Pub Date : 2024-06-01DOI: 10.1007/s13365-024-01220-z
Firoz Ahmad, Shad Ahmad, Adil Husain, Niharika Pandey, Mohd Khubaib, Rolee Sharma
{"title":"Correction: Role of inflammatory cytokine burst in neuro-invasion of Japanese Encephalitis virus infection: an immunotherapeutic approaches.","authors":"Firoz Ahmad, Shad Ahmad, Adil Husain, Niharika Pandey, Mohd Khubaib, Rolee Sharma","doi":"10.1007/s13365-024-01220-z","DOIUrl":"10.1007/s13365-024-01220-z","url":null,"abstract":"","PeriodicalId":16665,"journal":{"name":"Journal of NeuroVirology","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141300807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-31DOI: 10.1007/s13365-024-01211-0
Kimberly S Williams, Jaimie A Seawell, Viktoriya Zhuravleva, Kersten Pierre, Rick B Meeker
Neural damage due to inflammatory activation of macrophages and microglia is a consequence of HIV infection that leads to cognitive dysfunction. The damage is due, in part, to the release of factors that impair neuronal function but the mechanisms that control their release are poorly understood. Previous studies have shown that mature nerve growth factor (NGF) binding to tropomyosin receptor kinase A (TrkA), and proNGF acting through the p75 neurotrophin receptor (p75NTR) differentially control the phenotype of macrophages in response to HIV. However, the mechanisms responsible for these actions are unclear. The current studies demonstrated that in human monocyte-derived macrophages, CCR5 tropic HIV virions interact with the CXCR4 receptor to promote a neurotoxic macrophage phenotype. TrkA cooperatively interacted with CXCR4 to promote quick and dynamic changes in CXCR4 phosphorylation and more stable downstream actin remodeling in the form of membrane ruffles. TrkA signaling also promoted increased moacrophage calcium spiking, and low neurotoxic activity. Disruption of these interactions by HIV led to an alternative podosome-bearing phenotype with minimal calcium signaling and enhanced toxicity. Neurotrophin receptors provide an independent yet cooperative pathway for modifying the actin cytoskeleton in response to chemokines and subsequent degenerative activity. The strong opposing effects of mature and proneurotrophins may provide the opportunity to develop novel therapies that regulate the phenotype of macrophages in the context of HIV infection and perhaps other degenerative diseases.
巨噬细胞和小胶质细胞的炎症激活导致的神经损伤是艾滋病病毒感染的一个后果,会导致认知功能障碍。这种损伤部分是由于损害神经元功能的因子释放所致,但人们对控制这些因子释放的机制知之甚少。先前的研究表明,成熟的神经生长因子(NGF)与肌钙蛋白受体激酶 A(TrkA)结合,原神经生长因子通过 p75 神经营养素受体(p75NTR)发挥作用,以不同方式控制巨噬细胞对 HIV 的表型。然而,这些作用的机制尚不清楚。目前的研究表明,在源于人类单核细胞的巨噬细胞中,CCR5 滋养型 HIV 病毒与 CXCR4 受体相互作用,促进神经毒性巨噬细胞表型的形成。TrkA 与 CXCR4 相互合作,促进 CXCR4 磷酸化的快速动态变化,并以膜皱褶的形式促进更稳定的下游肌动蛋白重塑。TrkA 信号传导还促进了濡养细胞钙尖峰的增加和低神经毒性活性。艾滋病毒对这些相互作用的破坏导致了另一种荚膜表型,即钙信号转导最小、毒性增强的表型。神经营养素受体为改变肌动蛋白细胞骨架提供了一个独立而又合作的途径,以响应趋化因子和随后的退化活动。成熟神经营养素和前神经营养素的强烈对立效应可能为开发新型疗法提供了机会,这些疗法可在艾滋病病毒感染和其他变性疾病的情况下调节巨噬细胞的表型。
{"title":"Cooperative interactions between neurotrophin receptors and CXCR4 regulate macrophage phenotype and susceptibility to activation by HIV.","authors":"Kimberly S Williams, Jaimie A Seawell, Viktoriya Zhuravleva, Kersten Pierre, Rick B Meeker","doi":"10.1007/s13365-024-01211-0","DOIUrl":"https://doi.org/10.1007/s13365-024-01211-0","url":null,"abstract":"<p><p>Neural damage due to inflammatory activation of macrophages and microglia is a consequence of HIV infection that leads to cognitive dysfunction. The damage is due, in part, to the release of factors that impair neuronal function but the mechanisms that control their release are poorly understood. Previous studies have shown that mature nerve growth factor (NGF) binding to tropomyosin receptor kinase A (TrkA), and proNGF acting through the p75 neurotrophin receptor (p75<sup>NTR</sup>) differentially control the phenotype of macrophages in response to HIV. However, the mechanisms responsible for these actions are unclear. The current studies demonstrated that in human monocyte-derived macrophages, CCR5 tropic HIV virions interact with the CXCR4 receptor to promote a neurotoxic macrophage phenotype. TrkA cooperatively interacted with CXCR4 to promote quick and dynamic changes in CXCR4 phosphorylation and more stable downstream actin remodeling in the form of membrane ruffles. TrkA signaling also promoted increased moacrophage calcium spiking, and low neurotoxic activity. Disruption of these interactions by HIV led to an alternative podosome-bearing phenotype with minimal calcium signaling and enhanced toxicity. Neurotrophin receptors provide an independent yet cooperative pathway for modifying the actin cytoskeleton in response to chemokines and subsequent degenerative activity. The strong opposing effects of mature and proneurotrophins may provide the opportunity to develop novel therapies that regulate the phenotype of macrophages in the context of HIV infection and perhaps other degenerative diseases.</p>","PeriodicalId":16665,"journal":{"name":"Journal of NeuroVirology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141183857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-08DOI: 10.1007/s13365-024-01208-9
Tapio Nevalainen, Arttu Autio-Kimura, Mikko Hurme
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease. One of the basic mechanisms in this disease is the autoimmune response against the myelin sheet leading to axonal damage. There is strong evidence showing that this response is regulated by both genetic and environmental factors. In addition, the role of viruses has been extensively studied, especially in the case of human endogenous retroviruses (HERVs). However, although several associations with MS susceptibility, especially in the case of HERV-W family have been observed, the pathogenic mechanisms have remained enigmatic. To clarify these HERV-mediated mechanisms as well as the responsible HERV-W loci, we utilized RNA sequencing data obtained from the white matter of the brain of individuals with and without MS. CIBERSORTx tool was applied to estimate the proportions of neuronal, glial, and endothelial cells in the brain. In addition, the transcriptional activity of 215 HERV-W loci were analyzed. The results indicated that 65 HERV-W loci had detectable expression, of which 14 were differentially expressed between MS and control samples. Of these, 12 HERV-W loci were upregulated in MS. Expression levels of the 8 upregulated HERV-W loci had significant negative correlation with estimated oligodendrocyte proportions, suggesting that they are associated with the dynamics of oligodendrocyte generation and/or maintenance. Furthermore, Gene Set Enrichment Analysis (GSEA) results indicated that expression levels of three upregulated HERV-W loci: 2p16.2, 2q13, and Xq13.3, are associated with suppression of oligodendrocyte development and myelination. Taken together, these data suggest new HERV-W loci candidates that might take part in MS pathogenesis.
{"title":"Human endogenous retrovirus W in multiple sclerosis: transcriptional activity is associated with decline in oligodendrocyte proportions in the white matter of the brain.","authors":"Tapio Nevalainen, Arttu Autio-Kimura, Mikko Hurme","doi":"10.1007/s13365-024-01208-9","DOIUrl":"https://doi.org/10.1007/s13365-024-01208-9","url":null,"abstract":"<p><p>Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease. One of the basic mechanisms in this disease is the autoimmune response against the myelin sheet leading to axonal damage. There is strong evidence showing that this response is regulated by both genetic and environmental factors. In addition, the role of viruses has been extensively studied, especially in the case of human endogenous retroviruses (HERVs). However, although several associations with MS susceptibility, especially in the case of HERV-W family have been observed, the pathogenic mechanisms have remained enigmatic. To clarify these HERV-mediated mechanisms as well as the responsible HERV-W loci, we utilized RNA sequencing data obtained from the white matter of the brain of individuals with and without MS. CIBERSORTx tool was applied to estimate the proportions of neuronal, glial, and endothelial cells in the brain. In addition, the transcriptional activity of 215 HERV-W loci were analyzed. The results indicated that 65 HERV-W loci had detectable expression, of which 14 were differentially expressed between MS and control samples. Of these, 12 HERV-W loci were upregulated in MS. Expression levels of the 8 upregulated HERV-W loci had significant negative correlation with estimated oligodendrocyte proportions, suggesting that they are associated with the dynamics of oligodendrocyte generation and/or maintenance. Furthermore, Gene Set Enrichment Analysis (GSEA) results indicated that expression levels of three upregulated HERV-W loci: 2p16.2, 2q13, and Xq13.3, are associated with suppression of oligodendrocyte development and myelination. Taken together, these data suggest new HERV-W loci candidates that might take part in MS pathogenesis.</p>","PeriodicalId":16665,"journal":{"name":"Journal of NeuroVirology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140876698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-07DOI: 10.1007/s13365-024-01207-w
Stephanie B H Gumbs, Arjen J Stam, Tania Mudrikova, Pauline J Schipper, Andy I M Hoepelman, Petra M van Ham, Anne L Borst, LMarije Hofstra, Lavina Gharu, Stephanie van Wyk, Eduan Wilkinson, Lot D de Witte, Annemarie M J Wensing, Monique Nijhuis
Despite antiretroviral therapy (ART), HIV persistence in the central nervous system (CNS) continues to cause a range of cognitive impairments in people living with HIV (PLWH). Upon disease progression, transmigrating CCR5-using T-cell tropic viruses are hypothesized to evolve into macrophage-tropic viruses in the CNS that can efficiently infect low CD4-expressing cells, such as microglia. We examined HIV-1 RNA concentration, co-receptor usage, and CSF compartmentalization in paired CSF and blood samples from 19 adults not on treatment. Full-length envelope CSF- and plasma-derived reporter viruses were generated from 3 subjects and phenotypically characterized in human primary CD4+ T-cells and primary microglia. Median HIV RNA levels were higher in plasma than in CSF (5.01 vs. 4.12 log10 cp/mL; p = 0.004), and coreceptor usage was mostly concordant for CCR5 across the paired samples (n = 17). Genetically compartmentalized CSF viral populations were detected in 2 subjects, one with and one without neurological symptoms. All viral clones could replicate in T-cells (R5 T cell-tropic). In addition, 3 CSF and 1 plasma patient-derived viral clones also had the capacity to replicate in microglia/macrophages and, therefore have an intermediate macrophage tropic phenotype. Overall, with this study, we demonstrate that in a subset of PLWH, plasma-derived viruses undergo genetic and phenotypic evolution within the CNS, indicating viral infection and replication in CNS cells. It remains to be studied whether the intermediate macrophage-tropic phenotype observed in primary microglia represents a midpoint in the evolution towards a macrophage-tropic phenotype that can efficiently replicate in microglial cells and propagate viral infection in the CNS.
尽管采用了抗逆转录病毒疗法(ART),但艾滋病毒在中枢神经系统(CNS)中的持续存在仍会导致艾滋病毒感染者(PLWH)出现一系列认知障碍。据推测,在疾病进展过程中,使用 CCR5 的 T 细胞滋养型病毒会在中枢神经系统中进化为巨噬细胞滋养型病毒,从而有效感染小胶质细胞等低 CD4 表达细胞。我们研究了未接受治疗的 19 名成人的配对 CSF 和血液样本中 HIV-1 RNA 的浓度、共受体的使用情况以及 CSF 的分区。从 3 名受试者的 CSF 和血浆中生成了全长包膜报告病毒,并在人类原代 CD4+ T 细胞和原代小胶质细胞中进行了表型鉴定。血浆中的 HIV RNA 中位数水平高于 CSF(5.01 对 4.12 log10 cp/mL;p = 0.004),在配对样本(n = 17)中,CCR5 的核心受体使用情况基本一致。在两名受试者(一名有神经系统症状,一名无神经系统症状)中检测到了基因区隔的脑脊液病毒群。所有病毒克隆都能在 T 细胞中复制(R5 T 细胞趋向性)。此外,3 个 CSF 和 1 个血浆病毒克隆还能在小胶质细胞/巨噬细胞中复制,因此具有中间巨噬细胞滋养表型。总之,通过这项研究,我们证明了在一部分 PLWH 患者中,血浆衍生病毒在中枢神经系统内经历了基因和表型演变,表明病毒在中枢神经系统细胞内感染和复制。在原发性小胶质细胞中观察到的中间巨噬细胞-向性表型是否代表了向巨噬细胞-向性表型进化的一个中点,而巨噬细胞-向性表型可以在小胶质细胞中有效复制并在中枢神经系统中传播病毒感染,这还有待研究。
{"title":"Characterization of HIV variants from paired Cerebrospinal fluid and Plasma samples in primary microglia and CD4<sup>+</sup> T-cells.","authors":"Stephanie B H Gumbs, Arjen J Stam, Tania Mudrikova, Pauline J Schipper, Andy I M Hoepelman, Petra M van Ham, Anne L Borst, LMarije Hofstra, Lavina Gharu, Stephanie van Wyk, Eduan Wilkinson, Lot D de Witte, Annemarie M J Wensing, Monique Nijhuis","doi":"10.1007/s13365-024-01207-w","DOIUrl":"https://doi.org/10.1007/s13365-024-01207-w","url":null,"abstract":"<p><p>Despite antiretroviral therapy (ART), HIV persistence in the central nervous system (CNS) continues to cause a range of cognitive impairments in people living with HIV (PLWH). Upon disease progression, transmigrating CCR5-using T-cell tropic viruses are hypothesized to evolve into macrophage-tropic viruses in the CNS that can efficiently infect low CD4-expressing cells, such as microglia. We examined HIV-1 RNA concentration, co-receptor usage, and CSF compartmentalization in paired CSF and blood samples from 19 adults not on treatment. Full-length envelope CSF- and plasma-derived reporter viruses were generated from 3 subjects and phenotypically characterized in human primary CD4<sup>+</sup> T-cells and primary microglia. Median HIV RNA levels were higher in plasma than in CSF (5.01 vs. 4.12 log10 cp/mL; p = 0.004), and coreceptor usage was mostly concordant for CCR5 across the paired samples (n = 17). Genetically compartmentalized CSF viral populations were detected in 2 subjects, one with and one without neurological symptoms. All viral clones could replicate in T-cells (R5 T cell-tropic). In addition, 3 CSF and 1 plasma patient-derived viral clones also had the capacity to replicate in microglia/macrophages and, therefore have an intermediate macrophage tropic phenotype. Overall, with this study, we demonstrate that in a subset of PLWH, plasma-derived viruses undergo genetic and phenotypic evolution within the CNS, indicating viral infection and replication in CNS cells. It remains to be studied whether the intermediate macrophage-tropic phenotype observed in primary microglia represents a midpoint in the evolution towards a macrophage-tropic phenotype that can efficiently replicate in microglial cells and propagate viral infection in the CNS.</p>","PeriodicalId":16665,"journal":{"name":"Journal of NeuroVirology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140863414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-23DOI: 10.1007/s13365-024-01197-9
Qesya Rodrigues Ferreira, Ana Flávia Novaes, Carolina Souza Santana, Arthur Shigueru Umeda, Jéssica Oliveira de Souza Nascimento, João Pedro Melo de Freitas Santos, Larissa Alves Fernandes, Matheus Nascimento Moura, Rebeca Leão Amorim, Vinícius Nogueira Cavalcanti, Ariana Leal Borges da Cruz, F. K. Barreto, D. Costa
{"title":"Neurological aspects of HTLV-1 infection: symptoms in apparently asymptomatic carriers.","authors":"Qesya Rodrigues Ferreira, Ana Flávia Novaes, Carolina Souza Santana, Arthur Shigueru Umeda, Jéssica Oliveira de Souza Nascimento, João Pedro Melo de Freitas Santos, Larissa Alves Fernandes, Matheus Nascimento Moura, Rebeca Leão Amorim, Vinícius Nogueira Cavalcanti, Ariana Leal Borges da Cruz, F. K. Barreto, D. Costa","doi":"10.1007/s13365-024-01197-9","DOIUrl":"https://doi.org/10.1007/s13365-024-01197-9","url":null,"abstract":"","PeriodicalId":16665,"journal":{"name":"Journal of NeuroVirology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140669515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily targets respiratory cells, but emerging evidence shows neurological involvement, with the virus directly affecting neurons and glia. SARS-CoV-2 entry into a target cell requires co-expression of ACE2 (Angiotensin-converting enzyme-2) and TMPRSS2 (Trans membrane serine protease-2). Relevant literature on human neurological tissue is sparse and mostly focused on the olfactory areas. This prompted our study to map brain-wide expression of these entry proteins and assess age-related changes. The normal brain tissue samples were collected from cerebral cortex, hippocampus, basal ganglia, thalamus, hypothalamus, brain stem and cerebellum; and were divided into two groups - up to 40 years (n = 10) and above 40 years (n = 10). ACE2 and TMPRSS2 gene expression analysis was done using qRT-PCR and protein co-expression was seen by immunofluorescence. The ACE2 and TMPRSS2 gene expression was observed to be highest in hypothalamus and thalamus regions, respectively. Immunoreactivity for both ACE-2 and TMPRSS2 was observed in all examined brain regions, confirming the presence of these viral entry receptors. Co-localisation was maximum in hypothalamus. Our study did not find any trend related to different age groups. The expression of both these viral entry receptors suggests that normal human brain is susceptibility to SARS-CoV-2, perhaps which could be related to the cognitive and neurological impairment that occur in patients.
{"title":"Mapping ACE2 and TMPRSS2 co-expression in human brain tissue: implications for SARS-CoV-2 neurological manifestations","authors":"Tulika Gupta, Munish Kumar, Ujjwal Jit Kaur, Asha Rao, Ranjana Bharti","doi":"10.1007/s13365-024-01206-x","DOIUrl":"https://doi.org/10.1007/s13365-024-01206-x","url":null,"abstract":"<p>The Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily targets respiratory cells, but emerging evidence shows neurological involvement, with the virus directly affecting neurons and glia. SARS-CoV-2 entry into a target cell requires co-expression of ACE2 (Angiotensin-converting enzyme-2) and TMPRSS2 (Trans membrane serine protease-2). Relevant literature on human neurological tissue is sparse and mostly focused on the olfactory areas. This prompted our study to map brain-wide expression of these entry proteins and assess age-related changes. The normal brain tissue samples were collected from cerebral cortex, hippocampus, basal ganglia, thalamus, hypothalamus, brain stem and cerebellum; and were divided into two groups - up to 40 years (<i>n</i> = 10) and above 40 years (<i>n</i> = 10). ACE2 and TMPRSS2 gene expression analysis was done using qRT-PCR and protein co-expression was seen by immunofluorescence. The ACE2 and TMPRSS2 gene expression was observed to be highest in hypothalamus and thalamus regions, respectively. Immunoreactivity for both ACE-2 and TMPRSS2 was observed in all examined brain regions, confirming the presence of these viral entry receptors. Co-localisation was maximum in hypothalamus. Our study did not find any trend related to different age groups. The expression of both these viral entry receptors suggests that normal human brain is susceptibility to SARS-CoV-2, perhaps which could be related to the cognitive and neurological impairment that occur in patients.</p>","PeriodicalId":16665,"journal":{"name":"Journal of NeuroVirology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140588173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-10DOI: 10.1007/s13365-024-01204-z
Martina Donadoni, Senem Cakir, Anna Bellizzi, Michael Swingler, Ilker K. Sariyer
The human immunodeficiency virus (HIV) epidemic is an ongoing global health problem affecting 38 million people worldwide with nearly 1.6 million new infections every year. Despite the advent of combined antiretroviral therapy (cART), a large percentage of people with HIV (PWH) still develop neurological deficits, grouped into the term of HIV-associated neurocognitive disorders (HAND). Investigating the neuropathology of HIV is important for understanding mechanisms associated with cognitive impairment seen in PWH. The major obstacle for studying neuroHIV is the lack of suitable in vitro human culture models that could shed light into the HIV-CNS interactions. Recent advances in induced pluripotent stem cell (iPSC) culture and 3D brain organoid systems have allowed the generation of 2D and 3D culture methods that possess a potential to serve as a model of neurotropic viral diseases, including HIV. In this study, we first generated and characterized several hiPSC lines from healthy human donor skin fibroblast cells. hiPSCs were then used for the generation of microglia-containing human cerebral organoids (hCOs). Once fully characterized, hCOs were infected with HIV-1 in the presence and absence of cART regimens and viral infection was studied by cellular, molecular/biochemical, and virological assays. Our results revealed that hCOs were productively infected with HIV-1 as evident by viral p24-ELISA in culture media, RT-qPCR and RNAscope analysis of viral RNA, as well as ddPCR analysis of proviral HIV-1 in genomic DNA samples. More interestingly, replication and gene expression of HIV-1 were also greatly suppressed by cART in hCOs as early as 7 days post-infections. Our results suggest that hCOs derived from hiPSCs support HIV-1 replication and gene expression and may serve as a unique platform to better understand neuropathology of HIV infection in the brain.
{"title":"Modeling HIV-1 infection and NeuroHIV in hiPSCs-derived cerebral organoid cultures","authors":"Martina Donadoni, Senem Cakir, Anna Bellizzi, Michael Swingler, Ilker K. Sariyer","doi":"10.1007/s13365-024-01204-z","DOIUrl":"https://doi.org/10.1007/s13365-024-01204-z","url":null,"abstract":"<p>The human immunodeficiency virus (HIV) epidemic is an ongoing global health problem affecting 38 million people worldwide with nearly 1.6 million new infections every year. Despite the advent of combined antiretroviral therapy (cART), a large percentage of people with HIV (PWH) still develop neurological deficits, grouped into the term of HIV-associated neurocognitive disorders (HAND). Investigating the neuropathology of HIV is important for understanding mechanisms associated with cognitive impairment seen in PWH. The major obstacle for studying neuroHIV is the lack of suitable in vitro human culture models that could shed light into the HIV-CNS interactions. Recent advances in induced pluripotent stem cell (iPSC) culture and 3D brain organoid systems have allowed the generation of 2D and 3D culture methods that possess a potential to serve as a model of neurotropic viral diseases, including HIV. In this study, we first generated and characterized several hiPSC lines from healthy human donor skin fibroblast cells. hiPSCs were then used for the generation of microglia-containing human cerebral organoids (hCOs). Once fully characterized, hCOs were infected with HIV-1 in the presence and absence of cART regimens and viral infection was studied by cellular, molecular/biochemical, and virological assays. Our results revealed that hCOs were productively infected with HIV-1 as evident by viral p24-ELISA in culture media, RT-qPCR and RNAscope analysis of viral RNA, as well as ddPCR analysis of proviral HIV-1 in genomic DNA samples. More interestingly, replication and gene expression of HIV-1 were also greatly suppressed by cART in hCOs as early as 7 days post-infections. Our results suggest that hCOs derived from hiPSCs support HIV-1 replication and gene expression and may serve as a unique platform to better understand neuropathology of HIV infection in the brain.</p>","PeriodicalId":16665,"journal":{"name":"Journal of NeuroVirology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140588048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-04DOI: 10.1007/s13365-024-01200-3
Jasmini Alagaratnam, John P. Thornhill, Zhen Fan, Jaime H. Vera, Jonathan Underwood, Rebecca Hall, Graham Searle, David Owen, Paul Edison, Sarah Fidler, Alan Winston
Persistent inflammation is described in people with HIV (PWH) on antiretroviral treatment (ART). Early ART initiation is associated with reduced inflammation. We aimed to evaluate neuroinflammation, using translocator protein (TSPO) [11C]PBR28 PET neuroimaging in PWH who initiated ART during acute HIV (aPWH) versus chronic HIV infection (cPWH) versus a control population. This was a cross-sectional, observational study. All participants underwent [11C]PBR28 PET-CT neuroimaging. Using a two-tissue compartment model, total volume of distribution (VT) and distribution volume ratios (DVR) using cortical grey matter as a pseudo-reference region at 20 regions of interest (ROIs) were calculated. Differences in VT and DVR were compared between groups using the Kruskall-Wallis test. Seventeen neuro-asymptomatic male PWH on ART (9 aPWH, 8 cPWH) and 8 male control participants (CPs) were included. Median (interquartile range, IQR) age was 40 (30, 46), 44 (41, 47) and 21 (20, 25) years in aPWH, cPWH and CPs, respectively. Median (IQR) CD4 (cells/µL) and CD4:CD8 were 687 (652, 1014) and 1.37 (1.24, 1.42), and 700 (500, 720) and 0.67 (0.64, 0.82) in aPWH and cPWH, respectively. Overall, no significant difference in VT and DVR were observed between the three groups at any ROIs. cPWH demonstrated a trend towards higher mean VT compared with aPWH and CPs at most ROIs. No significant differences in neuroinflammation, using [11C]PBR28 binding as a proxy, were identified between cPWH, aPWH and CPs. A trend towards lower absolute [11C]PBR28 binding was seen amongst aPWH and CPs, suggesting early ART may mitigate neuroinflammation.
{"title":"Differences in neuroinflammation in people who started antiretroviral treatment during primary versus chronic HIV infection: an 18kDa Translocator protein (TSPO) positron emission tomography (PET) study","authors":"Jasmini Alagaratnam, John P. Thornhill, Zhen Fan, Jaime H. Vera, Jonathan Underwood, Rebecca Hall, Graham Searle, David Owen, Paul Edison, Sarah Fidler, Alan Winston","doi":"10.1007/s13365-024-01200-3","DOIUrl":"https://doi.org/10.1007/s13365-024-01200-3","url":null,"abstract":"<p>Persistent inflammation is described in people with HIV (PWH) on antiretroviral treatment (ART). Early ART initiation is associated with reduced inflammation. We aimed to evaluate neuroinflammation, using translocator protein (TSPO) [<sup>11</sup>C]PBR28 PET neuroimaging in PWH who initiated ART during acute HIV (aPWH) versus chronic HIV infection (cPWH) versus a control population. This was a cross-sectional, observational study. All participants underwent [<sup>11</sup>C]PBR28 PET-CT neuroimaging. Using a two-tissue compartment model, total volume of distribution (V<sub>T</sub>) and distribution volume ratios (DVR) using cortical grey matter as a pseudo-reference region at 20 regions of interest (ROIs) were calculated. Differences in V<sub>T</sub> and DVR were compared between groups using the Kruskall-Wallis test. Seventeen neuro-asymptomatic male PWH on ART (9 aPWH, 8 cPWH) and 8 male control participants (CPs) were included. Median (interquartile range, IQR) age was 40 (30, 46), 44 (41, 47) and 21 (20, 25) years in aPWH, cPWH and CPs, respectively. Median (IQR) CD4 (cells/µL) and CD4:CD8 were 687 (652, 1014) and 1.37 (1.24, 1.42), and 700 (500, 720) and 0.67 (0.64, 0.82) in aPWH and cPWH, respectively. Overall, no significant difference in V<sub>T</sub> and DVR were observed between the three groups at any ROIs. cPWH demonstrated a trend towards higher mean V<sub>T</sub> compared with aPWH and CPs at most ROIs. No significant differences in neuroinflammation, using [<sup>11</sup>C]PBR28 binding as a proxy, were identified between cPWH, aPWH and CPs. A trend towards lower absolute [<sup>11</sup>C]PBR28 binding was seen amongst aPWH and CPs, suggesting early ART may mitigate neuroinflammation.</p>","PeriodicalId":16665,"journal":{"name":"Journal of NeuroVirology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140588174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-03DOI: 10.1007/s13365-024-01202-1
Abstract
Apart from the typical respiratory symptoms, coronavirus disease 2019 (COVID-19) also affects the central nervous system, leading to central disorders such as encephalopathy and encephalitis. However, knowledge of pediatric COVID-19-associated encephalopathy is limited, particularly regarding specific subtypes of encephalopathy. This study aimed to assess the features of COVID-19-associated encephalopathy/encephalitis in children. We retrospectively analyzed a single cohort of 13 hospitalized children with COVID-19-associated encephalopathy. The primary outcome was the descriptive analysis of the clinical characteristics, magnetic resonance imaging and electroencephalography findings, treatment progression, and outcomes. Thirteen children among a total of 275 (5%) children with confirmed COVID-19 developed associated encephalopathy/encephalitis (median age, 35 months; range, 3–138 months). Autoimmune encephalitis was present in six patients, acute necrotizing encephalopathy in three, epilepsy in three, and central nervous system small-vessel vasculitis in one patient. Eight (62%) children presented with seizures. Six (46%) children exhibited elevated blood inflammatory indicators, cerebrospinal fluid inflammatory indicators, or both. Two (15%) critically ill children presented with multi-organ damage. The magnetic resonance imaging findings varied according to the type of encephalopathy/encephalitis. Electroencephalography revealed a slow background rhythm in all 13 children, often accompanied by epileptic discharges. Three (23%) children with acute necrotizing encephalopathy had poor prognoses despite immunotherapy and other treatments. Ten (77%) children demonstrated good functional recovery without relapse. This study highlights COVID-19 as a new trigger of encephalopathy/encephalitis in children. Autoimmune encephalitis is common, while acute necrotizing encephalopathy can induce poor outcomes. These findings provide valuable insights into the impact of COVID-19 on children’s brains.
{"title":"Clinical characteristics and outcomes of COVID-19-associated encephalopathy in children","authors":"","doi":"10.1007/s13365-024-01202-1","DOIUrl":"https://doi.org/10.1007/s13365-024-01202-1","url":null,"abstract":"<h3>Abstract</h3> <p>Apart from the typical respiratory symptoms, coronavirus disease 2019 (COVID-19) also affects the central nervous system, leading to central disorders such as encephalopathy and encephalitis. However, knowledge of pediatric COVID-19-associated encephalopathy is limited, particularly regarding specific subtypes of encephalopathy. This study aimed to assess the features of COVID-19-associated encephalopathy/encephalitis in children. We retrospectively analyzed a single cohort of 13 hospitalized children with COVID-19-associated encephalopathy. The primary outcome was the descriptive analysis of the clinical characteristics, magnetic resonance imaging and electroencephalography findings, treatment progression, and outcomes. Thirteen children among a total of 275 (5%) children with confirmed COVID-19 developed associated encephalopathy/encephalitis (median age, 35 months; range, 3–138 months). Autoimmune encephalitis was present in six patients, acute necrotizing encephalopathy in three, epilepsy in three, and central nervous system small-vessel vasculitis in one patient. Eight (62%) children presented with seizures. Six (46%) children exhibited elevated blood inflammatory indicators, cerebrospinal fluid inflammatory indicators, or both. Two (15%) critically ill children presented with multi-organ damage. The magnetic resonance imaging findings varied according to the type of encephalopathy/encephalitis. Electroencephalography revealed a slow background rhythm in all 13 children, often accompanied by epileptic discharges. Three (23%) children with acute necrotizing encephalopathy had poor prognoses despite immunotherapy and other treatments. Ten (77%) children demonstrated good functional recovery without relapse. This study highlights COVID-19 as a new trigger of encephalopathy/encephalitis in children. Autoimmune encephalitis is common, while acute necrotizing encephalopathy can induce poor outcomes. These findings provide valuable insights into the impact of COVID-19 on children’s brains.</p>","PeriodicalId":16665,"journal":{"name":"Journal of NeuroVirology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140588059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We aimed to examine the l differences in the assessment of neurocognitive impairment (NCI) using cognitive screening tools between PLWH and HIV-negative individuals and further compare the neurocognitive profiles between the two groups. This was baseline evaluation of Pudong HIV Aging Cohort, including 465 people living with HIV (PLWH) and 465 HIV-negative individuals aged over 50 years matched by age (± 3 years), sex and education. NCI was assessed using the Chinese version of Mini-mental State Examination (MMSE), the International HIV Dementia Scale (IHDS) and Beijing version of Montreal Cognitive Assessment (MoCA). In total, 258 (55.5%), 91 (19.6%), 273 (58.7%) of PLWH were classified as having NCI by the IHDS, MMSE and MoCA, compared to 90 (19.4%), 25 (5.4%), 135 (29.0%) of HIV-negative individuals, respectively (p < 0.05); such associations remained significant in multivariable analysis. PLWH showed a larger overlap of NCI detected by IHDS, MMSE, and MoCA. IHDS and MoCA detected almost all of the NCI detected by MMSE. IHDS-motor and psychomotor speeds and MoCA-executive function showed the greatest disparities between two groups. In multivariable analysis, older age and more depressive symptoms were positively associated with NCI regardless of the screening tools or HIV serostatus. PLWH over 50 years old display a higher prevalence of NCI and distinct neurocognitive profiles compared to HIV-negative individuals, despite viral suppression. Given the more considerable overlap in NCI classification in PLWH, it is advisable to choose one screening tool such as IHDS or MoCA to identify those potentially having NCI and then refer to more comprehensive neuropsychological assessment.
我们旨在研究艾滋病病毒感染者和阴性艾滋病患者在使用认知筛查工具评估神经认知障碍(NCI)时的差异,并进一步比较两组患者的神经认知状况。该研究对浦东 HIV 老年队列进行了基线评估,其中包括 465 名 HIV 感染者(PLWH)和 465 名年龄在 50 岁以上的 HIV 阴性者,他们的年龄(±3 岁)、性别和教育程度相匹配。NCI采用中文版小型精神状态检查(MMSE)、国际艾滋病痴呆量表(IHDS)和北京版蒙特利尔认知评估(MoCA)进行评估。在 IHDS、MMSE 和 MoCA 中,分别有 258(55.5%)、91(19.6%)和 273(58.7%)名 PLWH 患者被归类为患有 NCI,而在 HIV 阴性患者中,分别有 90(19.4%)、25(5.4%)和 135(29.0%)名 PLWH 患者被归类为患有 NCI。
{"title":"Cognitive impairment and neurocognitive profiles among people living with HIV and HIV-negative individuals older over 50 years: a comparison of IHDS, MMSE and MoCA.","authors":"Panpan Chen, Xin Xin, Shaotan Xiao, Hantao Liu, Xin Liu, Na He, Yingying Ding","doi":"10.1007/s13365-024-01205-y","DOIUrl":"10.1007/s13365-024-01205-y","url":null,"abstract":"<p><p>We aimed to examine the l differences in the assessment of neurocognitive impairment (NCI) using cognitive screening tools between PLWH and HIV-negative individuals and further compare the neurocognitive profiles between the two groups. This was baseline evaluation of Pudong HIV Aging Cohort, including 465 people living with HIV (PLWH) and 465 HIV-negative individuals aged over 50 years matched by age (± 3 years), sex and education. NCI was assessed using the Chinese version of Mini-mental State Examination (MMSE), the International HIV Dementia Scale (IHDS) and Beijing version of Montreal Cognitive Assessment (MoCA). In total, 258 (55.5%), 91 (19.6%), 273 (58.7%) of PLWH were classified as having NCI by the IHDS, MMSE and MoCA, compared to 90 (19.4%), 25 (5.4%), 135 (29.0%) of HIV-negative individuals, respectively (p < 0.05); such associations remained significant in multivariable analysis. PLWH showed a larger overlap of NCI detected by IHDS, MMSE, and MoCA. IHDS and MoCA detected almost all of the NCI detected by MMSE. IHDS-motor and psychomotor speeds and MoCA-executive function showed the greatest disparities between two groups. In multivariable analysis, older age and more depressive symptoms were positively associated with NCI regardless of the screening tools or HIV serostatus. PLWH over 50 years old display a higher prevalence of NCI and distinct neurocognitive profiles compared to HIV-negative individuals, despite viral suppression. Given the more considerable overlap in NCI classification in PLWH, it is advisable to choose one screening tool such as IHDS or MoCA to identify those potentially having NCI and then refer to more comprehensive neuropsychological assessment.</p>","PeriodicalId":16665,"journal":{"name":"Journal of NeuroVirology","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140865630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}