Targeting the Brain Reservoirs: Toward an HIV Cure

Marban, Céline; Forouzanfar, Faezeh; Aït-Ammar, Amina; Fahmi, Faiza; Mekdad, Hala El; Daouad, Fadoua; Rohr, Olivier; Schwartz, Christian

doi:10.3389/fimmu.2016.00397

Cited by 92 publications

(98 citation statements)

References 195 publications

(211 reference statements)

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“…Finally, a variety of additional strategies to purge HIV‐1 infection have been proposed and are currently under development, including the use of broadly neutralizing monoclonal antibodies, T‐cell immunotherapy, chimeric antigen receptor T cell therapy, gene editing, immune cell depletion and transplantation, as well as strategies intended to prevent reactivation of HIV‐1 expression, referred to as “lock and block.” Because of the extent that HIV‐1 infection is thought to penetrate multiple cell types and tissue compartments, it seems likely that no single strategy will provide a “cure all” therapy, and combinations of various treatments may be necessary for routine curative intervention.…”

Section: Resultsmentioning

confidence: 99%

Diversity of small molecule HIV‐1 latency reversing agents identified in low‐ and high‐throughput small molecule screens

Hashemi

Sadowski

2019

Medicinal Research Reviews

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The latency phenomenon produced by human immunodeficiency virus (HIV-1) prevents viral clearance by current therapies, and consequently development of a cure for HIV-1 disease represents a formidable challenge. Research over the past decade has resulted in identification of small molecules that are capable of exposing HIV-1 latent reservoirs, by reactivation of viral transcription, which is intended to render these infected cells sensitive to elimination by immune defense recognition or apoptosis. Molecules with this capability, known as latency-reversing agents (LRAs) could lead to realization of proposed HIV-1 cure strategies collectively termed "shock and kill," which are intended to eliminate the latently infected population by forced reactivation of virus replication in combination with additional interventions that enhance killing by the immune system or virus-mediated apoptosis. Here, we review efforts to discover novel LRAs via low-and high-throughput small molecule screens, and summarize characteristics and biochemical properties of chemical structures with this activity.We expect this analysis will provide insight toward further research into optimized designs for new classes of more potent LRAs.---

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Section: Resultsmentioning

confidence: 99%

Diversity of small molecule HIV‐1 latency reversing agents identified in low‐ and high‐throughput small molecule screens

Hashemi

Sadowski

2019

Medicinal Research Reviews

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“…We redesigned this strategy in order to target specifically latent brain reservoirs. As evoked above and in [7,35] promoter LTR which drives the expression of thymidine kinase. In the presence of the prodrug Ganciclovir, we thus expected to induce apoptosis preferentially in reactivated cells of the latently-infected reservoirs.…”

Section: Introductionmentioning

confidence: 84%

“…These molecular mechanisms, however are partially understood. We have notably shown that the cellular cofactor CTIP2 (Bcl11b) supports both the establishment and the maintenance of HIV-1 post-integration latency in microglial cells [5][6][7]. CTIP2 works as a scaffold protein by recruiting at least two different complexes in microglial cells.…”

Section: Introductionmentioning

confidence: 96%

Brain HIV-1 latently-infected reservoirs targeted by the suicide gene strategy

Saeb

Ravanshad

Pourkarim

et al. 2020

Preprint

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Abstract Several strategies are currently investigated to reduce the pool of all HIV-1 reservoirs in infected patients in order to achieve functional cure. The most prominent HIV-1 cell reservoirs in the brain are microglial cells. Virus infection maybe lifelong. Infected microglial cells are believed to be the source of peripheral tissues reseeding and responsible for the emergence of drug resistance. Clearing infected cells from the brain is therefore crucial. However, many characteristics of microglial cells and the central nervous system prevent the eradication of brain reservoirs. Current trials, such as “shock and kill”, the “deep and lock” and the gene editing strategies do not respond to these difficulties. Therefore, new strategies have to be designed when considering brain reservoirs such as microglial cells. We set up an original gene suicide strategy using a latently infected microglial model. In this paper we provide proof of concept of this strategy. Our results demonstrate that this strategy enables the eradication of latently-infected microglial cells.

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“…The brain is unique in terms of its "immune privileged" status and evidence does suggest that the brain is a viral reservoir for HIV-1. 5,6 In brain, macrophages, microglia, and astrocytes can be infected by HIV-1; HIV-1 infection of macrophages and microglia is more productive than astrocytes. 7 Although endocytosis is involved in HIV-1 entry in both macrophages 7,8 and astrocytes, 7 different receptors are used for HIV-1 entry in macrophages or astrocytes and this could help explain the restrictive nature of HIV-1 infection in astrocytes.…”

Section: Introductionmentioning

confidence: 99%

Two‐pore channels regulate Tat endolysosome escape and Tat‐mediated HIV‐1 LTR transactivation

et al. 2020

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Abbreviations: BAPTA-AM, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis(acetoxymethyl ester); CD26, cluster of differentiation 4; CD4+, cluster of differentiation 4; CNS, central nervous system; CRISPR, clustered regularly interspaced short palindromic repeats; CSF, cerebrospinal fluid; CXCR4, C-X-C chemokine receptor type 4; DMEM, Dulbecco's Modified Eagle Medium; FBS, fetal bovine serum; FITC, fluorescein isothiocyanate; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GFP, green fluorescent protein; gp120, envelope glycoprotein 120; HCl, hydrogen chloride; HIV-1, human immunodeficiency virus-1; kDa, kilodalton; LRP1, low density lipoprotein receptor-related protein 1; LTR, long terminal repeat; MERS-CoV, middle east respiratory syndrome coronavirus; MW, molecular weight; NAADP, nicotinic acid adenine dinucleotide phosphate; P2X4, purinergic P2X4 receptors; PAGE, polyacrylamide gel electrophoresis; PBS, phosphate-buffered saline; PI(3,5)P2, phosphatidylinositol 3,5-bisphosphate; PVDF, polyvinylidene difluoride; RIPA, radioimmunoprecipitation assay buffer; SD, standard deviation; SDS, sodium dodecyl sulfate; shRNA, short hairpin RNA; Tat, transcriptional activator; TFEB, transcription factor EB; TPCs, two-pore channels; Trans-Ned19, (1R,3S)-1- [3][4]piperazin-1-yl] methyl]-4-methoxyphenyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid; TRPM2, transient receptor potential melastatin 2; TRPML1, transient receptor potential mucolipin 1. AbstractHIV-1 Tat is essential for HIV-1 replication and appears to play an important role in the pathogenesis of HIV-associated neurological complications. Secreted from infected or transfected cells, Tat has the extraordinary ability to cross the plasma membrane. In the brain, Tat can be taken up by CNS cells via receptor-mediated endocytosis. Following endocytosis and its internalization into endolysosomes, Tat must be released in order for it to activate the HIV-1 LTR promoter and facilitate HIV-1 viral replication in the nucleus. However, the underlying mechanisms whereby Tat escapes endolysosomes remain unclear. Because Tat disrupts intracellular calcium homeostasis, we investigated the involvement of calcium in Tat endolysosome escape and subsequent LTR transactivation. We demonstrated that chelating endolysosome calcium with high-affinity rhodamine-dextran or chelating cytosolic calcium with BAPTA-AM attenuated Tat endolysosome escape and LTR transactivation.Significantly, we demonstrated that pharmacologically blocking and knocking down the endolysosome-resident two-pore channels (TPCs) attenuated Tat endolysosome escape and LTR transactivation. This calcium-mediated effect appears to be selective for TPCs because knocking down TRPML1 calcium channels was without effect. Our findings suggest that calcium released from TPCs is involved in Tat endolysosome escape and subsequent LTR transactivation. TPCs might represent a novel therapeutic target against HIV-1 infection and HIV-associated neurological complications.

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Targeting the Brain Reservoirs: Toward an HIV Cure

Cited by 92 publications

References 195 publications

Diversity of small molecule HIV‐1 latency reversing agents identified in low‐ and high‐throughput small molecule screens

Diversity of small molecule HIV‐1 latency reversing agents identified in low‐ and high‐throughput small molecule screens

Brain HIV-1 latently-infected reservoirs targeted by the suicide gene strategy

Two‐pore channels regulate Tat endolysosome escape and Tat‐mediated HIV‐1 LTR transactivation

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