Targeting Macrophage Dysregulation for Viral Infections: Novel Targets for Immunomodulators DOI Creative Commons
Monica D. Reece,

Ruby R. Taylor,

Colin Song

et al.

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

Monocyte-derived macrophages contain persistent latent HIV reservoirs DOI Creative Commons
Rebecca T. Veenhuis, Celina Monteiro Abreu, Pedro A. G. Costa

et al.

Nature Microbiology, Journal Year: 2023, Volume and Issue: 8(5), P. 833 - 844

Published: March 27, 2023

The development of persistent cellular reservoirs latent human immunodeficiency virus (HIV) is a critical obstacle to viral eradication since rebound takes place once anti-retroviral therapy (ART) interrupted. Previous studies show that HIV persists in myeloid cells (monocytes and macrophages) blood tissues virologically suppressed people with (vsPWH). However, how contribute the size reservoir what impact they have on after treatment interruption remain unclear. Here we report monocyte-derived macrophage quantitative outgrowth assay (MDM-QVOA) highly sensitive T cell detection assays confirm purity. We assess frequency monocytes using this longitudinal cohort vsPWH (n = 10, 100% male, ART duration 5-14 yr) find half participants showed monocytes. In some participants, these could be detected over several years. Additionally, assessed genomes from 30 (27% 5-22 utilizing myeloid-adapted intact proviral DNA (IPDA) demonstrate were present 40% higher total correlated reactivatable reservoirs. produced MDM-QVOA was capable infecting bystander resulting spread. These findings provide further evidence meet definition clinically relevant emphasize should included efforts towards an cure.

Language: Английский

Citations

98
HIV infects astrocytes in vivo and egresses from the brain to the periphery DOI Creative Commons

Victoria Lutgen,

Srinivas D. Narasipura,

Hannah J. Barbian

et al.

PLoS Pathogens, Journal Year: 2020, Volume and Issue: 16(6), P. e1008381 - e1008381

Published: June 11, 2020

HIV invades the brain during acute infection. Yet, it is unknown whether long-lived infected cells release productive virus that can egress from to re-seed peripheral organs. This understanding has significant implication for as a reservoir and most importantly interplay between Given sheer number of astrocytes in human their controversial role infection, we evaluated infection vivo support We developed two novel models chimeric astrocyte/human blood mononuclear cells: NOD/scid-IL-2Rgc null (NSG) mice (huAstro/HuPBMCs) whereby transplanted (non-pseudotyped or VSVg-pseudotyped) uninfected primary fetal (NHAs) an astrocytoma cell line (U138MG) into neonate adult NSG reconstituted animals with (PBMCs). also PBMCs mimic biological course. As expected, xenotransplanted did not escape/migrate out barrier (BBB) was intact this model. demonstrate organs, at least part, through trafficking CD4+ T brain. Astrocyte-derived persists, albeit low levels, under combination antiretroviral therapy (cART). Egressed evolved pattern rate typical Lastly, analysis cortical hippocampal regions donors cART revealed harbor 0.4–5.2% integrated gag DNA 2–7% are mRNA positive. These studies establish paradigm shift dynamic interaction organs which inform eradication reservoirs.

Language: Английский

Citations

133
Myeloid and CD4 T Cells Comprise the Latent Reservoir in Antiretroviral Therapy-Suppressed SIVmac251-Infected Macaques DOI Creative Commons
Celina Monteiro Abreu, Rebecca T. Veenhuis, Claudia R. Avalos

et al.

mBio, Journal Year: 2019, Volume and Issue: 10(4)

Published: Aug. 19, 2019

Human immunodeficiency virus (HIV) eradication or long-term suppression in the absence of antiretroviral therapy (ART) requires an understanding all viral reservoirs that could contribute to rebound after ART interruption. CD4 T cells (CD4s) are recognized as predominant reservoir HIV type 1 (HIV-1)-infected individuals. However, macrophages also infected by HIV-1 and simian (SIV) during acute infection may persist throughout ART, contributing size latent reservoir. We sought determine whether tissue SIVmac251 suppressed macaques. Using cell-specific quantitative outgrowth assays (CD4-QVOA MΦ-QVOA), we measured functional CD4s ART-suppressed SIVmac251-infected Spleen, lung, brain animals contained latently macrophages, undetectable low-level SIV RNA, detectable DNA. Silent genomes with potential for reactivation spread were identified blood monocytes, although these might not be considered due their short life span. Additionally, produced MΦ-QVOA was capable infecting healthy activated CD4s. Our results strongly suggest can reestablishment productive These findings should design implementation future cure strategies.

Language: Английский

Citations

78
The reservoir of latent HIV DOI Creative Commons
Jing Chen, Tong Zhou, Yuan Zhang

et al.

Frontiers in Cellular and Infection Microbiology, Journal Year: 2022, Volume and Issue: 12

Published: July 28, 2022

The persistence of latent reservoir the human immunodeficiency virus (HIV) is currently major challenge in curing HIV infection. After infects body, unable to be recognized by body’s immune system. Currently, widely adopted antiretroviral therapy (ART) also unble eliminate it, thus hindering progress treatment. This review discusses existence vault for treatment, its formation and factors affecting formation, cell, tissue localization, methods detection removing reservoir, provide a comprehensive understanding vault, order assist future research play potential role achieving

Language: Английский

Citations

61
The impact of substance abuse on HIV-mediated neuropathogenesis in the current ART era DOI

Vanessa Chilunda,

Tina M. Calderon, Pablo Martínez-Aguado

et al.

Brain Research, Journal Year: 2019, Volume and Issue: 1724, P. 146426 - 146426

Published: Aug. 29, 2019

Language: Английский

Citations

55
Chronic Immune Activation in TB/HIV Co-infection DOI

Riti Sharan,

Allison N. Bucşan, Shashank Ganatra

et al.

Trends in Microbiology, Journal Year: 2020, Volume and Issue: 28(8), P. 619 - 632

Published: April 22, 2020

Language: Английский

Citations

54
Central Nervous System (CNS) Viral Seeding by Mature Monocytes and Potential Therapies To Reduce CNS Viral Reservoirs in the cART Era DOI Creative Commons
Rosiris León‐Rivera,

Mike Veenstra,

Maribel Donoso

et al.

mBio, Journal Year: 2021, Volume and Issue: 12(2)

Published: March 15, 2021

The human immunodeficiency virus (HIV) enters the central nervous system (CNS) within a few days after primary infection, establishing viral reservoirs that persist even with combined antiretroviral therapy (cART). We show monocytes from people living HIV (PLWH) on suppressive cART harboring integrated HIV, mRNA, and/or proteins preferentially transmigrate across blood-brain barrier (BBB) to CCL2 and are significantly enriched post-transmigration, more highly posttransmigration than T cells similar properties. Using HIV-infected ART-treated mature cultured

Language: Английский

Citations

53
HIV replication and latency in monocytes and macrophages DOI
Rebecca T. Veenhuis, Celina Monteiro Abreu,

Erin N. Shirk

et al.

Seminars in Immunology, Journal Year: 2021, Volume and Issue: 51, P. 101472 - 101472

Published: Jan. 1, 2021

Language: Английский

Citations

42
HIV Tissue Reservoirs: Current Advances in Research DOI
Kangpeng Li, Bo Liu, Rui Ma

et al.

AIDS Patient Care and STDs, Journal Year: 2023, Volume and Issue: 37(6), P. 284 - 296

Published: May 15, 2023

Acquired immunodeficiency syndrome (AIDS), caused by the human virus (HIV), has become a heavy burden of disease and an important public health problem in world. Although current antiretroviral therapy (ART) is effective at suppressing blood, HIV still remains two different types reservoirs-the latently infected cells (represented CD4+ T cells) tissues containing those cells, which may block access to ART, HIV-neutralizing antibodies latency-reversing agents. The latter focus our review, as blood viral load drops below detectable levels after deeper more systematic understanding tissue reservoirs imperative. In this we take lymphoid system (including lymph nodes, gut-associated tissue, spleen bone marrow), nervous system, respiratory reproductive (divided into male female), urinary order, focusing on particularity importance each infection, infection target cell specific situation quantified DNA or RNA evidence compartmentalization pharmacokinetics. summary, found that present state both similarities differences. future, therapeutic principle need follow respect discrepancy basis grasping commonality. measures taken completely eliminate whole body cannot be generalized. It necessary formulate personalized treatment strategies according characteristics various tissues, so realize prospect curing AIDS soon possible.

Language: Английский

Citations

22
The Quest for Cellular Markers of HIV Reservoirs: Any Color You Like DOI Creative Commons
Gilles Darcis, Ben Berkhout, Alexander Pasternak

et al.

Frontiers in Immunology, Journal Year: 2019, Volume and Issue: 10

Published: Sept. 20, 2019

Combination antiretroviral therapy (ART) suppresses human immunodeficiency virus (HIV) replication and improves immune function, but is unable to eradicate the virus. Therefore, development of an HIV cure has become one main priorities research field. The obstacle for formation latent viral reservoirs, where able "hide" despite decades therapy, just reignite active once stopped. Revealing hiding places thus central research, absence markers these reservoir cells greatly complicates search a cure. Identification or several marker(s) latently infected would represent significant step forward towards better description cell types involved improved understanding latency. Moreover, it could provide "handle" selective therapeutic targeting reservoirs. A number cellular have recently been proposed, including checkpoint molecules, CD2, CD30. CD32a perhaps most promising as reported be associated with very prominent enrichment in DNA, although this finding challenged. In review, we update on current knowledge about markers. We specifically highlight studies that characterized persistently lymphoid tissues.

Language: Английский

Citations

54