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Article ; Online: Computational analysis of cas proteins unlocks new potential in HIV-1 targeted gene therapy.

Dampier, Will / Berman, Rachel / Nonnemacher, Michael R / Wigdahl, Brian

Frontiers in genome editing

2024 Volume 5, Page(s) 1248982

Abstract: Introduction: ...

Abstract	Introduction:
Language	English
Publishing date	2024-01-04
Publishing country	Switzerland
Document type	Journal Article
ISSN	2673-3439
ISSN (online)	2673-3439
DOI	10.3389/fgeed.2023.1248982
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Article ; Online: What's in a cure: designing a broad-spectrum HIV gene therapy.

Berman, Rachel E / Dampier, Will / Nonnemacher, Michael R / Wigdahl, Brian

Current opinion in HIV and AIDS

2024 Volume 19, Issue 3, Page(s) 150–156

Abstract: Purpose of review: The leading gene editing strategy for a human immunodeficiency virus type 1 (HIV-1) cure involves the delivery of SaCas9 and two guide RNAs (gRNAs) in an adeno-associated viral (AAV) vector. As a dual-component system, CRISPR is ... ...

Abstract	Purpose of review: The leading gene editing strategy for a human immunodeficiency virus type 1 (HIV-1) cure involves the delivery of SaCas9 and two guide RNAs (gRNAs) in an adeno-associated viral (AAV) vector. As a dual-component system, CRISPR is targeted to a genetic locus through the choice of a Cas effector and gRNA protospacer design pair. As CRISPR research has expanded in recent years, these components have been investigated for utilization in cure strategies, which will be discussed in this article. Recent findings: Type II SpCas9 and SaCas9 have been the leading Cas effectors across gene editing therapeutics to date. Additionally, extensive research has expanded the potential to multiplex gRNAs and target them effectively to the highly genetically diverse HIV-1 provirus. More recently, the Type V family of Cas12 effectors opens a new opportunity to use a smaller Cas protein for packaging into an AAV vector with multiplexed gRNAs. Summary: In understanding the individual components of a CRISPR/Cas therapeutic cure for HIV-1, it is important to know that the currently used strategies can be improved upon. Future areas will include alternative smaller Cas effectors, multiplexed gRNAs designs, and/or alternative delivery modalities.
MeSH term(s)	Humans ; CRISPR-Cas Systems ; RNA, Guide, CRISPR-Cas Systems ; HIV Infections ; Gene Editing ; HIV-1/genetics ; Genetic Therapy
Chemical Substances	RNA, Guide, CRISPR-Cas Systems
Language	English
Publishing date	2024-03-01
Publishing country	United States
Document type	Review ; Journal Article
ZDB-ID	2502511-9
ISSN	1746-6318 ; 1746-630X
ISSN (online)	1746-6318
ISSN	1746-630X
DOI	10.1097/COH.0000000000000846
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Article ; Online: Acute Administration of HIV-1 Tat Protein Drives Glutamatergic Alterations in a Rodent Model of HIV-Associated Neurocognitive Disorders.

Duffy, Brenna C / King, Kirsten M / Nepal, Binod / Nonnemacher, Michael R / Kortagere, Sandhya

Molecular neurobiology

2024

Abstract: HIV-1-associated neurocognitive disorders (HAND) are a major comorbidity of HIV-1 infection, marked by impairment of executive function varying in severity. HAND affects nearly half of people living with HIV (PLWH), with mild forms predominating since ... ...

Abstract	HIV-1-associated neurocognitive disorders (HAND) are a major comorbidity of HIV-1 infection, marked by impairment of executive function varying in severity. HAND affects nearly half of people living with HIV (PLWH), with mild forms predominating since the use of anti-retroviral therapies (ART). The HIV-1 transactivator of transcription (Tat) protein is found in the cerebrospinal fluid of patients adherent to ART, and its administration or expression in animals causes cognitive symptoms. Studies of Tat interaction with the N-methyl-D-aspartate receptor (NMDAR) suggest that glutamate toxicity contributes to Tat-induced impairments. To identify changes in regional glutamatergic circuitry underlying cognitive impairment, we injected recombinant Tat86 or saline to medial prefrontal cortex (mPFC) of male Sprague-Dawley rats. Rats were assessed with behavioral tasks that involve intact functioning of mPFC including the novel object recognition (NOR), spatial object recognition (SOR), and temporal order (TO) tasks at 1 and 2 postoperative weeks. Following testing, mPFC tissue was collected and analyzed by RT-PCR. Results showed Tat86 in mPFC-induced impairment in SOR, and upregulation of Grin1 and Grin2a transcripts. To further understand the mechanism of Tat toxicity, we assessed the effects of full-length Tat101 on gene expression in mPFC by RNA sequencing. The results of RNAseq suggest that glutamatergic effects of Tat86 are maintained with Tat101, as Grin2a was upregulated in Tat101-injected tissue, among other differentially expressed genes. Spatial learning and memory impairment and Grin2a upregulation suggest that exposure to Tat protein drives adaptation in mPFC, altering the function of circuitry supporting spatial learning and memory.
Language	English
Publishing date	2024-03-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	645020-9
ISSN	1559-1182 ; 0893-7648
ISSN (online)	1559-1182
ISSN	0893-7648
DOI	10.1007/s12035-024-04113-8
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Article ; Online: Roles of neuropathology-associated reactive astrocytes: a systematic review.

Lawrence, Jill M / Schardien, Kayla / Wigdahl, Brian / Nonnemacher, Michael R

Acta neuropathologica communications

2023 Volume 11, Issue 1, Page(s) 42

Abstract: In the contexts of aging, injury, or neuroinflammation, activated microglia signaling with TNF-α, IL-1α, and C1q induces a neurotoxic astrocytic phenotype, classified as A1, A1-like, or neuroinflammatory reactive astrocytes. In contrast to typical ... ...

Abstract	In the contexts of aging, injury, or neuroinflammation, activated microglia signaling with TNF-α, IL-1α, and C1q induces a neurotoxic astrocytic phenotype, classified as A1, A1-like, or neuroinflammatory reactive astrocytes. In contrast to typical astrocytes, which promote neuronal survival, support synapses, and maintain blood-brain barrier integrity, these reactive astrocytes downregulate supportive functions and begin to secrete neurotoxic factors, complement components like C3, and chemokines like CXCL10, which may facilitate recruitment of immune cells across the BBB into the CNS. The proportion of pro-inflammatory reactive astrocytes increases with age through associated microglia activation, and these pro-inflammatory reactive astrocytes are particularly abundant in neurodegenerative disorders. As the identification of astrocyte phenotypes progress, their molecular and cellular effects are characterized in a growing array of neuropathologies.
MeSH term(s)	Humans ; Astrocytes/metabolism ; Microglia/metabolism ; Central Nervous System/metabolism ; Blood-Brain Barrier/metabolism ; Chemokines/metabolism ; Neurotoxicity Syndromes/pathology
Chemical Substances	Chemokines
Language	English
Publishing date	2023-03-13
Publishing country	England
Document type	Systematic Review ; Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-023-01526-9
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Article: Extracellular HIV-1 Tat Mediates Increased Glutamate in the CNS Leading to Onset of Senescence and Progression of HAND.

Marino, Jamie / Wigdahl, Brian / Nonnemacher, Michael R

Frontiers in aging neuroscience

2020 Volume 12, Page(s) 168

Abstract: Human immunodeficiency virus type 1 (HIV-1)- associated neurocognitive disorders (HAND) is a disease of neurologic impairment that involves mechanisms of damage similar to other degenerative neurologic diseases such as Alzheimer's disease (AD). In the ... ...

Abstract	Human immunodeficiency virus type 1 (HIV-1)- associated neurocognitive disorders (HAND) is a disease of neurologic impairment that involves mechanisms of damage similar to other degenerative neurologic diseases such as Alzheimer's disease (AD). In the current era of antiretroviral therapy (ART), HIV-1 replication is well-suppressed, and yet, HIV-1-infected patients still have high levels of chronic inflammation, indicating that factors other than viral replication are contributing to the development of neurocognitive impairment in these patients. The underlying mechanisms of HAND are still unknown, but the HIV-1 protein, Tat, has been highlighted as a potential viral product that contributes to the development of cognitive impairment. In AD, the presence of senescent cells in the CNS has been discussed as a contributing factor to the progression of cognitive decline and may be a mechanism also involved in the development of HAND. This mini-review discusses the viral protein HIV-1 Tat, and its potential to induce senescence in the CNS, contributing to the development of HAND.
Language	English
Publishing date	2020-06-09
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2558898-9
ISSN	1663-4365
ISSN	1663-4365
DOI	10.3389/fnagi.2020.00168
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Article: Chronic Low Dose Morphine Does Not Alter Two In Vitro BBB Models.

Marino, Jamie / Maubert, Monique E / Lawrence, Jill M / Wigdahl, Brian / Nonnemacher, Michael R

Brain sciences

2022 Volume 12, Issue 7

Abstract: The blood-brain barrier (BBB) mediates cellular and molecular passage between the central nervous system (CNS) and peripheral circulation. Compromised BBB integrity has been linked to neurocognitive deficits in multiple diseases and various infections, ... ...

Abstract	The blood-brain barrier (BBB) mediates cellular and molecular passage between the central nervous system (CNS) and peripheral circulation. Compromised BBB integrity has been linked to neurocognitive deficits in multiple diseases and various infections, including those associated with HIV-1 infection. Understanding the impact of exposure to pharmaceuticals, such as those utilized for pain management by patients suffering from CNS disease, on BBB regulation and function is clinically important. In this study, we modelled two different BBB systems; a primary human co-culture and a cell line monoculture. These systems were both exposed to three daily repeat doses of morphine and examined for alterations to BBB integrity via permeability, PBMC transmigration, and chemokine gradient changes. We did not find any significant changes to either BBB system with repeat morphine dosing, suggesting that repeat morphine exposure may not play a significant role in BBB changes.
Language	English
Publishing date	2022-07-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2651993-8
ISSN	2076-3425
ISSN	2076-3425
DOI	10.3390/brainsci12070888
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Article: Immunomodulatory Effects of Non-Thermal Plasma in a Model for Latent HIV-1 Infection: Implications for an HIV-1-Specific Immunotherapy.

Mohamed, Hager / Berman, Rachel / Connors, Jennifer / Haddad, Elias K / Miller, Vandana / Nonnemacher, Michael R / Dampier, Will / Wigdahl, Brian / Krebs, Fred C

Biomedicines

2023 Volume 11, Issue 1

Abstract: In people living with HIV-1 (PLWH), antiretroviral therapy (ART) eventually becomes necessary to suppress the emergence of human immunodeficiency virus type 1 (HIV-1) replication from latent reservoirs because HIV-1-specific immune responses in PLWH are ... ...

Abstract	In people living with HIV-1 (PLWH), antiretroviral therapy (ART) eventually becomes necessary to suppress the emergence of human immunodeficiency virus type 1 (HIV-1) replication from latent reservoirs because HIV-1-specific immune responses in PLWH are suboptimal. Immunotherapies that enhance anti-HIV-1 immune responses for better control of virus reemergence from latent reservoirs are postulated to offer ART-free control of HIV-1. Toward the goal of developing an HIV-1-specific immunotherapy based on non-thermal plasma (NTP), the early immunological responses to NTP-exposed latently infected T lymphocytes were examined. Application of NTP to the J-Lat T-lymphocyte cell line (clones 10.6 and 15.4) stimulated monocyte recruitment and macrophage maturation, which are key steps in initiation of an immune response. In contrast, CD8+ T lymphocytes in a mixed lymphocyte reaction assay were not stimulated by the presence of NTP-exposed J-Lat cells. Furthermore, co-culture of NTP-exposed J-Lat cells with mature phagocytes did not modulate their antigen presentation to primary CD8+ T lymphocytes (cross-presentation). However, reactivation from latency was stimulated in a clone-specific manner by NTP. Overall, these studies, which demonstrated that ex vivo application of NTP to latently infected lymphocytes can stimulate key immune cell responses, advance the development of an NTP-based immunotherapy that will provide ART-free control of HIV-1 reactivation in PLWH.
Language	English
Publishing date	2023-01-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines11010122
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Article ; Online: HIV-1 cure strategies: why CRISPR?

Atkins, Andrew J / Allen, Alexander G / Dampier, Will / Haddad, Elias K / Nonnemacher, Michael R / Wigdahl, Brian

Expert opinion on biological therapy

2021 Volume 21, Issue 6, Page(s) 781–793

Abstract: Introduction: Antiretroviral therapy (ART) has transformed prognoses for HIV-1-infected individuals but requires lifelong adherence to prevent viral resurgence. Targeted elimination or permanent deactivation of the latently infected reservoir harboring ... ...

Abstract	Introduction: Antiretroviral therapy (ART) has transformed prognoses for HIV-1-infected individuals but requires lifelong adherence to prevent viral resurgence. Targeted elimination or permanent deactivation of the latently infected reservoir harboring integrated proviral DNA, which drives viral rebound, is a major focus of HIV-1 research. Areas covered: This review covers the current approaches to developing curative strategies for HIV-1 that target the latent reservoir. Discussed herein are shock and kill, broadly neutralizing antibodies (bNAbs), block and lock, Chimeric antigen receptor (CAR) T cells, immune checkpoint modulation, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) coreceptor ablation, and CRISPR/Cas9 proviral excision. Emphasis is placed on CRISPR/Cas9 proviral excision/inactivation. Recent advances and future directions toward discovery and translation of HIV-1 therapeutics are discussed. Expert opinion: CRISPR/Cas9 proviral targeting fills a niche amongst HIV-1 cure strategies by directly targeting the integrated provirus without the necessity of an innate or adaptive immune response. Each strategy discussed in this review has shown promising results with the potential to yield curative or adjuvant therapies. CRISPR/Cas9 is singular among these in that it addresses the root of the problem, integrated proviral DNA, with the capacity to permanently remove or deactivate the source of HIV-1 recrudescence.
MeSH term(s)	CRISPR-Cas Systems ; HIV Infections/drug therapy ; HIV-1/genetics ; Humans ; Proviruses ; Virus Activation
Language	English
Publishing date	2021-02-07
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2052501-1
ISSN	1744-7682 ; 1471-2598
ISSN (online)	1744-7682
ISSN	1471-2598
DOI	10.1080/14712598.2021.1865302
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Article ; Online: Targeting CCR5 as a Component of an HIV-1 Therapeutic Strategy.

Mohamed, Hager / Gurrola, Theodore / Berman, Rachel / Collins, Mackenzie / Sariyer, Ilker K / Nonnemacher, Michael R / Wigdahl, Brian

Frontiers in immunology

2022 Volume 12, Page(s) 816515

Abstract: Globally, human immunodeficiency virus type 1 (HIV-1) infection is a major health burden for which successful therapeutic options are still being investigated. Challenges facing current drugs that are part of the established life-long antiretroviral ... ...

Abstract	Globally, human immunodeficiency virus type 1 (HIV-1) infection is a major health burden for which successful therapeutic options are still being investigated. Challenges facing current drugs that are part of the established life-long antiretroviral therapy (ART) include toxicity, development of drug resistant HIV-1 strains, the cost of treatment, and the inability to eradicate the provirus from infected cells. For these reasons, novel anti-HIV-1 therapeutics that can prevent or eliminate disease progression including the onset of the acquired immunodeficiency syndrome (AIDS) are needed. While development of HIV-1 vaccination has also been challenging, recent advancements demonstrate that infection of HIV-1-susceptible cells can be prevented in individuals living with HIV-1, by targeting C-C chemokine receptor type 5 (CCR5). CCR5 serves many functions in the human immune response and is a co-receptor utilized by HIV-1 for entry into immune cells. Therapeutics targeting CCR5 generally involve gene editing techniques including CRISPR, CCR5 blockade using antibodies or antagonists, or combinations of both. Here we review the efficacy of these approaches and discuss the potential of their use in the clinic as novel ART-independent therapies for HIV-1 infection.
MeSH term(s)	Anti-HIV Agents/pharmacology ; Anti-HIV Agents/therapeutic use ; Biomarkers ; CCR5 Receptor Antagonists/pharmacology ; CCR5 Receptor Antagonists/therapeutic use ; Carrier Proteins ; Combined Modality Therapy ; Disease Management ; Disease Progression ; Disease Susceptibility ; Gene Expression Regulation ; HIV Infections/drug therapy ; HIV Infections/genetics ; HIV Infections/metabolism ; HIV Infections/virology ; HIV-1/drug effects ; HIV-1/physiology ; Humans ; Lymphocytes/drug effects ; Lymphocytes/immunology ; Lymphocytes/metabolism ; Macrophages/drug effects ; Macrophages/immunology ; Macrophages/metabolism ; Molecular Targeted Therapy ; Protein Binding ; Receptors, CCR5/chemistry ; Receptors, CCR5/genetics ; Receptors, CCR5/metabolism ; Signal Transduction ; Treatment Outcome
Chemical Substances	Anti-HIV Agents ; Biomarkers ; CCR5 Receptor Antagonists ; CCR5 protein, human ; Carrier Proteins ; Receptors, CCR5
Language	English
Publishing date	2022-01-20
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.816515
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Article ; Online: Prediction of Human Immunodeficiency Virus Type 1 Subtype-Specific Off-Target Effects Arising from CRISPR-Cas9 Gene Editing Therapy.

Link, Robert W / Nonnemacher, Michael R / Wigdahl, Brian / Dampier, Will

The CRISPR journal

2019 Volume 1, Page(s) 294–302

Abstract: Chronic human immunodeficiency virus type 1 (HIV-1) disease is characterized by the retention of provirus within latently infected cells. Anti-HIV-1 CRISPR-Cas9 gene editing is an attractive strategy to excise or inactivate the HIV-1 genome. Recent ... ...

Abstract	Chronic human immunodeficiency virus type 1 (HIV-1) disease is characterized by the retention of provirus within latently infected cells. Anti-HIV-1 CRISPR-Cas9 gene editing is an attractive strategy to excise or inactivate the HIV-1 genome. Recent strategies have focused on designing gRNAs that target the long terminal repeat (LTR) because 5' and 3' LTR symmetry can facilitate proviral excision. However, the promiscuity of CRISPR-Cas9 gene editing system necessitates the investigation of potential off-target effects. Here, potential gRNAs designed from HIV-1 phylogenetic subtypes using the CRISPRseek tool were investigated. Across the LTR, it was found that certain regions show higher human homology than others. When using recommended cutoffs, 96.40% of gRNAs were predicted to have no high probability off-target effects. Given this observation, while high-probability off-target effects are a potential danger, they can be avoided with proper gRNA design.
Language	English
Publishing date	2019-04-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	3017891-5
ISSN	2573-1602 ; 2573-1599
ISSN (online)	2573-1602
ISSN	2573-1599
DOI	10.1089/crispr.2018.0020
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