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1.
Sex Transm Dis ; 49(10): 719-725, 2022 10 01.
Article in English | MEDLINE | ID: mdl-35797525

ABSTRACT

BACKGROUND: People who exchange sex (PWES) for money or drugs are at increased risk for poor health outcomes and may be reluctant to engage in health services. METHODS: We conducted a cross-sectional analysis of patients seen for new problem visits at the Public Health-Seattle and King County Sexual Health Clinic between October 2010 and March 2020 who reported exchanging sex for drugs or money in a computer assisted self-interview. We analyzed demographics; sexually transmitted infections (STIs), human immunodeficiency virus (HIV), and hepatitis C virus (HCV) history; and HIV preexposure prophylaxis (PrEP) use, stratified by gender. We compared characteristics of people who ever versus never exchanged sex using χ 2 tests and analyzed the visit reason and outcomes among PWES. RESULTS: Among 30,327 patients, 1611 (5%) reported ever exchanging sex: 981 (61%) cisgender men, 545 (34%) cisgender women, and 85 (5%) transgender and gender diverse persons. Compared with people who never exchanged sex, PWES were more likely to report homelessness (29% vs 7%, P < 0.001), injection drug use (39% vs 4%, P < 0.001), prior STIs (36% vs 19%, P < 0.001), prior HIV diagnosis (13% vs 5%, P < 0.001), and prior HCV diagnosis (13% vs 2%, P < 0.001). People who exchange sex came to the clinic seeking STI tests (60%), HIV tests (45%), and care for STI symptoms (38%). Overall, 320 (20%) PWES were diagnosed with STIs, 15 (1%) were newly diagnosed with HIV, and 12 (1%) initiated PrEP at the visit. CONCLUSION: People who exchange sex have complex barriers to care, and sexual health clinic visits present an opportunity to improve health services for this population.


Subject(s)
HIV Infections , Hepatitis C , Pre-Exposure Prophylaxis , Sexual Health , Sexually Transmitted Diseases , Cross-Sectional Studies , Female , HIV Infections/diagnosis , HIV Infections/epidemiology , HIV Infections/prevention & control , Hepatitis C/diagnosis , Hepatitis C/epidemiology , Hepatitis C/prevention & control , Homosexuality, Male , Humans , Male , Sexual Behavior , Sexually Transmitted Diseases/diagnosis , Sexually Transmitted Diseases/epidemiology , Sexually Transmitted Diseases/prevention & control
2.
Infect Immun ; 81(1): 2-10, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23071135

ABSTRACT

Mycobacterium tuberculosis disease represents an enormous global health problem, with exceptionally high morbidity and mortality in HIV-seropositive (HIV(+)) persons. Alveolar macrophages from HIV(+) persons demonstrate specific and targeted impairment of critical host cell responses, including impaired M. tuberculosis-mediated tumor necrosis factor (TNF) release and macrophage apoptosis. Vitamin D may promote anti-M. tuberculosis responses through upregulation of macrophage NO, NADPH oxidase, cathelicidin, and autophagy mechanisms, but whether vitamin D promotes anti-M. tuberculosis mechanisms in HIV(+) macrophages is not known. In the current study, human macrophages exposed to M. tuberculosis demonstrated robust release of TNF, IκB degradation, and NF-κB nuclear translocation, and these responses were independent of vitamin D pretreatment. In marked contrast, HIV(+) U1 human macrophages exposed to M. tuberculosis demonstrated very low TNF release and no significant IκB degradation or NF-κB nuclear translocation, whereas vitamin D pretreatment restored these critical responses. The vitamin D-mediated restored responses were dependent in part on macrophage CD14 expression. Importantly, similar response patterns were observed with clinically relevant human alveolar macrophages from healthy individuals and asymptomatic HIV(+) persons at high clinical risk of M. tuberculosis infection. Taken together with the observation that local bronchoalveolar lavage fluid (BALF) levels of vitamin D are severely deficient in HIV(+) persons, the data from this study demonstrate that exogenous vitamin D can selectively rescue impaired critical innate immune responses in vitro in alveolar macrophages from HIV(+) persons at risk for M. tuberculosis disease, supporting a potential role for exogenous vitamin D as a therapeutic adjuvant in M. tuberculosis infection in HIV(+) persons.


Subject(s)
HIV Seropositivity/microbiology , Macrophages, Alveolar/immunology , Mycobacterium tuberculosis/immunology , Toll-Like Receptors/immunology , Tumor Necrosis Factor-alpha/immunology , Vitamin D/pharmacology , Bronchoalveolar Lavage Fluid/immunology , Cell Line , HIV Seropositivity/immunology , HIV Seropositivity/metabolism , Humans , Lipopolysaccharide Receptors/genetics , Lipopolysaccharide Receptors/immunology , Lipopolysaccharide Receptors/metabolism , Macrophages, Alveolar/drug effects , Macrophages, Alveolar/metabolism , Macrophages, Alveolar/virology , Mycobacterium tuberculosis/metabolism , NF-kappa B/immunology , NF-kappa B/metabolism , RNA, Messenger/genetics , RNA, Messenger/immunology , RNA, Messenger/metabolism , Signal Transduction/immunology , Toll-Like Receptors/metabolism , Tuberculosis/metabolism , Tuberculosis/virology , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , U937 Cells , Up-Regulation/immunology , Vitamin D/immunology , Vitamin D/metabolism
3.
PLoS One ; 7(9): e41024, 2012.
Article in English | MEDLINE | ID: mdl-23028423

ABSTRACT

Macrophages serve to maintain organ homeostasis in response to challenges from injury, inflammation, malignancy, particulate exposure, or infection. Until now, receptor ligation has been understood as being the central mechanism that regulates macrophage function. Using macrophages of different origins and species, we report that macrophage elasticity is a major determinant of innate macrophage function. Macrophage elasticity is modulated not only by classical biologic activators such as LPS and IFN-γ, but to an equal extent by substrate rigidity and substrate stretch. Macrophage elasticity is dependent upon actin polymerization and small rhoGTPase activation, but functional effects of elasticity are not predicted by examination of gene expression profiles alone. Taken together, these data demonstrate an unanticipated role for cell elasticity as a common pathway by which mechanical and biologic factors determine macrophage function.


Subject(s)
Elasticity , Macrophages/physiology , Actins/metabolism , Animals , Cell Line , Elasticity/drug effects , Gene Expression Profiling , Humans , Inflammation/immunology , Interferon-gamma/pharmacology , Lipopolysaccharides/immunology , Lipopolysaccharides/pharmacology , Macrophages/cytology , Macrophages/drug effects , Mice , Phagocytosis/drug effects , Phagocytosis/immunology , Protein Multimerization/drug effects , Transcriptome , rho GTP-Binding Proteins/metabolism
4.
J Immunol ; 187(11): 6052-8, 2011 Dec 01.
Article in English | MEDLINE | ID: mdl-22025552

ABSTRACT

TLR-4-mediated signaling is significantly impaired in macrophages from HIV(+) persons, predominantly owing to altered MyD88-dependent pathway signaling caused in part by constitutive activation of PI3K. In this study we assessed in these macrophages if the blunted increase in TLR-4-mediated TNF-α release induced by lipid A (LA) is associated with PI3K-induced upregulation of mammalian target of rapamycin (mTOR) activity. mTOR inhibition with rapamycin enhanced TLR-4-mediated TNF-α release, but suppressed anti-inflammatory IL-10 release. Targeted gene silencing of mTOR in macrophages resulted in LA-induced TNF-α and IL-10 release patterns similar to those induced by rapamycin. Rapamycin restored MyD88/IL-1R-associated kinase interaction in a dose-dependent manner. Targeted gene silencing of MyD88 (short hairpin RNA) and mTOR (RNA interference) inhibition resulted in TLR-4-mediated 70-kDa ribosomal protein S6 kinase activation and enhanced TNF-α release, whereas IL-10 release was inhibited in both silenced and nonsilenced HIV(+) macrophages. Furthermore, mTOR inhibition augmented LA-induced TNF-α release through enhanced and prolonged phosphorylation of ERK1/2 and JNK1/2 MAPK, which was associated with time-dependent MKP-1 destabilization. Taken together, impaired TLR-4-mediated TNF-α release in HIV(+) macrophages is attributable in part to mTOR activation by constitutive PI3K expression in a MyD88-dependent signaling pathway. These changes result in MAPK phosphatase 1 stabilization, which shortens and blunts MAPK activation. mTOR inhibition may serve as a potential therapeutic target to upregulate macrophage innate immune host defense responsiveness in HIV(+) persons.


Subject(s)
HIV Infections/metabolism , MAP Kinase Signaling System/immunology , Macrophages/metabolism , TOR Serine-Threonine Kinases/metabolism , Tumor Necrosis Factor-alpha/metabolism , Blotting, Western , Enzyme Activation/immunology , Enzyme-Linked Immunosorbent Assay , Gene Knockdown Techniques , HIV Infections/immunology , Humans , Immunoprecipitation , Macrophages/immunology , Macrophages/virology , TOR Serine-Threonine Kinases/immunology , Toll-Like Receptor 4/immunology , Toll-Like Receptor 4/metabolism , Tumor Necrosis Factor-alpha/immunology
5.
Blood ; 115(17): 3606-15, 2010 Apr 29.
Article in English | MEDLINE | ID: mdl-20197549

ABSTRACT

Alveolar macrophages (AMs) are the predominant effector cell in the lungs and contribute to a critical first line of defense against bacterial pathogens through recognition by pattern recognition receptors such as Toll-like receptor 4 (TLR4). TLR4-mediated tumor necrosis factor alpha (TNFalpha) release is significantly impaired in HIV(+) macrophages, but whether HIV impairs myeloid differentiation factor 88 (MyD88)-dependent and/or MyD-independent TLR4 signaling pathways in human macrophages is not known. Comparing human U937 macrophages with HIV(+) U1 macrophages (HIV-infected U937 subclone), the current study shows that HIV infection is associated with impaired macrophage TLR4-mediated signaling, specifically targeting the MyD88-dependent TLR4-mediated signaling pathway (reduced MyD88-interleukin-1 receptor-associated kinase [IRAK] interaction, IRAK phosphorylation, nuclear factor [NF]-kappaB nuclear translocation, and TNFalpha release) while preserving the MyD88-independent TLR4-mediated signaling pathway (preserved STAT1 phosphorylation, interferon regulatory factor [IRF] nuclear translocation, and interleukin-10 [IL-10] and RANTES release). Extracellular TLR4 signaling complex was intact (similar levels of CD14 and MD2), and similar patterns of response were observed in clinically relevant AMs from healthy and asymptomatic HIV(+) persons at high clinical risk of pneumonia. Taken together, these data support the concept that chronic HIV infection is associated with specific and targeted disruption of critical macrophage TLR4 signaling, which in turn may contribute to disease pathogenesis of bacterial pneumonia.


Subject(s)
HIV Infections/metabolism , HIV , Macrophages, Alveolar/metabolism , Myeloid Differentiation Factor 88/metabolism , Signal Transduction , Toll-Like Receptor 4/metabolism , Active Transport, Cell Nucleus/immunology , Cell Nucleus/immunology , Cell Nucleus/metabolism , Cytokines/immunology , Cytokines/metabolism , Female , HIV Infections/immunology , Humans , Interferon Regulatory Factors/immunology , Interferon Regulatory Factors/metabolism , Interleukin-1 Receptor-Associated Kinases/immunology , Interleukin-1 Receptor-Associated Kinases/metabolism , Macrophages, Alveolar/immunology , Male , Myeloid Differentiation Factor 88/immunology , Phosphorylation/immunology , Pneumonia/immunology , Pneumonia/metabolism , Risk , Risk Factors , Toll-Like Receptor 4/immunology , U937 Cells
6.
Mol Biosyst ; 4(12): 1212-9, 2008 Dec.
Article in English | MEDLINE | ID: mdl-19396385

ABSTRACT

Fragile X syndrome, the most common form of inherited mental retardation is caused by the expansion of a CGG trinucleotide repeat in the fragile X mental retardation 1 (fmr1) gene. The abnormal expansion of the CGG repeat causes hypermethylation and subsequent silencing of the fmr1 gene, resulting in the loss of the fragile X mental retardation protein (FMRP). FMRP has been shown to use its arginine-glycine-glycine rich region (RGG box) to bind to messenger RNAs that form G quadruplex structures. Several studies reported that the G quadruplex RNA recognition alone is not sufficient for FMRP RGG box binding and that an additional stem and/or a G quadruplex-stem junction region may also be important in recognition. In this study we have used biophysical methods such as fluorescence, UV, CD and NMR spectroscopy to demonstrate that the recognition of the RNA G quadruplex structure per se, in the absence of a stem region, is sufficient for the FMRP high affinity and specific binding. These findings indicate that the presence of a stem structure in some of the FMRP G quadruplex forming mRNAs is not a requirement for protein recognition as previously believed, but rather for the proper formation of the correct RNA G quadruplex structure recognized by FMRP.


Subject(s)
Fragile X Mental Retardation Protein/metabolism , G-Quadruplexes , RNA/metabolism , Biophysical Phenomena , Fragile X Mental Retardation Protein/genetics , Humans , Nucleic Acid Conformation , Sensitivity and Specificity , Static Electricity , Thermodynamics
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