Lipopolysaccharide-enhanced, Toll-like Receptor 4–dependent T Helper Cell Type 2 Responses to Inhaled Antigen

Allergic asthma is an inflammatory lung disease initiated and directed by T helper cells type 2 (Th2). The mechanism involved in generation of Th2 responses to inert inhaled antigens, however, is unknown. Epidemiological evidence suggests that exposure to lipopolysaccharide (LPS) or other microbial products can influence the development and severity of asthma. However, the mechanism by which LPS influences asthma pathogenesis remains undefined. Although it is known that signaling through Toll-like receptors (TLR) is required for adaptive T helper cell type 1 (Th1) responses, it is unclear if TLRs are needed for Th2 priming. Here, we report that low level inhaled LPS signaling through TLR4 is necessary to induce Th2 responses to inhaled antigens in a mouse model of allergic sensitization. The mechanism by which LPS signaling results in Th2 sensitization involves the activation of antigen-containing dendritic cells. In contrast to low levels, inhalation of high levels of LPS with antigen results in Th1 responses. These studies suggest that the level of LPS exposure can determine the type of inflammatory response generated and provide a potential mechanistic explanation of epidemiological data on endotoxin exposure and asthma prevalence

Addressing and Inspiring Vaccine Confidence in Black, Indigenous, and People of Color During the Coronavirus Disease 2019 Pandemic

During the coronavirus disease 2019 (COVID-19) pandemic, we have witnessed profound health inequities suffered by Black, Indigenous, and People of Color (BIPOC). These manifested as differential access to testing early in the pandemic, rates of severe disease and death 2-3 times higher than white Americans, and, now, significantly lower vaccine uptake compared with their share of the population affected by COVID-19. This article explores the impact of these COVID-19 inequities (and the underlying cause, structural racism) on vaccine acceptance in BIPOC populations, ways to establish trustworthiness of healthcare institutions, increase vaccine access for BIPOC communities, and inspire confidence in COVID-19 vaccines

Association between HIV infection and mitochondrial DNA copy number in peripheral blood: A population-based, prospective cohort study

Background. Low mitochondrial DNA (mtDNA) copy number (CN) is a predictor of adverse aging outcomes, and its status may be altered in human immunodefciency virus (HIV)-infected persons. Tis study evaluated the cross-sectional and longitudinal change of mtDNA CN by HIV markers. Methods. mtDNA CN was measured in the ALIVE (AIDS Linked to the Intravenous Experience) cohort of persons with a history of injecting drugs. Multivariable linear regression models controlling for demographic characteristics, behavior, and hepatitis C virus (HCV) seropositivity assessed the relationship of mtDNA CN to HIV markers (CD4+ T-cell counts, viral load, antiretroviral therapy [ART] use). Linear mixed models tested the association between HIV markers and age-related mtDNA CN trajectories. Results. Among 741 individuals at baseline, 436 (59%) were infected with HIV. HIV-infected individuals who had lower CD4+ T-cell counts (P =.01), had higher viral loads (P \u3c.01), and were not receiving ART (P \u3c.01) had signifcantly lower mtDNA CNs than uninfected persons; there was no difference between participants who were uninfected and HIV-infected individuals who had well-controlled HIV levels. In longitudinal follow-up of 507 participants, from age 50 years onward, mtDNA CN declined signifcantly faster among HIV-infected individuals than among HIV-uninfected persons (-0.03 units of change/year vs 0.006 units of change/year; P =.04), even among infected individuals with well-controlled HIV. Conclusion. Before 50 years of age, mtDNA CN is similar between HIV-infected individuals with well-controlled HIV and uninfected persons, but from age 50 onward, mtDNA CN declines signifcantly faster among all infected individuals than among HIV-uninfected persons

Differential Relationships among Circulating Inflammatory and Immune Activation Biomediators and Impact of Aging and Human Immunodeficiency Virus Infection in a Cohort of Injection Drug Users

As individuals with human immunodeficiency virus (HIV) infection live longer, aging and age-related chronic conditions have become major health concerns for this vulnerable population. Substantial evidence suggests that chronic inflammation and immune activation contribute significantly to chronic conditions in people aging with or without HIV infection. As a result, increasing numbers of inflammation and immune activation biomediators have been measured. While very few studies describe their in vivo relationships, such studies can serve as an important and necessary initial step toward delineating the complex network of chronic inflammation and immune activation. In this study, we evaluated in vivo relationships between serum levels of neopterin, a biomediator of immune activation, and four commonly described inflammatory biomediators: soluble tumor necrosis factor (TNF)-α receptor (sTNFR)-1, sTNFR-2, interleukin (IL)-6, and C-reactive protein (CRP), as well as the impact of HIV infection and aging in the AIDS Linked to the Intravenous Experience (ALIVE) study, a community-recruited observational study of former and current injection drug users (IDUs) with or at high risk for HIV infection in Baltimore, MD, USA. The study included 1,178 participants in total with 316 HIV-infected (HV+) and 862 HIV-uninfected (HIV−) IDUs. Multivariate regression analyses were employed, adjusting for age, sex, body mass index, smoking, hepatitis C virus co-infection, injection drug use, comorbidities, and HIV status (for all participants), and HIV viral load, CD4+ T-cell counts, and antiretroviral therapy (for HIV+ participants). The results showed significant impact of aging on all five biomediators and that of HIV infection on all but sTNFR-1. In the adjusted model, neopterin had positive associations with sTNFR-1 and sTNFR-2 (partial correlation coefficients: 0.269 and 0.422, respectively, for all participants; 0.292 and 0.354 for HIV+; and 0.262 and 0.435 for HIV−, all p < 0.0001). No significant associations between neopterin and IL-6 or CRP were identified. Such differential relationships between circulating neopterin and sTNFR-1, sTNFR-2, IL-6, and CRP may help inform their selection in future studies. These findings may also facilitate elucidation of underlying inflammatory and immune activation pathways that contribute to age-related chronic conditions, potentially leading to identification of key biomediators, particularly those upstream of CRP, as novel targets for intervention

MyD88-dependent induction of allergic Th2 responses to intranasal antigen

MyD88 is a common Toll-like receptor (TLR) adaptor molecule found to be essential for induction of adaptive Th1 immunity. Conversely, innate control of adaptive Th2 immunity has been shown to occur in a MyD88-independent manner. In this study, we show that MyD88 is an essential innate component in the induction of TLR4-dependent Th2 responses to intranasal antigen; thus we demonstrate what we believe to be a novel role for MyD88 in pulmonary Th2 immunity. Induction of the MyD88-independent type I IFN response to LPS is defective in the pulmonary environment. Moreover, in the absence of MyD88, LPS-induced upregulation of costimulatory molecule expression on pulmonary DCs is defective, in contrast to what has been observed with bone marrow–derived DCs (BMDCs). Reconstitution of Th2 responses occurs upon adoptive pulmonary transfer of activated BMDCs to MyD88-deficient recipients. Furthermore, the dependence of Th2 responses on MyD88 is governed by the initial route of antigen exposure; this demonstrates what we believe are novel site-specific innate mechanisms for control of adaptive Th2 immunity

The relationship of physical performance with HIV disease and mortality

ObjectiveTo evaluate whether HIV infection was associated with reduced physical performance, and to examine if reduced physical performance predicted mortality in our aging cohort of HIV-infected and HIV-uninfected persons.DesignProspective, observational cohort of current and former injection drug users in the AIDS Linked to the IntraVenous Experience study in Baltimore, Maryland, USA.MethodsThe Short Physical Performance Battery (SPPB) was used as an objective measure of physical performance and measured semiannually along with behavioral and demographic data. Correlates of reduced physical performance (SPPB score ≤10) were identified and the relationship between reduced physical performance, HIV infection and mortality was analyzed by Cox regression.ResultsAmong 12 270 person-visits contributed by 1627 participants, the median age was 51, 30.3% were HIV-infected and 32.6% had an SPPB score 10 or less. In multivariable models, HIV infection was independently associated with 30% increased odds of reduced physical performance [odds ratio 1.30; 95% confidence interval (CI):1.12-1.52]. Reduced physical performance predicted mortality in a dose-response manner and within all HIV disease strata. Whereas reduced physical performance alone (hazard ratio 2.52, 95% CI: 1.59-4.00) and HIV infection alone (hazard ratio 2.78, 95% CI: 1.70-4.54) increased mortality, HIV-infected participants with reduced physical performance had a six-fold increased mortality risk (hazard ratio 6.03, 95% CI: 3.80-10.0) compared with HIV-uninfected participants with higher physical performance.ConclusionHIV infection was independently associated with reduced physical performance. HIV and reduced physical performance have independent and joint effects on mortality. Physical performance measurement may be an important research and clinical tool to predict adverse outcomes among aging HIV-infected persons

Frailty, HIV Infection, and Mortality in an Aging Cohort of Injection Drug Users

<div><h3>Background</h3><p>Frailty is associated with morbidity and premature mortality among elderly HIV-uninfected adults, but the determinants and consequences of frailty in HIV-infected populations remain unclear. We evaluated the correlates of frailty, and the impact of frailty on mortality in a cohort of aging injection drug users (IDUs).</p> <h3>Methods</h3><p>Frailty was assessed using standard criteria among HIV-infected and uninfected IDUs in 6-month intervals from 2005 to 2008. Generalized linear mixed-model analyses assessed correlates of frailty. Cox proportional hazards models estimated risk for all-cause mortality.</p> <h3>Results</h3><p>Of 1230 participants at baseline, the median age was 48 years and 29% were HIV-infected; the frailty prevalence was 12.3%. In multivariable analysis of 3,365 frailty measures, HIV-infected IDUs had an increased likelihood of frailty (OR, 1.66; 95% CI, 1.24–2.21) compared to HIV-uninfected IDUs; the association was strongest (OR, 2.37; 95% CI, 1.62–3.48) among HIV-infected IDUs with advanced HIV disease (CD4<350 cells/mm3 and detectable HIV RNA). No significant association was seen with less advanced disease. Sociodemographic factors, comorbidity, depressive symptoms, and prescription drug abuse were also independently associated with frailty. Mortality risk was increased with frailty alone (HR 2.63, 95% CI, 1.23–5.66), HIV infection alone (HR 3.29, 95% CI, 1.85–5.88), and being both HIV-infected and frail (HR, 7.06; 95%CI 3.49–14.3).</p> <h3>Conclusion</h3><p>Frailty was strongly associated with advanced HIV disease, but IDUs with well-controlled HIV had a similar prevalence to HIV-uninfected IDUs. Frailty was independently associated with mortality, with a marked increase in mortality risk for IDUs with both frailty and HIV infection.</p> </div