 Pathogenesis and Persistence

Cited by 42 publications

References 181 publications

Induction of selective cell death in HIV-1-infected cells by DDX3 inhibitors leads to depletion of the inducible reservoir

Induction of selective cell death in HIV-1-infected cells by DDX3 inhibitors leads to depletion of the inducible reservoir

Lyn inhibited BCR signal pathway mediates B-cell anergy induced by avian leukosis virus subgroup J

HIV-1 Latency and Viral Reservoirs: Existing Reversal Approaches and Potential Technologies, Targets, and Pathways Involved in HIV Latency Studies

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