Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 17 de 17
Filter
1.
J Leukoc Biol ; 112(5): 1233-1243, 2022 11.
Article in English | MEDLINE | ID: mdl-36073341

ABSTRACT

Macrophages play a significant role in HIV infection and contribute to pathogenesis of comorbidities as well as establishment of the viral reservoir in people living with HIV. While CD4+ T cells are considered the main targets of HIV infection, infected macrophages resist the cytopathic effects of infection, contributing to the persistent HIV reservoir. Furthermore, activated macrophages drive inflammation and contribute to the development of comorbidities, including HIV-associated CNS dysfunction. Better understanding the role of macrophages in HIV infection, persistence, and comorbidities can lead to development of innovative therapeutic strategies to address HIV-related outcomes in people living with HIV. In October 2021, the National Institute of Mental Health and the Ragon Institute of MGH, MIT, and Harvard conducted a virtual meeting on role of macrophages in HIV infection, pathogenesis, and cure. This review article captures the key highlights from this meeting and provides an overview of interests and activities of various NIH institutes involved in supporting research on macrophages and HIV.


Subject(s)
HIV Infections , Humans , HIV Infections/drug therapy , Virus Latency , Macrophages/pathology , CD4-Positive T-Lymphocytes
2.
Jt Comm J Qual Patient Saf ; 46(7): 417-426, 2020 07.
Article in English | MEDLINE | ID: mdl-32473966

ABSTRACT

INTRODUCTION: Hospitals have become an important venue for identifying medical patients with occult suicidality. This article describes the implementation of a quality improvement project at the National Institutes of Health Clinical Center (NIHCC) to systematically screen medical/surgical inpatients for suicide risk. METHODS: Using the Plan-Do-Study-Act method, questions from the Ask Suicide-Screening Questions (ASQ) tool were deployed with medical inpatients aged 10 years and older between April 2018 and April 2019. Goals included the development of a training program, policy and procedure review, electronic medical record integration and data collection, and ongoing management and troubleshooting. RESULTS: A total of 4,284 patients were screened for suicide risk with a nurse screening compliance rate of 94.3%. Prevalence data on patients aged 10 years and older revealed an overall screen positive rate of 2.3% (97/4,284), with 3.1% of youth aged 10 to 24 years and 2.2% of adults screening positive. Of the 97 patients who screened positive, 96 were non-acute positive screens. Of the full sample, only 1 patient (0.02%) was deemed acute positive, requiring a 1:1 observer and full safety precautions. CONCLUSION: Universal suicide risk screening was successfully implemented in the NIHCC without incurring a need for additional resources. The intermediate step of a brief suicide safety assessment is a critical part of the workflow, providing guidance for determining appropriate follow-up in a safe and efficient manner that spares limited mental health and hospital resources. Given the increasing suicide rates in the general population, medical venues offer important opportunities for early detection, assessment, and referral.


Subject(s)
Suicide Prevention , Adolescent , Adult , Humans , Inpatients , Mass Screening , Quality Improvement , Referral and Consultation
3.
J Virus Erad ; 5(1): 50-59, 2019 Jan 01.
Article in English | MEDLINE | ID: mdl-30800428

ABSTRACT

The National Institute of Allergy and Infectious Diseases (NIAID) organised the Strategies for an HIV Cure 2018 meeting focused on research to develop innovative strategies for eradicating or achieving long-term remission of HIV infection. The purpose was to bring together researchers studying HIV persistence and cure strategies, including the six National Institutes of Health (NIH)-funded Martin Delaney Collaboratories for HIV Cure Research (MDCs), as well as industry and community partners, to share scientific results and stimulate active discussion among all stakeholders about the merits of various approaches under investigation. These discussions were intended to stimulate new collaborations and ideas for future research. The meeting covered a comprehensive range of topics spanning basic and translational research, drug discovery and development, and clinical research. Aside from the oral presentations described here, the meeting also included 130 poster presentations. Each of the three days of presentations is available for viewing via the NIH VideoCast website at: https://videocast.nih.gov/PastEvents.asp.

4.
J Virus Erad ; 3(1): 69-76, 2017 Jan 01.
Article in English | MEDLINE | ID: mdl-28275462

ABSTRACT

Since the first Strategies for an HIV Cure Meeting organised by the National Institute of Allergy and Infectious Diseases (NIAID) in 2012, one of the primary purposes of the meeting has been to facilitate communication and foster collaboration across the NIAID-funded Martin Delaney Collaboratories for HIV cure research (MDC), the broader HIV cure-related research field, and industry and community stakeholders. This year's meeting agenda reflected NIAID's increasing investment over the last 5 years in research to identify strategies for eradicating or achieving long-term remission of HIV infection. Overviews and research highlights were presented from each of the Martin Delaney Collaboratories, as well as projects funded through the Beyond HAART programme, the Consortia for Innovative AIDS Research in Nonhuman Primates (CIAR) programme, the ACTG and IMPAACT clinical trial networks, and the NIAID Vaccine Research Center in hopes of stimulating cross-talk and synergy among these and other programmes focused on HIV cure research. Aside from the oral presentations described here, the meeting also included 75 poster presentations. Finally, community engagement activities and community participation in the MDC was highlighted throughout the first day and in a special session on Day 2. This reflects NIAID's commitment to engage community partners in the earliest stages of research towards curative interventions through the MDC programme. The entire meeting is available for viewing via the NIH VideoCast website at: https://videocast.nih.gov/PastEvents.asp.

5.
Am Nat ; 187(2): 236-48, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26807750

ABSTRACT

Theory predicts that immigration can either enhance or impair the rate at which species and whole communities adapt to environmental change, depending on the traits of genotypes and species in the source pool relative to local conditions. These responses, in turn, will determine how well whole communities function in changing environments. We tested the effects of immigration and experimental warming on microbial communities during an 81-day field experiment. The effects of immigration depended on the warming treatment. In warmed communities, immigration was detrimental to community growth, whereas in ambient communities it was beneficial. This result is explained by colonists coming from a local species pool preadapted to ambient conditions. Loss of metabolic diversity, however, was buffered by immigration in both environments. Communities showed increasing local adaptation to temperature conditions during the experiment, and this was independent of whether they received immigration. Genotypes that comprised the communities were not locally adapted, however, indicating that community local adaptation can be independent of adaptation of component genotypes. Our results are consistent with a greater role for species interactions rather than adaptation of constituent species in determining local adaptation of whole communities and confirm that immigration can either enhance or impair community responses to environmental change depending on the environmental context.


Subject(s)
Biodiversity , Fresh Water/microbiology , Hot Temperature , Microbiota , Acclimatization
7.
PLoS Biol ; 10(5): e1001330, 2012.
Article in English | MEDLINE | ID: mdl-22615541

ABSTRACT

Studies of evolutionary responses to novel environments typically consider single species or perhaps pairs of interacting species. However, all organisms co-occur with many other species, resulting in evolutionary dynamics that might not match those predicted using single species approaches. Recent theories predict that species interactions in diverse systems can influence how component species evolve in response to environmental change. In turn, evolution might have consequences for ecosystem functioning. We used experimental communities of five bacterial species to show that species interactions have a major impact on adaptation to a novel environment in the laboratory. Species in communities diverged in their use of resources compared with the same species in monocultures and evolved to use waste products generated by other species. This generally led to a trade-off between adaptation to the abiotic and biotic components of the environment, such that species evolving in communities had lower growth rates when assayed in the absence of other species. Based on growth assays and on nuclear magnetic resonance (NMR) spectroscopy of resource use, all species evolved more in communities than they did in monocultures. The evolutionary changes had significant repercussions for the functioning of these experimental ecosystems: communities reassembled from isolates that had evolved in polyculture were more productive than those reassembled from isolates that had evolved in monoculture. Our results show that the way in which species adapt to new environments depends critically on the biotic environment of co-occurring species. Moreover, predicting how functioning of complex ecosystems will respond to an environmental change requires knowing how species interactions will evolve.


Subject(s)
Adaptation, Physiological , Bacteria/growth & development , Biological Evolution , Environment , Microbial Interactions , Bacteria/isolation & purification , Bacterial Physiological Phenomena , Bacteriological Techniques , Biota , Culture Techniques , Magnetic Resonance Spectroscopy , Monte Carlo Method , Principal Component Analysis
8.
Arch Psychiatr Nurs ; 24(4): 227-38, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20650368

ABSTRACT

Growing up with Asperger's disorder is complex and fraught with difficulty. Although the literature includes some research related to the transition of youth with Asperger's disorder to school and employment, none pertains to the transition to adulthood and independent living. Although a marginal number of young adults with Asperger's disorder eventually achieve independence, many of them continue to depend on families for supportive services. Currently, health care organizations and social services lack coherent, integrated systems to assist youth with Asperger's disorder and their families with the out-of-home transition. To better facilitate the process, this article reviews the literature on Asperger's disorder, leading to a comprehensive, evidence-based transition assessment guide framed by A. Maslow's (1972) hierarchy of needs.


Subject(s)
Adolescent Development , Asperger Syndrome/psychology , Adolescent , Asperger Syndrome/drug therapy , Asperger Syndrome/therapy , Friends , Humans , Interpersonal Relations , Love , Psychotherapy , Young Adult
9.
J Virol ; 82(10): 4991-5006, 2008 May.
Article in English | MEDLINE | ID: mdl-18353960

ABSTRACT

Barley stripe mosaic virus (BSMV) encodes three movement proteins in an overlapping triple gene block (TGB), but little is known about the physical interactions of these proteins. We have characterized a ribonucleoprotein (RNP) complex consisting of the TGB1 protein and plus-sense BSMV RNAs from infected barley plants and have identified TGB1 complexes in planta and in vitro. Homologous TGB1 binding was disrupted by site-specific mutations in each of the first two N-terminal helicase motifs but not by mutations in two C-terminal helicase motifs. The TGB2 and TGB3 proteins were not detected in the RNP, but affinity chromatography and yeast two-hybrid experiments demonstrated that TGB1 binds to TGB3 and that TGB2 and TGB3 form heterologous interactions. These interactions required the TGB2 glycine 40 and the TGB3 isoleucine 108 residues, and BSMV mutants containing these amino acid substitution were unable to move from cell to cell. Infectivity experiments indicated that TGB1 separated on a different genomic RNA from TGB2 and TGB3 could function in limited cell-to-cell movement but that the rates of movement depended on the levels of expression of the proteins and the contexts in which they are expressed. Moreover, elevated expression of the wild-type TGB3 protein interfered with cell-to-cell movement but movement was not affected by the similar expression of a TGB3 mutant that fails to interact with TGB2. These experiments suggest that BSMV movement requires physical interactions of TGB2 and TGB3 and that substantial deviation from the TGB protein ratios expressed by the wild-type virus compromises movement.


Subject(s)
Hordeum/virology , Plant Viral Movement Proteins/metabolism , Plant Viruses/physiology , RNA Viruses/physiology , Amino Acid Substitution/genetics , Chromatography, Affinity , Mutagenesis, Site-Directed , Nucleoproteins/chemistry , Nucleoproteins/isolation & purification , Protein Binding , Protein Interaction Mapping , Two-Hybrid System Techniques
11.
J Neurovirol ; 13(3): 274-83, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17613718

ABSTRACT

Human immunodeficiency virus type 1 (HIV-1) central nervous system (CNS) infection in children is associated with impaired brain growth and neurodevelopmental delays. Neural progenitors are critical for neurogenesis. Human multipotential neural progenitors grown in culture are permissive for HIV-1 infection, but it is not known if infection of these cells occurs in vivo. Brain tissue from pre-highly active antiretroviral therapy (HAART) era pediatric acquired immunodeficiency syndrome (AIDS) patients was examined for evidence of HIV-1 infection of nestin-positive neural progenitors by in situ hybridization; or after laser microdissection harvest, DNA extraction, and polymerase chain reaction (PCR). HIV-1 or viral DNA was identified in nestin-positive cells in four of seven HIV-1-infected children, suggesting in vivo infection of neural progenitors.


Subject(s)
AIDS Dementia Complex/pathology , HIV-1/isolation & purification , Stem Cells/virology , Biomarkers/metabolism , Child, Preschool , DNA, Viral/metabolism , Female , HIV-1/genetics , Humans , In Situ Hybridization , Infant , Intermediate Filament Proteins/metabolism , Male , Microdissection , Nerve Tissue Proteins/metabolism , Nestin , Neurons/pathology , Stem Cells/metabolism , Stem Cells/pathology
12.
Glia ; 53(1): 81-91, 2006 Jan 01.
Article in English | MEDLINE | ID: mdl-16206198

ABSTRACT

Chemokines (chemoattractant cytokines) and their receptors are present in the brain and may play roles in both neurodevelopment and neuropathology. Increased brain levels of monocyte chemoattractant protein-1 (MCP-1), also known as CCL2, are found in patients with human immunodeficiency virus type 1 (HIV-1)-associated dementia and other acute and chronic neurologic diseases. Although the function of CCL2 in the brain is unclear, it is believed that upregulation of this chemokine during neuropathologic or neuroinflammatory conditions leads to recruitment of activated monocytes into the brain, where they differentiate into macrophages producing neurotoxic and inflammatory molecules. We recently showed that human fetal brain-derived progenitor cells are susceptible to HIV-1 and JC virus infection, and that differentiation toward an astrocyte phenotype increased virus production from these cells. In the current study, we found that in the absence of infection, progenitors produced moderate levels of CCL2 (5.6 ng per million cells). Astrocyte differentiation over 3 weeks increased CCL2 protein levels 30-fold in a biphasic manner, whereas neuronal differentiation decreased production 20-fold. Electromobility shift assays (EMSAs) demonstrated increased nuclear NF-kappaB levels within 2 h of initiating astrocyte differentiation, and inhibitors of NF-kappaB activation partially blocked the CCL2 increase in differentiating astrocytes. Transfection of progenitors with mutated CCL2 promoter/CAT reporter constructs showed that the distal promoter region, containing NF-kappaB and NF-I binding sites, is important for differentiation-induced CCL2 upregulation. Together these results suggest that the transcription factor NF-kappaB, and possibly NF-I, contribute to the upregulation of CCL2 chemokine production during the differentiation of human progenitor cells toward an astrocyte phenotype.


Subject(s)
Astrocytes/metabolism , Cell Differentiation/immunology , Central Nervous System/embryology , Chemokine CCL2/metabolism , Stem Cells/metabolism , Up-Regulation/immunology , AIDS Dementia Complex/immunology , AIDS Dementia Complex/metabolism , AIDS Dementia Complex/physiopathology , Astrocytes/cytology , Astrocytes/immunology , Binding Sites/physiology , Cell Differentiation/genetics , Cells, Cultured , Central Nervous System/cytology , Central Nervous System/metabolism , Chemokine CCL2/genetics , Chemotaxis/genetics , Chemotaxis/immunology , HIV-1/immunology , HIV-1/metabolism , Humans , JC Virus/immunology , JC Virus/metabolism , NF-kappa B/genetics , NF-kappa B/metabolism , NFI Transcription Factors/genetics , NFI Transcription Factors/metabolism , Phenotype , Polyomavirus Infections/immunology , Polyomavirus Infections/metabolism , Polyomavirus Infections/physiopathology , Promoter Regions, Genetic/genetics , Stem Cells/cytology , Stem Cells/immunology , Transcriptional Activation/physiology , Tumor Virus Infections/immunology , Tumor Virus Infections/metabolism , Tumor Virus Infections/physiopathology , Up-Regulation/genetics
13.
J Virol ; 78(14): 7319-28, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15220405

ABSTRACT

Although cells of monocytic lineage are the primary source of human immunodeficiency virus type 1 (HIV-1) in the brain, other cell types in the central nervous system, including astrocytes, can harbor a latent or persistent HIV-1 infection. In the present study, we examined whether immature, multipotential human brain-derived progenitor cells (nestin positive) are also permissive for infection. When exposed to IIIB and NL4-3 strains of HIV-1, progenitor cells and progenitor-derived astrocytes became infected, with peak p24 levels of 100 to 500 pg/ml at 3 to 6 days postinfection. After 10 days, virus production was undetectable but could be stimulated by the addition of tumor necrosis factor alpha (TNF-alpha). To bypass limitations to receptor entry, we compared the fate of infection in these cell populations by transfection with the infectious HIV-1 clone, pNL4-3. Again, transfected progenitors and astrocytes produced virus for 7 days but diminished to low levels beyond 8 days posttransfection. During the nonproductive phase, TNF-alpha stimulated virus production from progenitors as late as 5 weeks posttransfection. Astrocytes produced 5- to 20-fold more infectious virus (27 ng of p24/10(6) cells) than progenitors at the peak of 3 days posttransfection. Differentiation of infected progenitors toward an astrocyte phenotype increased virus production to levels consistent with infected astrocytes, suggesting a phenotypic difference in viral replication. Using this cell culture system of multipotential human brain-derived progenitor cells, we provide evidence that progenitor cells may be a reservoir for HIV-1 in the brains of AIDS patients.


Subject(s)
Brain/virology , HIV-1/pathogenicity , Stem Cells/virology , Astrocytes/virology , Brain/cytology , Cells, Cultured , Humans , Neurons/virology , Receptors, CXCR4/metabolism , Transfection
14.
J Virol ; 78(14): 7379-91, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15220411

ABSTRACT

Barley stripe mosaic virus RNAgamma encodes gammab, a cysteine-rich protein that affects pathogenesis. Nine of the eleven cysteines are concentrated in two clusters, designated C1 (residues 1 to 23) and C2 (residues 60 to 85), that are arranged in zinc finger-like motifs. A basic motif (BM) rich in lysine and arginine (residues 19 to 47) resides between the C1 and C2 clusters. We have demonstrated that gammab binds zinc and that the C1, BM, and C2 motifs have independent zinc-binding activities. To evaluate the requirements for binding, mutations were introduced into each region. Cysteine residues at positions 7, 9, 10, 19, and 23 in the C1 motif were replaced with serines. In the BM, asparagines were substituted for lysines at positions 26 and 35, glutamine for arginine at position 25, and glycines for arginines at positions 33 and 36. The C2 mutations included cysteine replacements with serines at positions 60, 64, 71, and 81, and a histidine-to-leucine change at position 85. These mutations destroyed zinc-binding activity in each of the isolated motifs. gammab derivatives containing mutations in only two of the motifs retained the ability to bind zinc, whereas a gammab derivative containing mutations inactivating all three motifs destroyed the ability to bind zinc. Plants inoculated with transcripts containing combinations of the C1, BM, and C2 mutations elicited a "null" phenotype in barley characteristic of gammab deletion mutants and also delayed the appearance and reduced the size of local lesions in Chenopodium amaranticolor. These results show that zinc binding of each of the motifs is critical for the biological activity of gammab.


Subject(s)
Hordeum/virology , RNA Viruses/pathogenicity , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism , Zinc/metabolism , Chromatography, Affinity , Mutation , Plant Diseases/virology , Plant Leaves/virology , Viral Nonstructural Proteins/genetics , Zinc Fingers
15.
Virology ; 313(1): 66-80, 2003 Aug 15.
Article in English | MEDLINE | ID: mdl-12951022

ABSTRACT

Barley stripe mosaic virus (BSMV) contains three positive-sense, single-stranded genomic RNAs, designated alpha, beta, and gamma, that encode seven major proteins and one minor translational readthrough protein. Three proteins (alphaa, betaa, and gammaa) are translated directly from the genomic RNAs and the remaining proteins encoded on RNAbeta and RNAgamma are expressed via three subgenomic messenger RNAs (sgRNAs). sgRNAbeta1 directs synthesis of the triple gene block 1 (TGB1) protein. The TGB2 protein, the TGB2' minor translational readthrough protein, and the TGB3 protein are expressed from sgRNAbeta2, which is present in considerably lower abundance than sgRNAbeta1. A third sgRNA, sgRNAgamma, is required for expression of the gammab protein. We have used deletion analyses and site-specific mutations to define the boundaries of promoter regions that are critical for expression of the BSMV sgRNAs in infected protoplasts. The results reveal that the sgRNAbeta1 promoter encompasses positions -29 to -2 relative to its transcription start site and is adjacent to a cis-acting element required for RNAbeta replication that maps from -107 to -74 relative to the sgRNAbeta1 start site. The core sgRNAbeta2 promoter includes residues -32 to -17 relative to the sgRNAbeta2 transcriptional start site, although maximal activity requires an upstream hexanucleotide sequence residing from positions -64 to -59. The sgRNAgamma promoter maps from -21 to +2 relative to its transcription start site and therefore partially overlaps the gammaa gene. The sgRNAbeta1, beta2, and gamma promoters also differ substantially in sequence, but have similarities to the putative homologous promoters of other Hordeiviruses. These differences are postulated to affect competition for the viral polymerase, coordination of the temporal expression and abundance of the TGB proteins, and constitutive expression of the gammab protein.


Subject(s)
Hordeum/virology , Mosaic Viruses/genetics , RNA, Viral/genetics , Base Sequence , Gene Expression , Molecular Sequence Data , Point Mutation , Promoter Regions, Genetic , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA-Binding Proteins/genetics , Sequence Alignment , Transcription, Genetic , Viral Nonstructural Proteins/genetics
16.
J Virol ; 76(9): 4497-506, 2002 May.
Article in English | MEDLINE | ID: mdl-11932415

ABSTRACT

Neurons of the mammalian central nervous system (CNS) are an essential and largely nonrenewable cell population. Thus, virus infections that result in neuronal depletion, either by virus-mediated cell death or by induction of the cytolytic immune response, could cause permanent neurological impairment of the host. In a transgenic mouse model of measles virus (MV) infection of neurons, we have previously shown that the host T-cell response was required for resolution of infection in susceptible adult mice. In this report, we show that this protective response did not result in neuronal death, even during the peak of T-cell infiltration into the brain parenchyma. When susceptible mice were intercrossed with specific immune knockout mice, a critical role for gamma interferon (IFN-gamma) was identified in protection against MV infection and CNS disease. Moreover, the addition of previously activated splenocytes or recombinant murine IFN-gamma to MV-infected primary neurons resulted in the inhibition of viral replication in the absence of neuronal death. Together, these data support the hypothesis that the host immune response can promote viral clearance without concomitant neuronal loss, a process that appears to be mediated by cytokines.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Central Nervous System Infections/immunology , Interferon-gamma/metabolism , Measles virus/immunology , Animals , Brain/cytology , Brain/immunology , Brain/virology , Central Nervous System Infections/virology , In Situ Nick-End Labeling , Measles/immunology , Measles/virology , Measles virus/pathogenicity , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neurons/virology
17.
Microbes Infect ; 4(3): 301-8, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11909740

ABSTRACT

AIDS patients frequently exhibit neurological disorders due to the neurotoxic events that result from HIV-1 and/or opportunistic infections in the brain. This review examines recent clinical findings related to HIV-1-associated dementia, and outlines current areas of basic research that may clarify how HIV-1-associated encephalopathy produces clinical symptoms of brain dysfunction.


Subject(s)
AIDS Dementia Complex/immunology , AIDS Dementia Complex/pathology , HIV-1/pathogenicity , Brain/immunology , Brain/pathology , Encephalitis, Viral/immunology , Humans , Models, Immunological
SELECTION OF CITATIONS
SEARCH DETAIL
...