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Article ; Online: Current strategies to induce selective killing of HIV-1-infected cells.

Campbell, Grant R / Spector, Stephen A

2022 Volume 112, Issue 5, Page(s) 1273–1284

Abstract: Although combination antiretroviral therapy (ART) has led to significant HIV-1 suppression and improvement in immune function, persistent viral reservoirs remain that are refractory to intensified ART. ART poses many challenges such as adherence to drug ... ...

Abstract	Although combination antiretroviral therapy (ART) has led to significant HIV-1 suppression and improvement in immune function, persistent viral reservoirs remain that are refractory to intensified ART. ART poses many challenges such as adherence to drug regimens, the emergence of resistant virus, and cumulative toxicity resulting from long-term therapy. Moreover, latent HIV-1 reservoir cells can be stochastically activated to produce viral particles despite effective ART and contribute to the rapid viral rebound that typically occurs within 2 weeks of ART interruption; thus, lifelong ART is required for continued viral suppression. Several strategies have been proposed to address the HIV-1 reservoir such as reactivation of HIV-1 transcription using latency reactivating agents with a combination of ART, host immune clearance and HIV-1-cytotoxicity to purge the infected cells-a "shock and kill" strategy. However, these approaches do not take into account the multiple transcriptional and translational blocks that contribute to HIV-1 latency or the complex heterogeneity of the HIV-1 reservoir, and clinical trials have thus far failed to produce the desired results. Here, we describe alternative strategies being pursued that are designed to kill selectively HIV-1-infected cells while sparing uninfected cells in the absence of enhanced humoral or adaptive immune responses.
MeSH term(s)	Humans ; HIV-1 ; Virus Latency ; HIV Infections ; CD4-Positive T-Lymphocytes ; Virus Replication
Language	English
Publishing date	2022-06-16
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	605722-6
ISSN	1938-3673 ; 0741-5400
ISSN (online)	1938-3673
ISSN	0741-5400
DOI	10.1002/JLB.4MR0422-636R
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Article ; Online: Induction of Autophagy to Achieve a Human Immunodeficiency Virus Type 1 Cure.

Campbell, Grant R / Spector, Stephen A

Cells

2021 Volume 10, Issue 7

Abstract: Effective antiretroviral therapy has led to significant human immunodeficiency virus type 1 (HIV-1) suppression and improvement in immune function. However, the persistence of integrated proviral DNA in latently infected reservoir cells, which drive ... ...

Abstract	Effective antiretroviral therapy has led to significant human immunodeficiency virus type 1 (HIV-1) suppression and improvement in immune function. However, the persistence of integrated proviral DNA in latently infected reservoir cells, which drive viral rebound post-interruption of antiretroviral therapy, remains the major roadblock to a cure. Therefore, the targeted elimination or permanent silencing of this latently infected reservoir is a major focus of HIV-1 research. The most studied approach in the development of a cure is the activation of HIV-1 expression to expose latently infected cells for immune clearance while inducing HIV-1 cytotoxicity-the "kick and kill" approach. However, the complex and highly heterogeneous nature of the latent reservoir, combined with the failure of clinical trials to reduce the reservoir size casts doubt on the feasibility of this approach. This concern that total elimination of HIV-1 from the body may not be possible has led to increased emphasis on a "functional cure" where the virus remains but is unable to reactivate which presents the challenge of permanently silencing transcription of HIV-1 for prolonged drug-free remission-a "block and lock" approach. In this review, we discuss the interaction of HIV-1 and autophagy, and the exploitation of autophagy to kill selectively HIV-1 latently infected cells as part of a cure strategy. The cure strategy proposed has the advantage of significantly decreasing the size of the HIV-1 reservoir that can contribute to a functional cure and when optimised has the potential to eradicate completely HIV-1.
MeSH term(s)	Antiretroviral Therapy, Highly Active/methods ; Autophagy/physiology ; DNA/metabolism ; HIV-1/drug effects ; HIV-1/pathogenicity ; Humans ; Infections/drug therapy
Chemical Substances	DNA (9007-49-2)
Language	English
Publishing date	2021-07-16
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells10071798
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Article ; Online: Impact of Genetic Variants in ABCG2 , NR1I2 , and UGT1A1 on the Pharmacokinetics of Dolutegravir in Children.

Spector, Stephen A / Brummel, Sean S / Chang, Audrey / Wiznia, Andrew / Ruel, Theodore D / Acosta, Edward P

Journal of acquired immune deficiency syndromes (1999)

2024 Volume 95, Issue 3, Page(s) 297–303

Abstract: Background: Dolutegravir plasma concentrations and pharmacokinetic (PK) parameters in children display considerable variability. Here, the impact of genetic variants in ABCG2 421C>A (rs2231142), NR1I2 63396 C>T (rs2472677), and UGT1A1 (rs5839491) on ... ...

Abstract	Background: Dolutegravir plasma concentrations and pharmacokinetic (PK) parameters in children display considerable variability. Here, the impact of genetic variants in ABCG2 421C>A (rs2231142), NR1I2 63396 C>T (rs2472677), and UGT1A1 (rs5839491) on dolutegravir PK was examined. Methods: Children defined by age and administered dolutegravir formulation had AUC 24 at steady state, C max and C 24h determined. Associations between genetic variants and PK parameters were assessed using the dominant inheritance model. Results: The 59 children studied had a median age of 4.6 years, log 10 plasma HIV RNA of 4.79 (copies/mm 3 ), and CD4 + lymphocyte count of 1041 cells/mm 3 51% were female. For ABCG2 , participants with ≥1 minor allele had lower adjusted mean AUC difference (hrmg/L) controlling for weight at entry, cohort and sex (-15.7, 95% CI: [-32.0 to 0.6], P = 0.06), and log 10 C max adjusted mean difference (-0.15, 95% CI: [-0.25 to -0.05], P = 0.003). Participants with ≥1 minor allele had higher adjusted mean AUC difference (11.9, 95% CI: [-1.1 to 25.0], P = 0.07). For UGT1A1 , poor metabolizers had nonsignificant higher concentrations (adjusted log 10 C max mean difference 11.8; 95% CI: [-12.3 to 36.0], P = 0.34) and lower mean log 10 adjusted oral clearance -0.13 L/h (95% CI: [-0.3 to 0.06], P = 0.16). No association was identified between time-averaged AUC differences by genotype for adverse events, plasma HIV RNA, or CD4 + cell counts. Conclusions:* Dolutegravir AUC 24 for genetic variants in ABCG2 , NR1l2 , and UGT1A1 varied from -25% to +33%. These findings help to explain some of the variable pharmacokinetics identified with dolutegravir in children.
MeSH term(s)	Child ; Humans ; Female ; Child, Preschool ; Male ; Pregnane X Receptor/genetics ; HIV Infections/drug therapy ; HIV Infections/genetics ; Genotype ; Heterocyclic Compounds, 3-Ring ; Pyridones ; RNA ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics ; Neoplasm Proteins/genetics ; Oxazines ; Piperazines
Chemical Substances	dolutegravir (DKO1W9H7M1) ; Pregnane X Receptor ; Heterocyclic Compounds, 3-Ring ; Pyridones ; RNA (63231-63-0) ; ABCG2 protein, human ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Neoplasm Proteins ; Oxazines ; Piperazines
Language	English
Publishing date	2024-01-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	645053-2
ISSN	1944-7884 ; 1077-9450 ; 0897-5965 ; 0894-9255 ; 1525-4135
ISSN (online)	1944-7884 ; 1077-9450
ISSN	0897-5965 ; 0894-9255 ; 1525-4135
DOI	10.1097/QAI.0000000000003358
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Article ; Online: IRAK1 inhibition blocks the HIV-1 RNA mediated pro-inflammatory cytokine response from microglia.

Campbell, Grant R / Rawat, Pratima / Teodorof-Diedrich, Carmen / Spector, Stephen A

The Journal of general virology

2023 Volume 104, Issue 5

Abstract: Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) are a common source of morbidity in people living with HIV (PLWH). Although antiretroviral therapy (ART) has lessened the severity of neurocognitive disorders, cognitive ... ...

Abstract	Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) are a common source of morbidity in people living with HIV (PLWH). Although antiretroviral therapy (ART) has lessened the severity of neurocognitive disorders, cognitive impairment still occurs in PLWH receiving ART. The pathogenesis of HAND is likely multifaceted, but common factors include the persistence of HIV transcription within the central nervous system, higher levels of pro-inflammatory cytokines in the cerebrospinal fluid, and the presence of activated microglia. Toll-like receptor (TLR) 7 and TLR8 are innate pathogen recognition receptors located in microglia and other immune and non-immune cells that can recognise HIV RNA and trigger pro-inflammatory responses. IL-1 receptor-associated kinase (IRAK) 1 is key to these signalling pathways. Here, we show that IRAK1 inhibition inhibits the TLR7 and TLR8-dependent pro-inflammatory response to HIV RNA. Using genetic and pharmacological inhibition, we demonstrate that inhibition of IRAK1 prevents IRAK1 phosphorylation and ubiquitination, and the subsequent recruitment of TRAF6 and the TAK1 complex to IRAK1, resulting in the inhibition of downstream signalling and the suppression of pro-inflammatory cytokine and chemokine release.
MeSH term(s)	Humans ; Cytokines/genetics ; Interleukin-1 Receptor-Associated Kinases/genetics ; Interleukin-1 Receptor-Associated Kinases/metabolism ; HIV-1/genetics ; Microglia ; Toll-Like Receptor 8 ; RNA ; HIV Infections
Chemical Substances	Cytokines ; Interleukin-1 Receptor-Associated Kinases (EC 2.7.11.1) ; Toll-Like Receptor 8 ; RNA (63231-63-0) ; IRAK1 protein, human (EC 2.7.11.1)
Language	English
Publishing date	2023-05-31
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	219316-4
ISSN	1465-2099 ; 0022-1317
ISSN (online)	1465-2099
ISSN	0022-1317
DOI	10.1099/jgv.0.001858
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Zs.A 610: Show issues

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Article ; Online: HIV-1 Tat Upregulates TREM1 Expression in Human Microglia.

Campbell, Grant R / Rawat, Pratima / To, Rachel K / Spector, Stephen A

Journal of immunology (Baltimore, Md. : 1950)

2023 Volume 211, Issue 3, Page(s) 429–442

Abstract: Because microglia are a reservoir for HIV and are resistant to the cytopathic effects of HIV infection, they are a roadblock for any HIV cure strategy. We have previously identified that triggering receptor expressed on myeloid cells 1 (TREM1) plays a ... ...

Abstract	Because microglia are a reservoir for HIV and are resistant to the cytopathic effects of HIV infection, they are a roadblock for any HIV cure strategy. We have previously identified that triggering receptor expressed on myeloid cells 1 (TREM1) plays a key role in human macrophage resistance to HIV-mediated cytopathogenesis. In this article, we show that HIV-infected human microglia express increased levels of TREM1 and are resistant to HIV-induced apoptosis. Moreover, upon genetic inhibition of TREM1, HIV-infected microglia undergo cell death in the absence of increased viral or proinflammatory cytokine expression or the targeting of uninfected cells. We also show that the expression of TREM1 is mediated by HIV Tat through a TLR4, TICAM1, PG-endoperoxide synthase 2, PGE synthase, and PGE2-dependent manner. These findings highlight the potential of TREM1 as a therapeutic target to eradicate HIV-infected microglia without inducing a proinflammatory response.
MeSH term(s)	Humans ; Triggering Receptor Expressed on Myeloid Cells-1 ; Microglia/metabolism ; HIV-1/physiology ; HIV Infections/pathology ; Macrophages/metabolism
Chemical Substances	Triggering Receptor Expressed on Myeloid Cells-1 ; TREM1 protein, human
Language	English
Publishing date	2023-06-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2300152
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Ud II Zs.37: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MG 28: Show issues

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Article ; Online: Pacritinib Inhibition of IRAK1 Blocks Aberrant TLR8 Signalling by SARS-CoV-2 and HIV-1-Derived RNA.

Campbell, Grant R / Rawat, Pratima / Spector, Stephen A

Journal of innate immunity

2022 Volume 15, Issue 1, Page(s) 96–106

Abstract: Macrophages promote an early host response to infection by releasing pro-inflammatory cytokines such as interleukin (IL) 1β (IL-1β), tumour necrosis factor (TNF), and IL-6. One of the mechanisms through which cells sense pathogenic microorganisms is ... ...

Abstract	Macrophages promote an early host response to infection by releasing pro-inflammatory cytokines such as interleukin (IL) 1β (IL-1β), tumour necrosis factor (TNF), and IL-6. One of the mechanisms through which cells sense pathogenic microorganisms is through Toll-like receptors (TLRs). IL-1 receptor-associated kinase (IRAK) 1, IRAK2, IRAK3, and IRAK4 are integral to TLR and IL-1 receptor signalling pathways. Recent studies suggest a role for aberrant TLR8 and NLRP3 inflammasome activation during both COVID-19 and HIV-1 infection. Here, we show that pacritinib inhibits the TLR8-dependent pro-inflammatory cytokine response elicited by GU-rich single-stranded RNA derived from SARS-CoV-2 and HIV-1. Using genetic and pharmacologic inhibition, we demonstrate that pacritinib inhibits IRAK1 phosphorylation and ubiquitination which then inhibits the recruitment of the TAK1 complex to IRAK1, thus inhibiting the activation of downstream signalling and the production of pro-inflammatory cytokines.
MeSH term(s)	Humans ; Interleukin-1 Receptor-Associated Kinases/genetics ; Interleukin-1 Receptor-Associated Kinases/metabolism ; Toll-Like Receptor 8 ; SARS-CoV-2/genetics ; SARS-CoV-2/metabolism ; HIV-1/genetics ; COVID-19 ; Cytokines ; RNA
Chemical Substances	Interleukin-1 Receptor-Associated Kinases (EC 2.7.11.1) ; Toll-Like Receptor 8 ; 11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene ; Cytokines ; RNA (63231-63-0) ; TLR8 protein, human ; IRAK1 protein, human (EC 2.7.11.1)
Language	English
Publishing date	2022-07-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2454158-8
ISSN	1662-8128 ; 1662-811X
ISSN (online)	1662-8128
ISSN	1662-811X
DOI	10.1159/000525292
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Zs.A 6727: Show issues

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Book: Ganciclovir therapy for cytomegalovirus infection

Spector, Stephen A.

1991

Author's details	ed. by Stephen A. Spector
Keywords	Ganciclovir / therapeutic use ; Cytomegalovirus Infections / drug therapy ; Cytomegalie ; Gancidovir ; Ganciclovir ; Cytomegalie-Virus ; Infektion
Subject	HCMV ; Humanes Cytomegalievirus ; Zytomegalie-Virus ; CMV ; Cytomegalovirus ; Ansteckung ; Erstinfektion ; Infektionen ; Wyatt-Syndrom ; Zytomegalie-Syndrom ; Cytomegalie-Virus-Infektion ; Speicheldrüsenviruskrankheit ; Einschlusskörperchenkrankheit ; Inclusion body disease ; IBD ; Cytomegalievirus-Infektion ; CMV-Infektion
Size	VIII, 246 S. : Ill., graph. Darst.
Edition	1. print.
Publisher	Dekker
Publishing place	New York u.a.
Publishing country	United States
Document type	Book
HBZ-ID	HT003901346
ISBN	0-8247-8572-X ; 978-0-8247-8572-7
Database	Catalogue ZB MED Medicine, Health

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Article ; Online: DIABLO/SMAC mimetics selectively kill HIV-1-infected resting memory CD4

Campbell, Grant R / Spector, Stephen A

Autophagy

2019 Volume 15, Issue 4, Page(s) 744–746

Abstract: Despite advances in HIV therapy, there is no cure, and lifelong antiretroviral treatment is required to suppress viral replication. We hypothesized that HIV maintains the survival of latently infected ... ...

Abstract	Despite advances in HIV therapy, there is no cure, and lifelong antiretroviral treatment is required to suppress viral replication. We hypothesized that HIV maintains the survival of latently infected CD4
MeSH term(s)	Apoptosis ; Apoptosis Regulatory Proteins ; Autophagy ; CD4-Positive T-Lymphocytes ; HIV Infections ; HIV-1 ; Humans ; Intracellular Signaling Peptides and Proteins ; Mitochondrial Proteins ; T-Lymphocytes ; Virus Latency
Chemical Substances	Apoptosis Regulatory Proteins ; DIABLO protein, human ; Intracellular Signaling Peptides and Proteins ; Mitochondrial Proteins
Language	English
Publishing date	2019-01-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.1080/15548627.2019.1569950
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Zs.A 6741: Show issues

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Article ; Online: Human Immunodeficiency Virus Type 1 and Methamphetamine-Mediated Mitochondrial Damage and Neuronal Degeneration in Human Neurons.

Teodorof-Diedrich, Carmen / Spector, Stephen A

Journal of virology

2020 Volume 94, Issue 20

Abstract: Methamphetamine, a potent psychostimulant, is a highly addictive drug commonly used by persons living with HIV (PLWH), and its use can result in cognitive impairment and memory deficits long after its use is discontinued. Although the mechanism(s) ... ...

Abstract	Methamphetamine, a potent psychostimulant, is a highly addictive drug commonly used by persons living with HIV (PLWH), and its use can result in cognitive impairment and memory deficits long after its use is discontinued. Although the mechanism(s) involved with persistent neurological deficits is not fully known, mitochondrial dysfunction is a key component in methamphetamine neuropathology. Specific mitochondrial autophagy (mitophagy) and mitochondrial fusion and fission are protective quality control mechanisms that can be dysregulated in HIV infection, and the use of methamphetamine can further negatively affect these protective cellular mechanisms. Here, we observed that treatment of human primary neurons (HPNs) with methamphetamine and HIV gp120 and Tat increase dynamin-related protein 1 (DRP1)-dependent mitochondrial fragmentation and neuronal degeneration. Methamphetamine and HIV proteins increased microtubule-associated protein 1 light chain 3 beta-II (LC3B-II) lipidation and induced sequestosome 1 (SQSTM1, p62) translocation to damaged mitochondria. Additionally, the combination inhibited autophagic flux, increased reactive oxygen species (ROS) production and mitochondrial damage, and reduced microtubule-associated protein 2 (MAP2) dendrites in human neurons.
MeSH term(s)	Cells, Cultured ; Dynamins/genetics ; Dynamins/metabolism ; HIV Envelope Protein gp120/genetics ; HIV Envelope Protein gp120/metabolism ; HIV Infections/genetics ; HIV Infections/metabolism ; HIV Infections/pathology ; HIV-1/genetics ; HIV-1/metabolism ; Humans ; Methamphetamine/adverse effects ; Methamphetamine/pharmacology ; Microtubule-Associated Proteins/genetics ; Microtubule-Associated Proteins/metabolism ; Mitochondria/genetics ; Mitochondria/metabolism ; Mitochondria/pathology ; Neurodegenerative Diseases/chemically induced ; Neurodegenerative Diseases/genetics ; Neurodegenerative Diseases/metabolism ; Neurodegenerative Diseases/virology ; Neurons/metabolism ; Neurons/pathology ; Neurons/virology ; Sequestosome-1 Protein/genetics ; Sequestosome-1 Protein/metabolism ; tat Gene Products, Human Immunodeficiency Virus/genetics ; tat Gene Products, Human Immunodeficiency Virus/metabolism
Chemical Substances	HIV Envelope Protein gp120 ; MAP1LC3B protein, human ; Microtubule-Associated Proteins ; SQSTM1 protein, human ; Sequestosome-1 Protein ; gp120 protein, Human immunodeficiency virus 1 ; tat Gene Products, Human Immunodeficiency Virus ; Methamphetamine (44RAL3456C) ; DNM1L protein, human (EC 3.6.5.5) ; Dynamins (EC 3.6.5.5)
Language	English
Publishing date	2020-09-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.00924-20
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Zs.A 609: Show issues

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Article ; Online: SARS-CoV-2, SARS-CoV-1, and HIV-1 derived ssRNA sequences activate the NLRP3 inflammasome in human macrophages through a non-classical pathway.

Campbell, Grant R / To, Rachel K / Hanna, Jonathan / Spector, Stephen A

iScience

2021 Volume 24, Issue 4, Page(s) 102295

Abstract: Macrophages promote an early host response to infection by releasing pro-inflammatory cytokines such as interleukin-1β (IL-1β), TNF, and IL-6. The bioactivity of IL-1β is classically dependent on NLRP3 inflammasome activation, which culminates in caspase- ...

Abstract	Macrophages promote an early host response to infection by releasing pro-inflammatory cytokines such as interleukin-1β (IL-1β), TNF, and IL-6. The bioactivity of IL-1β is classically dependent on NLRP3 inflammasome activation, which culminates in caspase-1 activation and pyroptosis. Recent studies suggest a role for NLRP3 inflammasome activation in lung inflammation and fibrosis in both COVID-19 and SARS, and there is evidence of NLRP3 involvement in HIV-1 disease. Here, we show that GU-rich single-stranded RNA (GU-rich RNA) derived from SARS-CoV-2, SARS-CoV-1, and HIV-1 trigger a TLR8-dependent pro-inflammatory cytokine response from human macrophages in the absence of pyroptosis, with GU-rich RNA from the SARS-CoV-2 spike protein triggering the greatest inflammatory response. Using genetic and pharmacological inhibition, we show that the induction of mature IL-1β is through a non-classical pathway dependent on caspase-1, caspase-8, the NLRP3 inflammasome, potassium efflux, and autophagy while being independent of TRIF (TICAM1), vitamin D3, and pyroptosis.
Language	English
Publishing date	2021-03-09
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2021.102295
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