Chloroquine mediated molecular tuning of astrocytes for enhanced permissiveness to HIV infection

Vijaykumar, Theophilus S.; Nath, Avindra; Chauhan, Ankur

doi:10.1016/j.virol.2008.07.039

Cited by 43 publications

(118 citation statements)

References 14 publications

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“…HIV enters astrocytes in a nonclassical way, either via endocytosis and escape of HIV from the endosome (27,30,42), utilization of alternative receptors for HIV entry including the promiscuous CC chemokine receptor D6 (28), or a decreased requirement of neurotropic HIV strains for CD4 (16). Despite lack of a clear understanding of how HIV enters astrocytes, a number of groups of investigators have demonstrated the presence of HIV protein and/or DNA within astrocytes in HIV-positive (HIV ϩ ) postmortem tissue (11,15,29,40,41,44).…”

Section: Discussionmentioning

confidence: 99%

Role of β-Catenin and TCF/LEF Family Members in Transcriptional Activity of HIV in Astrocytes

Narasipura

Henderson

et al. 2012

J Virol

101

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The Wnt/␤-catenin pathway is involved in diverse cell functions governing development and disease. ␤-Catenin, a central mediator of this pathway, binds to members of the TCF/LEF family of transcription factors to modulate hundreds of genes. Active Wnt/␤-catenin/TCF-4 signaling plays a significant role in repression of HIV-1 replication in multiple cell targets, including astrocytes. To determine the mechanism by which active ␤-catenin/TCF-4 leads to inhibition of HIV replication, we knocked down ␤-catenin or TCF/LEF members in primary astrocytes and astrocytomas transiently transfected with an HIV long terminal repeat (LTR)-luciferase reporter that contained an integrated copy of the HIV LTR-luciferase construct. Knockdown of either ␤-catenin or TCF-4 induced LTR activity by 2-to 3-fold under both the episomal and integrated conditions. This knockdown also increased presence of serine 2-phosphorylated RNA polymerase II (Pol II) on the HIV LTR as well as enhanced its processivity. Knockdown of ␤-catenin/TCF-4 also impacted tethering of other transcription factors on the HIV promoter. Specifically, knockdown of TCF-4 enhanced binding of C/EBP␤, C/EBP␦, and NF-B to the HIV LTR, while ␤-catenin knockdown increased binding of C/EBP␤ and C/EBP␦ but had no effect on NF-B. Approximately 150 genes in astrocytes were impacted by ␤-catenin knockdown, including genes involved in inflammation/immunity, uptake/transport, vesicular transport/exocytosis, apoptosis/ cellular stress, and cytoskeleton/trafficking. These findings indicate that modulation of the ␤-catenin/TCF-4 axis impacts the basal level of HIV transcription in astrocytes, which may drive low level/persistent HIV in astrocytes that can contribute to ongoing neuroinflammation, and this axis also has profound effects on astrocyte biology.

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Section: Discussionmentioning

confidence: 99%

Role of β-Catenin and TCF/LEF Family Members in Transcriptional Activity of HIV in Astrocytes

Narasipura

Henderson

et al. 2012

J Virol

101

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“…Conceivably, blockade of TLR7/TLR8 signaling may limit induction of host antiviral defenses such as those mediated by type 1 interferons. Alternatively, the effect on plasma viremia could have been the result of a direct enhancement of infectivity by chloroquine, a finding in some in vitro studies, 38,39 while others have shown chloroquine to inhibit HIV replication. 40,41 Other researchers have assessed the effects of chloroquine or hydroxychloroquine, a related compound, on immune activation in HIV-infected participants.…”

Section: Figmentioning

confidence: 99%

The Effect of Chloroquine on Immune Activation and Interferon Signatures Associated with HIV-1

Jacobson

Bosinger

Kang

et al. 2016

AIDS Research and Human Retroviruses

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Immune activation associated with HIV-1 infection contributes to morbidity and mortality. We studied whether chloroquine, through Toll-like receptor (TLR) antagonist properties, could reduce immune activation thought to be driven by TLR ligands, such as gut-derived bacterial elements and HIV-1 RNAs. AIDS Clinical Trials Group A5258 was a randomized, double-blind, placebo-controlled study in 33 HIV-1-infected participants off antiretroviral therapy (ART) and 37 participants on ART. Study participants in each cohort were randomized 1:1 to receive chloroquine 250 mg orally for the first 12 weeks then cross over to placebo for 12 weeks or placebo first and then chloroquine. Combining the periods of chloroquine use in both arms of the on-ART cohort yielded a modest reduction in the proportions of CD8 T cells co-expressing CD38 and DR (median decrease = 3.0%, p = .003). The effect on immune activation in the off-ART cohort was likely confounded by increased plasma HIV-1 RNA during chloroquine administration (median 0.29 log 10 increase, p < .001). Transcriptional analyses in the off-ART cohort showed decreased expression of interferon-stimulated genes in 5 of 10 chloroquinetreated participants and modest decreases in CD38 and CCR5 RNAs in all chloroquine-treated participants. Chloroquine modestly reduced immune activation in ART-treated HIV-infected participants. Clinical Trials Registry Number: NCT00819390.

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“…Briefly, 17 μg of each of the respective HIV-1 DNA vectors was transfected in 100 mm culture dishes (BD Falcon) using Lipofectamine 2000 (Invitrogen) as described earlier (Vijaykumar et al, 2008;Chauhan et al, 2014). Similarly, HIV-1 NLENY1 was pseudotyped with VSV-G envelope using 4.0 μg of VSV-G expression vector.…”

Section: Virus Packaging and Pseudotypingmentioning

confidence: 99%

“…Primary cultures (HFA and HFN) were characterized using immunofluorescence staining as described previously (Vijaykumar et al, 2008;Mehla et al, 2012). Slide flaskets (Nunc) were coated with poly-D-lysine; on the next day primary neurons were seeded.…”

Section: Immunofluorescence and Flow Cytometrymentioning

confidence: 99%

“…Given that HIV-1-infected monocytes or lymphocytes enter the brain (Price, 1996) and that a part from R5-tropic HIV-1, a subset of primary X4 viruses can infect macrophages and microglia (Ghorpade et al, 1998;Simmons et al, 1998;Verani et al, 1998;Ohagen et al, 1999), we tested both X4-and R5-HIV-1 virus particles. To investigate autophagy and HIV-1-induced direct toxicity, X4-or R5-tropic HIV-1 viruses were assembled in 293T cells by transfection of HIV-1 full-length infectious DNA (Vijaykumar et al, 2008;Chauhan et al, 2014). Assembled viruses harvested at 72 h after transfection were titrated for p24 capsid protein and used in subsequent experiments.…”

Section: Hiv-1-induced Neuronal Damage Involves Suppression Of Autophagymentioning

confidence: 99%

See 1 more Smart Citation

HIV-1 differentially modulates autophagy in neurons and astrocytes

Mehla

Chauhan

2015

Journal of Neuroimmunology

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Chloroquine mediated molecular tuning of astrocytes for enhanced permissiveness to HIV infection

Cited by 43 publications

References 14 publications

Role of β-Catenin and TCF/LEF Family Members in Transcriptional Activity of HIV in Astrocytes

Role of β-Catenin and TCF/LEF Family Members in Transcriptional Activity of HIV in Astrocytes

The Effect of Chloroquine on Immune Activation and Interferon Signatures Associated with HIV-1

HIV-1 differentially modulates autophagy in neurons and astrocytes

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