HIV-1 Persistence and Chronic Induction of Innate Immune Responses in Macrophages

Viruses, Journal Year: 2020, Volume and Issue: 12(7), P. 711 - 711

Published: June 30, 2020

A hallmark of HIV-1 infection is chronic inflammation, which plays a significant role in disease pathogenesis. Acute HIV induces robust inflammatory responses, are insufficient to prevent or eliminate virus mucosal tissues. While establishment viral set-point coincident with downregulation acute innate systemic responses persist during the course infection. Since introduction combination antiviral therapy (cART), most HIV-1+ individuals can suppress viremia under detection levels for decades. However, immune activation persists and has been postulated cause associated non-AIDS complications (HANA). Importantly, cytokines markers macrophages strongly selectively correlated incidence HIV-associated neurocognitive disorder (HAND), cardiovascular dysfunctions (CVD) other HANA conditions. In this review, we discuss roles facilitating persistence contributing generation persistent responses.

Language: Английский

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Microglia-Specific Promoter Activities of HEXB Gene

Frontiers in Cellular Neuroscience, Journal Year: 2022, Volume and Issue: 16

Published: March 10, 2022

Adeno-associated virus (AAV)-mediated genetic targeting of microglia remains a challenge. Overcoming this hurdle is essential for gene editing in the central nervous system (CNS). Here, we characterized minimal/native promoter HEXB gene, which known to be specifically and stably expressed during homeostatic pathological conditions. Dual reporter serial deletion assays identified critical role natural 5' untranslated region (-97 bp related first ATG) driving transcriptional activity mouse Hexb gene. The native mouse, human, monkey are located at -135, -134, -170 ATG, respectively. These promoters were highly active specific with strong cross-species activities, but did not exhibit primary astrocytes. In addition, 135 CD68 that was Considering microglia, these data suggest newly microglia-specific can an ideal candidate microglia-targeting AAV therapy CNS.

Language: Английский

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HIV-1-induced type I IFNs promote viral latency in macrophages

Journal of Leukocyte Biology, Journal Year: 2022, Volume and Issue: 112(5), P. 1343 - 1356

Published: May 19, 2022

Abstract Macrophages chronically infected with HIV-1 serve as a reservoir that contributes to persistence during antiretroviral therapy; however, the mechanisms governing establishment and maintenance of this virus have not been fully elucidated. Here, we show enters state reminiscent latency in monocyte-derived macrophages (MDMs), characterized by integrated proviral DNA decreased viral transcription. This quiescent is associated NF-κB p65, RNA polymerase II, p-TEFb recruitment promoter well chromatin transcriptionally nonpermissive state. MDM transition mediated type I IFN signaling, inhibiting signaling or blocking 1 prevents latent infection. Knockdown studies demonstrate innate immune molecule mitochondrial antiviral protein (MAVS) required for latency. Finally, role accessory Vpr macrophages. Our data indicate HIV-1-induced production responsible MDMs identify possible therapeutic targets prevention elimination important reservoir.

Language: Английский

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New Latency Reversing Agents for HIV-1 Cure: Insights from Nonhuman Primate Models

Viruses, Journal Year: 2021, Volume and Issue: 13(8), P. 1560 - 1560

Published: Aug. 6, 2021

Antiretroviral therapy (ART) controls human immunodeficiency virus 1 (HIV-1) replication and prevents disease progression but does not eradicate HIV-1. The persistence of a reservoir latently infected cells represents the main barrier to cure. “Shock kill” is promising strategy involving latency reversing agents (LRAs) reactivate HIV-1 from cells, thus exposing killing by immune system or clearance agents. Here, we review advances “shock made through nonhuman primate (NHP) model, highlighting recently identified approaches such as mimetics second mitochondrial activator caspase (SMACm), experimental CD8+ T cell depletion, checkpoint blockade (ICI), toll-like receptor (TLR) agonists. We also discuss advantages limits NHP model for HIV cure research methods developed evaluate efficacy in vivo treatment with LRAs NHPs.

Language: Английский

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Targeting Macrophage Dysregulation for Viral Infections: Novel Targets for Immunomodulators

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: Nov. 1, 2021

A major barrier to human immunodeficiency virus (HIV-1) cure is the latent viral reservoir, which persists despite antiretroviral therapy (ART), including across non-dividing myeloid reservoir found systemically in sanctuary sites tissues and central nervous system (CNS). Unlike activated CD4+ T cells that undergo rapid cell death during initial infection (due replication kinetics), kinetics are delayed cells, resulting long-lived survival of infected macrophages macrophage-like cells. Simultaneously, persistent inflammation confers immune dysregulation a key driver co-morbidities cardiovascular disease (CVD) neurological deficits people living with HIV-1 (PLWH). Macrophage activation also progression other infections SARS-CoV-2, influenza, chikungunya viruses, underscoring interplay between progression, pathogenesis, comorbidity setting. This review discusses role persistence pathogenesis related comorbidities, SARS-CoV-2 viruses. special focus given novel immunomodulatory targets for events driving maintenance diverse array infections.

Language: Английский

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