Human iPSC-derived brain organoids: A 3D mini-brain model for studying HIV infection

Wei, Zhengyu; Bodnar, Brittany; Zhao, Ruo-Tong; Xiao, Qian-Hao; Saribas, Sami; Wang, Xu; Ho, Wen‐Zhe; Hu, Wenhui

doi:10.1016/j.expneurol.2023.114386

Cited by 6 publications

(3 citation statements)

References 88 publications

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“…Some HIV-1 studies take advantage of brain organoids made of human CNS cells [53][54][55], but these systems fail to recapitulate the structure of the human brain and lack its cellular diversity [56]. Further, they require addition of microglia from an external source or derive microglia from induced pluripotent stem cells [57], which is an important caveat since microglia remain as HIV reservoirs in people taking antiretroviral therapies [58]. Other groups have studied postmortem brain tissues from people with HIV, and although these retrospective studies provided important insights, they have so far mostly examined tissues from people with AIDS or HIV encephalitis that are less relevant to the modern era [59].…”

Section: Discussionmentioning

confidence: 99%

Adult human brain tissue cultures to study neuroHIV

Van Duyne,

Irollo,

Lin

et al. 2024

Preprint

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HIV-associated neurocognitive disorders (HAND) persist under antiretroviral therapy as a complex pathology that has been difficult to study in cellular and animal models. Therefore, we generated an ex vivo human brain slice model of HIV-1 infection from surgically resected adult brain tissue. Brain slice cultures processed for flow cytometry showed >90% viability of dissoci-ated cells within the first three weeks in vitro, with parallel detection of astrocyte, myeloid, and neuronal populations. Neurons within brain slices showed stable dendritic spine density and mature spine morphologies in the first weeks in culture, and they generated detectable activity in multi-electrode arrays. We infected cultured brain slices using patient-matched CD4+ T-cells or monocyte-derived macrophages (MDMs) that were exposed to a GFP-expressing R5-tropic HIV-1 in vitro. Infected slice cultures expressed viral RNA and developed a spreading infection up to 9-days post-infection, which were significantly decreased by antiretrovirals. We also detected infected myeloid cells and astrocytes within slices and observed minimal effect on cellular via-bility over time. Overall, this human-centered model offers a promising resource to study the cel-lular mechanisms contributing to HAND (including antiretroviral toxicity, substance use, and aging), infection of resident brain cells, and new neuroprotective therapeutics.

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Section: Discussionmentioning

confidence: 99%

Adult human brain tissue cultures to study neuroHIV

Van Duyne,

Irollo,

Lin

et al. 2024

Preprint

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“…This way, patients can receive a specialized treatment option to fight against the virus present in their bodies. The development of 3D microglia-containing brain organoids to study HIV pathogenesis and CRISPR application in HIV eradication has been developed [ 253 ]. These 3D brain organoids represent valuable resources for studying HIV infection and latency and explore the effective delivery of the CRISPR/Cas editor for HIV eradication.…”

Section: Crispr/cas-based Gene Therapies and Therapeutic Applicationsmentioning

confidence: 99%

Precision in Action: The Role of Clustered Regularly Interspaced Short Palindromic Repeats/Cas in Gene Therapies

Banda,

Impomeni,

Singh

et al. 2024

Vaccines

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Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-associated enzyme-CAS holds great promise for treating many uncured human diseases and illnesses by precisely correcting harmful point mutations and disrupting disease-causing genes. The recent Food and Drug Association (FDA) approval of the first CRISPR-based gene therapy for sickle cell anemia marks the beginning of a new era in gene editing. However, delivering CRISPR specifically into diseased cells in vivo is a significant challenge and an area of intense research. The identification of new CRISPR/Cas variants, particularly ultra-compact CAS systems with robust gene editing activities, paves the way for the low-capacity delivery vectors to be used in gene therapies. CRISPR/Cas technology has evolved beyond editing DNA to cover a wide spectrum of functionalities, including RNA targeting, disease diagnosis, transcriptional/epigenetic regulation, chromatin imaging, high-throughput screening, and new disease modeling. CRISPR/Cas can be used to engineer B-cells to produce potent antibodies for more effective vaccines and enhance CAR T-cells for the more precise and efficient targeting of tumor cells. However, CRISPR/Cas technology has challenges, including off-target effects, toxicity, immune responses, and inadequate tissue-specific delivery. Overcoming these challenges necessitates the development of a more effective and specific CRISPR/Cas delivery system. This entails strategically utilizing specific gRNAs in conjunction with robust CRISPR/Cas variants to mitigate off-target effects. This review seeks to delve into the intricacies of the CRISPR/Cas mechanism, explore progress in gene therapies, evaluate gene delivery systems, highlight limitations, outline necessary precautions, and scrutinize the ethical considerations associated with its application.

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“…Recent advances in stem cell technologies have opened up new possibilities for modeling and studying HAND, particularly the development of human iPSC derived neurons, astrocytes, and microglia capable of mimicking complex in vivo neuroimmune interactions when grown in three dimensional cerebral organoid cultures (Abud et al 2017; Ormel et al 2018; Xu et al 2021). Cerebral organoids offer a powerful and physiologically relevant platform to study complex neuroimmune interactions, but traditional organoid differentiation protocols do not produce microglia [reviewed in(Dos Reis, Sant, and Ayyavoo 2023; Swingler et al 2023; Wei et al 2023)]. Recent studies have demonstrated the feasibility of infecting iPSC-derived macrophages (Vaughan-Jackson et al 2021) and microglia (Rai et al 2020) with HIV-1.…”

Section: Introductionmentioning

confidence: 99%

Dysregulated neuroimmune interactions and sustained type I interferon signaling after human immunodeficiency virus type 1 infection of human iPSC derived microglia and cerebral organoids

Boreland,

Stillitano,

Lin

et al. 2023

Preprint

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Human immunodeficiency virus type-1 (HIV-1) associated neurocognitive disorder (HAND) affects up to half of HIV-1 positive patients with long term neurological consequences, including dementia. There are no effective therapeutics for HAND because the pathophysiology of HIV-1 induced glial and neuronal functional deficits in humans remains enigmatic. To bridge this knowledge gap, we established a model simulating HIV-1 infection in the central nervous system using human induced pluripotent stem cell (iPSC) derived microglia combined with sliced neocortical organoids. Upon incubation with two replication-competent macrophage-tropic HIV-1 strains (JRFL and YU2), we observed that microglia not only became productively infected but also exhibited inflammatory activation. RNA sequencing revealed a significant and sustained activation of type I interferon signaling pathways. Incorporating microglia into sliced neocortical organoids extended the effects of aberrant type I interferon signaling in a human neural context. Collectively, our results illuminate the role of persistent type I interferon signaling in HIV-1 infected microglial in a human neural model, suggesting its potential significance in the pathogenesis of HAND.

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Human iPSC-derived brain organoids: A 3D mini-brain model for studying HIV infection

Cited by 6 publications

References 88 publications

Adult human brain tissue cultures to study neuroHIV

Adult human brain tissue cultures to study neuroHIV

Precision in Action: The Role of Clustered Regularly Interspaced Short Palindromic Repeats/Cas in Gene Therapies

Dysregulated neuroimmune interactions and sustained type I interferon signaling after human immunodeficiency virus type 1 infection of human iPSC derived microglia and cerebral organoids

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