Cross-talk between microglia and neurons regulates HIV latency

Alvarez-Carbonell, David; Ye, Fengchun; Ramanath, Nirmala; García-Mesa, Yoelvis; Knapp, Pamela E.; Hauser, Kurt F.; Karn, Jonathan

doi:10.1371/journal.ppat.1008249

Cited by 75 publications

(90 citation statements)

References 163 publications

(127 reference statements)

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“…Although macrophages have been postulated to harbor HIV-1 as transcriptionally silent provirus or unintegrated DNA (see the review in [38]), frequency and mode of HIV-1 latency in tissue-resident macrophages in patients on therapy are largely unknown. HIV latency has been hypothesized to be reactivated by multiple mechanisms such as co-infections and cytokines [39,40]. Whether latently infected microglia in HIV + individuals are reactivated with such stimuli and to what extent HIV production from microglia can contribute to systemic viremia remain to be determined.…”

Section: Hiv Persistence In Tissue-resident Macrophagesmentioning

confidence: 99%

“…Additional advantages include the feasibility of establishing iPSC lines from patients with diverse genetic backgrounds, such as those with microglia-associated neurodegenerative diseases [81] or those with higher CNS HIV reservoirs, which might reveal pathways that could be harnessed to suppress disease states. A recent study has used commercially available iPSC-derived microglia and demonstrated that neuronal status (healthy or damaged) affects HIV replication in microglia, indicating interplay between microglia and neurons [40]. Further studies are warranted to use microglia and neurons from the same iPSC line and to include other CNS-resident cells such as astrocytes to form self-organizing three-dimensional organoid cell cultures to recapitulate cell-to-cell interactions and model brain structures in HIV-infected states.…”

Section: Pro-inflammatory Responses In Tissue (Cns)-resident Macrophagesmentioning

confidence: 99%

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

Akiyama

Gummuluru

2020

Viruses

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

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Section: Hiv Persistence In Tissue-resident Macrophagesmentioning

confidence: 99%

Section: Pro-inflammatory Responses In Tissue (Cns)-resident Macrophagesmentioning

confidence: 99%

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

Akiyama

Gummuluru

2020

Viruses

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“…Microglia are the resident tissue macrophages of the brain, derived from yolk sac progenitors, and are known to interact extensively with surrounding brain parenchymal cells including neurons and astrocytes, where they perform many essential functions [22][23][24]. In HIV-1 infection, microglia may contribute to CNS dysfunction and the development of HAND through excessive or unchecked activation [25] and may also serve as a viral reservoir [19,26,27]. Understanding HIV-1 interactions with microglia will likely be important in developing a comprehensive strategy to prevent or treat HAND.…”

Section: Introductionmentioning

confidence: 99%

“…This cell line and subsequent derivatives have also been termed CHME-5 [30] and C13-NJ [31]. More recently, Alvarez-Carbonell and coworkers [32] transformed cells from adult brain tissue with lentiviral vectors expressing SV40 T antigen or a combination of SV40 T antigen and hTERT [26]. They demonstrated that these immortalized cells have microglia-like morphology and express key microglial surface markers, and utilized them for generating latently infected clones that reactive HIV in response to inflammatory signals [32].…”

Section: Introductionmentioning

confidence: 99%

Comparative Analysis of Human Microglial Models for Studies of HIV Replication and Pathogenesis

Mohammad

Hammonds

Pujato

et al. 2020

Preprint

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Background: HIV associated neurocognitive disorders cause significant morbidity and mortality despite the advent of highly active antiretroviral therapy. A deeper understanding of fundamental mechanisms underlying HIV infection and pathogenesis in the central nervous system is warranted. Microglia are resident myeloid cells of the brain that are readily infected by HIV and may constitute a CNS reservoir. We evaluated two microglial model cell lines (C20, HMC3) and two sources of primary cell-derived microglia (monocyte-derived microglia [MMG] and induced pluripotent stem cell-derived microglia [iPSC-MG]) as potential model systems for studying HIV-microglia interactions. Results: All four microglial model cells expressed typical myeloid markers with the exception of low or absent CD45 and CD11b expression by C20 and HMC3, and all four expressed the microglia-specific markers P2RY12 and TMEM119. Marked differences were observed upon gene expression profiling, however, indicating that MMG and iPSC-MG cluster closely together with primary human microglial cells, while C20 and HMC3 were similar to each other but very different from primary microglia. Expression of HIV-relevant genes also revealed important differences, with iPSC-MG and MMG expressing relevant genes at levels more closely resembling primary microglia. iPSC-MG and MMG were readily infected with R5-tropic HIV, while C20 and HMC3 lack CD4 and require pseudotyping for infection. Despite many similarities, HIV replication dynamics and HIV-1 particle capture by Siglec-1 differed markedly between the MMG and iPSC-MG. Conclusions: MMG and iPSC-MG appear to be viable microglial models that are susceptible to HIV infection and bear more similarities to authentic microglia than two transformed microglia cell lines. The observed differences in HIV replication and particle capture between MMG and iPSC-MG warrant further study.

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“…This cell line and subsequent derivatives have also been termed CHME-5 [30] and C13-NJ [31]. More recently, Alvarez-Carbonell and coworkers [32] transformed cells from adult brain tissue with lentiviral vectors expressing SV40 T antigen or a combination of SV40 T antigen and hTERT [26]. They demonstrated that these immortalized cells have microglia-like morphology and express key microglial surface markers, and utilized them for generating latently infected clones that reactivate HIV in response to in ammatory signals [32].…”

mentioning

confidence: 99%

Comparative Analysis of Human Microglial Models for Studies of HIV Replication and Pathogenesis

Mohammad

Hammonds

Pujato

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: HIV associated neurocognitive disorders cause significant morbidity and mortality despite the advent of highly active antiretroviral therapy. A deeper understanding of fundamental mechanisms underlying HIV infection and pathogenesis in the central nervous system is warranted. Microglia are resident myeloid cells of the brain that are readily infected by HIV and may constitute a CNS reservoir. We evaluated two microglial model cell lines (C20, HMC3) and two sources of primary cell-derived microglia (monocyte-derived microglia [MMG] and induced pluripotent stem cell-derived microglia [iPSC-MG]) as potential model systems for studying HIV-microglia interactions.Results: All four microglial model cells expressed typical myeloid markers with the exception of low or absent CD45 and CD11b expression by C20 and HMC3, and all four expressed the microglia-specific markers P2RY12 and TMEM119. Marked differences were observed upon gene expression profiling, however, indicating that MMG and iPSC-MG cluster closely together with primary human microglial cells, while C20 and HMC3 were similar to each other but very different from primary microglia. Expression of HIV-relevant genes also revealed important differences, with iPSC-MG and MMG expressing relevant genes at levels more closely resembling primary microglia. iPSC-MG and MMG were readily infected with R5-tropic HIV, while C20 and HMC3 lack CD4 and require pseudotyping for infection. Despite many similarities, HIV replication dynamics and HIV-1 particle capture by Siglec-1 differed markedly between the MMG and iPSC-MG.Conclusions: MMG and iPSC-MG appear to be viable microglial models that are susceptible to HIV infection and bear more similarities to authentic microglia than two transformed microglia cell lines. The observed differences in HIV replication and particle capture between MMG and iPSC-MG warrant further study.

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Cross-talk between microglia and neurons regulates HIV latency

Abstract: Despite effective antiretroviral therapy (

Cited by 75 publications

References 163 publications

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

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

Comparative Analysis of Human Microglial Models for Studies of HIV Replication and Pathogenesis

Comparative Analysis of Human Microglial Models for Studies of HIV Replication and Pathogenesis

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