Multi-organ Targeting of HIV-1 Viral Reservoirs with Etravirine Loaded Nanostructured Lipid Carrier: An In-vivo Proof of Concept

2021 ◽  
pp. 105916
Author(s):  
Satish Rojekar ◽  
Leila Fotooh ◽  
Rohan Pai ◽  
Ketan Mahajan ◽  
Smita Kulkarni ◽  
...  
Keyword(s):  
Nanostructured Lipid Carrier ◽  
Proof Of Concept ◽  
Viral Reservoirs ◽  
Organ Targeting ◽  
Hiv 1

scholarly journals Expression of MDM2 in Macrophages Promotes the Early Postentry Steps of HIV-1 Infection through Inhibition of p53

2019 ◽  
Vol 93 (7) ◽  
Author(s):  
Yann Breton ◽  
Vincent Desrosiers ◽  
Michel Ouellet ◽  
Alexandre Deshiere ◽  
Cynthia Torresilla ◽  
...  
Keyword(s):  
Infected Individual ◽  
Human Monocyte ◽  
Careful Analysis ◽  
Binding Activity ◽  
Individual Identification ◽  
Small Interfering Rnas ◽  
Viral Reservoirs ◽  
Cellular Environment ◽  
Hiv 1

ABSTRACT The molecular basis for HIV-1 susceptibility in primary human monocyte-derived macrophages (MDMs) was previously evaluated by comparing the transcriptome of infected and bystander populations. Careful analysis of the data suggested that the ubiquitin ligase MDM2 acted as a positive regulator of HIV-1 replication in MDMs. In this study, MDM2 silencing through transcript-specific small interfering RNAs in MDMs induced a reduction in HIV-1 reverse transcription and integration along with an increase in the expression of p53-induced genes, including CDKN1A. Experiments with Nutlin-3, a pharmacological inhibitor of MDM2 p53-binding activity, showed a similar effect on HIV-1 infection, suggesting that the observed restriction in HIV-1 production results from the release/activation of p53 and not the absence of MDM2 per se. Knockdown and inhibition of MDM2 also both correlate with a decrease in the Thr592-phosphorylated inactive form of SAMHD1. The expression level of MDM2 and the p53 activation status are therefore important factors in the overall susceptibility of macrophages to HIV-1 infection, bringing a new understanding of signaling events controlling the process of virus replication in this cell type. IMPORTANCE Macrophages, with their long life span in vivo and their resistance to HIV-1-mediated cytopathic effect, might serve as viral reservoirs, contributing to virus persistence in an infected individual. Identification of host factors that increase the overall susceptibility of macrophages to HIV-1 might provide new therapeutic targets for the efficient control of viral replication in these cells and limit the formation of reservoirs in exposed individuals. In this study, we demonstrate the importance of p53 regulation by MDM2, which creates a cellular environment more favorable to the early steps of HIV-1 replication. Moreover, we show that p53 stabilization reduces virus infection in human macrophages, highlighting the important role of p53 in antiviral immunity.

scholarly journals Excision of HIV-1 DNA by gene editing: a proof-of-concept in vivo study

Gene Therapy ◽  
2016 ◽  
Vol 23 (8-9) ◽  
pp. 690-695 ◽  
Author(s):  
R Kaminski ◽  
R Bella ◽  
C Yin ◽  
J Otte ◽  
P Ferrante ◽  
...  
Keyword(s):  
Gene Editing ◽  
In Vivo Study ◽  
Proof Of Concept ◽  
Hiv 1

scholarly journals An ultrasensitive planar array p24 Gag ELISA to detect individual HIV-1 viral particles and infected cells

2021 ◽  
Author(s):  
Alberto Bosque ◽  
Callie Levinger ◽  
J Natalie Howard ◽  
Pingtao Tang ◽  
Amit Joshi
Keyword(s):  
Biological Fluids ◽  
Low Frequency ◽  
Viral Reservoirs ◽  
Hiv Persistence ◽  
Viral Particles ◽  
Planar Array ◽  
Infected Cells ◽  
Major Loss ◽  
Hiv 1

Abstract Human Immunodeficiency virus-1 (HIV-1) persistence in the presence of antiretroviral therapy (ART) has halted the development of curative strategies. Measuring HIV persistence is complex due to the low frequency of cells containing virus in vivo. Most of the commercially available assays to date measure nucleic acid. These assays have the advantage of being highly sensitive and allow for the analysis of sequence diversity, intactness of the HIV genome or evaluation of diverse RNA species. However, these assays are limited in evaluating translational competent viral reservoirs. In here, we developed an ultrasensitive p24 ELISA that uses the SimoaTM planar array technology that can detect as low as a single HIV-1 particle and a single HIV-1 infected cell. Furthermore, the assay is optimized to measure very low levels of p24 in different biological fluids without a major loss of sensitivity or reproducibility. Our results demonstrate that the ‘homebrew' planar p24 ELISA immunoassay is a broadly applicable new tool to evaluate HIV persistence in diverse biological fluids.

scholarly journals HIV-1 can infect northern pig-tailed macaques ( Macaca leonina ) and form viral reservoirs in vivo

2017 ◽  
Vol 62 (19) ◽  
pp. 1315-1324 ◽  
Author(s):  
Wei Pang ◽  
Gao-Hong Zhang ◽  
Jin Jiang ◽  
Hong-Yi Zheng ◽  
Lin-Tao Zhang ◽  
...  
Keyword(s):  
Viral Reservoirs ◽  
Macaca Leonina ◽  
Hiv 1

scholarly journals HIV-1 and microglia: EcoHIV and HIV-1 transgenic rats

2020 ◽  
Author(s):  
Hailong Li ◽  
Kristen A. McLaurin ◽  
Jessica M. Illenberger ◽  
Charles F. Mactutus ◽  
Rosemarie M. Booze
Keyword(s):  
Distribution Pattern ◽  
Biological System ◽  
Cell Type ◽  
Viral Reservoirs ◽  
Major Cell Type ◽  
Key Aspects ◽  
The Brain ◽  
Hiv 1

ABSTRACTThe persistence of HIV-1 viral reservoirs in the brain, despite treatment with combination antiretroviral therapy (cART), remains a critical roadblock for the development of a novel cure strategy for HIV-1. To enhance our understanding of viral reservoirs, two complementary studies were conducted to 1) evaluate the HIV-1 mRNA neuroanatomical distribution pattern and major cell type expressing HIV-1 mRNA in the HIV-1 transgenic (Tg) rat (i.e., under conditions of latent infection), and 2) to validate our findings by developing and critically testing a novel biological system to model active HIV-1 infection in the rat. First, a restricted, region-specific HIV-1 mRNA distribution pattern was observed in the HIV-1 Tg rat. Microglia were the predominant cell type expressing HIV-1 mRNA in the HIV-1 Tg rat. Second, we developed and critically tested a novel biological system to model key aspects of HIV-1 by infusing F344/N control rats with chimeric HIV (EcoHIV). In vitro, primary cultured microglia were treated with EcoHIV revealing prominent expression within 24 hours of infection. In vivo, EcoHIV expression was observed seven days after stereotaxic injections. Following EcoHIV infection, microglia were the major cell type expressing HIV-1 mRNA, results which are consistent with observations in the HIV-1 Tg rat. Within eight weeks of infection, EcoHIV rats exhibited neurocognitive impairments, synaptic dysfunction, which may result from activation of the NogoA-NgR3/PirB-RhoA signaling pathway, and neuroinflammation. Collectively, these studies enhance our understanding of HIV-1 viral reservoirs in the brain and offer a novel biological system to model HIV-associated neurocognitive disorders and associated comorbidities (i.e., drug abuse) in rats.

scholarly journals Erratum: Excision of HIV-1 DNA by gene editing: a proof-of-concept in vivo study

Gene Therapy ◽  
2016 ◽  
Vol 23 (8-9) ◽  
pp. 696-696 ◽  
Author(s):  
R Kaminski ◽  
R Bella ◽  
C Yin ◽  
J Otte ◽  
P Ferrante ◽  
...  
Keyword(s):  
Gene Editing ◽  
In Vivo Study ◽  
Proof Of Concept ◽  
Hiv 1

scholarly journals Microglial HIV-1 Expression: Role in HIV-1 Associated Neurocognitive Disorders

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 924
Author(s):  
Hailong Li ◽  
Kristen A. McLaurin ◽  
Jessica M. Illenberger ◽  
Charles F. Mactutus ◽  
Rosemarie M. Booze
Keyword(s):  
Distribution Pattern ◽  
Biological System ◽  
Neurocognitive Disorders ◽  
Cell Type ◽  
Viral Reservoirs ◽  
Major Cell Type ◽  
The Brain ◽  
Hiv 1

The persistence of HIV-1 viral reservoirs in the brain, despite treatment with combination antiretroviral therapy (cART), remains a critical roadblock for the development of a novel cure strategy for HIV-1. To enhance our understanding of viral reservoirs, two complementary studies were conducted to (1) evaluate the HIV-1 mRNA distribution pattern and major cell type expressing HIV-1 mRNA in the HIV-1 transgenic (Tg) rat, and (2) validate our findings by developing and critically testing a novel biological system to model active HIV-1 infection in the rat. First, a restricted, region-specific HIV-1 mRNA distribution pattern was observed in the HIV-1 Tg rat. Microglia were the predominant cell type expressing HIV-1 mRNA in the HIV-1 Tg rat. Second, we developed and critically tested a novel biological system to model key aspects of HIV-1 by infusing F344/N control rats with chimeric HIV (EcoHIV). In vitro, primary cultured microglia were treated with EcoHIV revealing prominent expression within 24 h of infection. In vivo, EcoHIV expression was observed seven days after stereotaxic injections. Following EcoHIV infection, microglia were the major cell type expressing HIV-1 mRNA, results that are consistent with observations in the HIV-1 Tg rat. Within eight weeks of infection, EcoHIV rats exhibited neurocognitive impairments and synaptic dysfunction, which may result from activation of the NogoA-NgR3/PirB-RhoA signaling pathway and/or neuroinflammation. Collectively, these studies enhance our understanding of HIV-1 viral reservoirs in the brain and offer a novel biological system to model HIV-associated neurocognitive disorders and associated comorbidities (i.e., drug abuse) in rats.

scholarly journals An ultrasensitive planar array p24 Gag ELISA to detect HIV-1 in diverse biological matrixes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Callie Levinger ◽  
JNatalie Howard ◽  
Jie Cheng ◽  
Pingtao Tang ◽  
Amit Joshi ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Limit Of Detection ◽  
Biological Fluids ◽  
Low Frequency ◽  
Viral Reservoirs ◽  
Hiv Persistence ◽  
Planar Array ◽  
Major Loss ◽  
Hiv 1

AbstractHuman immunodeficiency virus-1 (HIV-1) persistence in the presence of antiretroviral therapy (ART) has halted the development of curative strategies. Measuring HIV persistence is complex due to the low frequency of cells containing virus in vivo. Most of the commercially available assays to date measure nucleic acid. These assays have the advantage of being highly sensitive and allow for the analysis of sequence diversity, intactness of the HIV genome or evaluation of diverse RNA species. However, these assays are limited in evaluating translational competent viral reservoirs. In here, we developed an ultrasensitive p24 ELISA that uses the Simoa planar array technology that can detect HIV-1 virions and HIV-1 infected cell with limit of detection similar to nucleic acid assays. Furthermore, the assay is optimized to measure very low levels of p24 in different biological fluids without a major loss of sensitivity or reproducibility. Our results demonstrate that the ‘homebrew’ planar p24 ELISA immunoassay is a broadly applicable new tool to evaluate HIV persistence in diverse biological fluids and cells.

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