Block and Lock HIV Cure Strategies to Control the Latent Reservoir DOI Creative Commons
Chantelle Ahlenstiel,

Geoff Symonds,

Stephen J. Kent

et al.

Frontiers in Cellular and Infection Microbiology, Journal Year: 2020, Volume and Issue: 10

Published: Aug. 14, 2020

The HIV latent reservoir represents the major challenge to cure development. Residing in resting CD4+ T cells and myeloid at multiple locations body, including sanctuary sites such as brain, is not eliminated by ART has ability reactivate virus replication pre-therapy levels when ceased. There are four broad areas of research. only successful strategy, thus far, stem cell transplantation using naturally resistant CCR5Δ32 cells. A second potential approach uses gene editing technology, zinc-finger nucleases CRISPR/Cas9. Another two strategies aim control reservoir, with polar opposite concepts; "shock kill" approach, which aims "shock" or then "kill" infected via targeted immune responses. Lastly, "block lock" enhance state "blocking" transcription "locking" promoter a deep epigenetic modifications. "Shock approaches focus studies, however we predict that increased specificity will be required for development sustained clinical remission absence ART. This review focuses on current research novel being explored generate an induction silencing. We also discuss future therapeutic delivery challenges associated progressing these move toward trials.

Language: Английский

Infectious Virus Persists in CD4 + T Cells and Macrophages in Antiretroviral Therapy-Suppressed Simian Immunodeficiency Virus-Infected Macaques DOI Creative Commons
Celina Monteiro Abreu, Rebecca T. Veenhuis, Claudia R. Avalos

et al.

Journal of Virology, Journal Year: 2019, Volume and Issue: 93(15)

Published: May 23, 2019

Understanding the cellular and anatomical sites of latent virus that contribute to human immunodeficiency (HIV) rebound is essential for eradication. In HIV-positive patients, CD4+ T lymphocytes comprise a well-defined functional reservoir, defined as cells containing transcriptionally silent genomes able produce infectious once reactivated. However, persistence in compartments other than blood lymph nodes unclear. Macrophages (Mϕ) are infected by HIV/simian (SIV) likely carry viral during antiretroviral therapy (ART), contributing reservoir. Currently, gold standard assay used measure reservoirs replication-competent quantitative outgrowth (QVOA). Using an SIV-macaque model, cell Mϕ were measured various tissues using cell-specific QVOAs. Our results showed blood, spleen, lung majority suppressed animals contain latently Mϕs. Surprisingly, numbers cells, monocytes, Mϕs carrying spleen at comparable frequencies (∼1 per million). We also demonstrate ex vivo viruses produced QVOA capable infecting activated cells. These strongly suggest tissue can reestablish productive infection upon treatment interruption. This study provides first comparison macaque model. It confirmation monocytes SIV-infected ART-suppressed macaques. after ART interruption should be considered future HIV cure strategies.IMPORTANCE suggests found throughout body SIV addition, this demonstrates macrophages another reservoir may new insight into size location could have great implications HIV-infected individuals taken consideration development strategies.

Language: Английский

Citations

66
The Use of Toll-Like Receptor Agonists in HIV-1 Cure Strategies DOI Creative Commons

Janne Tegder Martinsen,

Jesper Damsgaard Gunst, Jesper Falkesgaard Højen

et al.

Frontiers in Immunology, Journal Year: 2020, Volume and Issue: 11

Published: June 11, 2020

Toll-like receptors (TLRs) are a family of pattern recognition and part the first line defense against invading microbes. In humans, we know 10 different TLRs, which expressed to varying degrees in immune cell subsets. Engaging TLRs through their specific ligands leads activation innate system secondarily priming adaptive system. Because these unique properties, TLR agonists have been investigated as immunotherapy cancer treatment for many years, but recent years there has also growing interest use context human immunodeficiency virus type 1 (HIV-1) cure research. The primary obstacle curing HIV-1 is presence latent viral reservoir transcriptionally silent cells. Due very limited transcription integrated proviruses, latently infected cells cannot be targeted cleared by effector mechanisms. interesting this because potential dual effects latency reverting agents (LRAs) modulatory compounds. Here, review preclinical clinical data on impact stimulation well antiviral HIV-1-specific immunity. We focus promising role combination strategies Different combinations broadly neutralizing antibodies or adjuvants vaccines shown encouraging results non-human primate experiments concepts now moving into testing.

Language: Английский

Citations

62
Between a shock and a hard place: challenges and developments in HIV latency reversal DOI
Jennifer M. Zerbato,

Harrison V Purves,

Sharon R. Lewin

et al.

Current Opinion in Virology, Journal Year: 2019, Volume and Issue: 38, P. 1 - 9

Published: April 29, 2019

Language: Английский

Citations

61
Mannose-decorated hybrid nanoparticles for enhanced macrophage targeting DOI Creative Commons
Elham Hatami,

Ying Mu,

Deanna N. Shields

et al.

Biochemistry and Biophysics Reports, Journal Year: 2019, Volume and Issue: 17, P. 197 - 207

Published: Jan. 27, 2019

Our goal was to design nanocarriers that specifically target and deliver therapeutics polarized macrophages. Mannose receptors are highly overexpressed on In this study, we constructed Pluronic® -F127 polymer tannic acid (TA) based nanoparticles (F127-TA core nanoparticles) with varying mannose densities. The particle size of the optimized mannose-decorated F127-TA hybrid (MDNPs) found be ~ 265 nm a negative zeta potential - 4.5 mV. No significant changes in potentials were observed, which demonstrated structural integrity stability nanoformulation. Physicochemical characteristics MDNPs evaluated by FTIR TGA presence units surface nanoparticles. A mannose-dependent cellular targeting uptake U937 process vary directly time volume pattern is higher M2 than M1. This behavior also evident from instantaneous superior binding profile macrophage lysate protein over M1 protein. These results an appropriate ligand density confirmed, suggesting efficient M2. Altogether, these data support formulation could serve as targeted therapeutic guide generation nanomedicine treat various conditions anti-inflammation therapy.

Language: Английский

Citations

60
Block and Lock HIV Cure Strategies to Control the Latent Reservoir DOI Creative Commons
Chantelle Ahlenstiel,

Geoff Symonds,

Stephen J. Kent

et al.

Frontiers in Cellular and Infection Microbiology, Journal Year: 2020, Volume and Issue: 10

Published: Aug. 14, 2020

The HIV latent reservoir represents the major challenge to cure development. Residing in resting CD4+ T cells and myeloid at multiple locations body, including sanctuary sites such as brain, is not eliminated by ART has ability reactivate virus replication pre-therapy levels when ceased. There are four broad areas of research. only successful strategy, thus far, stem cell transplantation using naturally resistant CCR5Δ32 cells. A second potential approach uses gene editing technology, zinc-finger nucleases CRISPR/Cas9. Another two strategies aim control reservoir, with polar opposite concepts; "shock kill" approach, which aims "shock" or then "kill" infected via targeted immune responses. Lastly, "block lock" enhance state "blocking" transcription "locking" promoter a deep epigenetic modifications. "Shock approaches focus studies, however we predict that increased specificity will be required for development sustained clinical remission absence ART. This review focuses on current research novel being explored generate an induction silencing. We also discuss future therapeutic delivery challenges associated progressing these move toward trials.

Language: Английский

Citations

56