Brain macrophages harbor latent, infectious simian immunodeficiency virus

Abreu, Celina Monteiro; Shirk, Erin N.; Queen, Suzanne E.; Beck, Sarah E.; Mangus, Lisa M.; Pate, Kelly A. Metcalf; Mankowski, Joseph L.; Gama, Lúcio; Clements, Janice E.

doi:10.1097/qad.0000000000002269

Cited by 48 publications

(62 citation statements)

References 68 publications

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“…Cytoscape (version 3.7.2.) 6 was employed to visualize expression data in specific molecular networks (30). GraphPad Prism version 8.4.1 (GraphPad Software, Inc.) and Excel (Microsoft Corp.) were used for statistical analyses and graphs drawing.…”

Section: Rna-sequencing and Data Analysismentioning

confidence: 99%

“…Total RNA was isolated with the miRNeasy mini kit (Qiagen) that allows detecting small RNAs, following the manufacturer's 1 https://cran.r-project.org/web/packages/pheatmap 2 https://biit.cs.ut.ee/clustvis/ 3 https://www.rdocumentation.org/packages/graphics/versions/3.6.2/topics/ boxplot 4 https://www.rdocumentation.org/packages/EnhancedVolcano/versions/1.5.4 5 http://bioinfogp.cnb.csic.es/tools/venny/index.html 6 https://cytoscape.org/ procedure. The extracted RNA (500 ng) was retrotranscribed by using the TaqMan Micro-RNA Reverse Transcription Kit and the Megaplex RT Primers (Applied Biosystems).…”

Section: Microrna Expression Profiling and Data Analysismentioning

confidence: 99%

“…Although the precise contribution of these cells to the pathogenesis of HIV-1 infection is still a matter of debate, their increased resistance to virus-induced cytopathic effect and reduced susceptibility to some antiretroviral drugs suggest they may contribute to residual viremia under combined antiretroviral therapy (cART). Recent discoveries in humanized mice and non-human primates models have indeed highlighted macrophage involvement in both viral persistence and development of either HIV-1 or simian immunodeficiency virus infection-associated comorbidities (3)(4)(5)(6)(7). Macrophages may thus represent an obstacle to cure HIV-1 infection and efforts defining the mechanisms and factors controlling HIV-1 replication in these cells may aid devising new treatments to interfere with viral persistence.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptome Profiling of Human Monocyte-Derived Macrophages Upon CCL2 Neutralization Reveals an Association Between Activation of Innate Immune Pathways and Restriction of HIV-1 Gene Expression

et al. 2020

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Macrophages are key targets of human immunodeficiency virus type 1 (HIV-1) infection and main producers of the proinflammatory chemokine CC chemokine ligand 2 (CCL2), whose expression is induced by HIV-1 both in vitro and in vivo. We previously found that CCL2 neutralization in monocyte-derived macrophages (MDMs) strongly inhibited HIV-1 replication affecting post-entry steps of the viral life cycle. Here, we used RNAsequencing to deeply characterize the cellular factors and pathways modulated by CCL2 blocking in MDMs and involved in HIV-1 replication restriction. We report that exposure to CCL2 neutralizing antibody profoundly affected the MDM transcriptome. Functional annotation clustering of up-regulated genes identified two clusters enriched for antiviral defense and immune response pathways, comprising several interferonstimulated, and restriction factor coding genes. Transcripts in the clusters were enriched for RELA and NFKB1 targets, suggesting the activation of the canonical nuclear factor κB pathway as part of a regulatory network involving miR-155 up-regulation. Furthermore, while HIV-1 infection caused small changes to the MDM transcriptome, with no evidence of host defense gene expression and type I interferon signature, CCL2 blocking enabled the activation of a strong host innate response in infected macrophage cultures, and potently inhibited viral genes expression. Notably, an inverse correlation was found between levels of viral transcripts and of the restriction factors APOBEC3A (apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 A),

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Section: Rna-sequencing and Data Analysismentioning

confidence: 99%

Section: Microrna Expression Profiling and Data Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Transcriptome Profiling of Human Monocyte-Derived Macrophages Upon CCL2 Neutralization Reveals an Association Between Activation of Innate Immune Pathways and Restriction of HIV-1 Gene Expression

et al. 2020

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“…Nonhuman primate models of SIV infection have clearly shown that infection of the CNS occurs soon after primary viremia [18], and indicate that microglia are infected and may serve as a viral reservoir [19]. Analysis of viral isolates derived from the CNS reveal compartmentalized replication of CCR5-tropic isolates that are adapted to replication in macrophages/microglia [14,20].…”

Section: Introductionmentioning

confidence: 99%

“…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%

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

Dickey

Martins

Planelles

et al. 2022

Journal of Leukocyte Biology

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

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Brain macrophages harbor latent, infectious simian immunodeficiency virus

Cited by 48 publications

References 68 publications

Transcriptome Profiling of Human Monocyte-Derived Macrophages Upon CCL2 Neutralization Reveals an Association Between Activation of Innate Immune Pathways and Restriction of HIV-1 Gene Expression

Transcriptome Profiling of Human Monocyte-Derived Macrophages Upon CCL2 Neutralization Reveals an Association Between Activation of Innate Immune Pathways and Restriction of HIV-1 Gene Expression

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

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

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