Regional Differences in the Prevalence of Major Opportunistic Infections among Antiretroviral-Naive Human Immunodeficiency Virus Patients in Japan, Northern Thailand, Northern Vietnam, and the Philippines

To identify regional differences in the distribution of opportunistic infections (OIs) among human immunodeficiency virus (HIV)-infected patients in Asia, the medical records of antiretroviral therapy (ART)-naive patients who attended the following tertiary hospitals from 2003 to 2011 were reviewed: Nagoya Medical Center (NMC, Nagoya, Japan), Lampang Hospital (LPH, Lampang, northern Thailand), Bach Mai Hospital (BMH, Hanoi, northern Vietnam), and Philippine General Hospital (PGH, Manila, Philippines). Logistic regression analyses were performed to identify associations between country of origin and risk of major OIs. In total, 1,505 patients were included: NMC, N = 365; LPH, N = 442; BMH, N = 384; and PGH, N = 314. The median age was 32 years, and 73.3% of all patients were male. The median CD4 count was 200 cells/μL. Most patients at NMC and PGH were men who have sex with men. Injection drug users were most common at BMH (35.7%). Mycobacterium tuberculosis (TB) was most common at PGH (N = 75) but was rare at NMC (N = 4). Pneumocystis pneumonia (PCP) prevalence was highest at NMC (N = 74) and lowest at BMH (N = 13). Multivariable logistic regression showed increased odds of TB at PGH (adjusted odds ratio [aOR] = 42.2, 95% confidence interval [CI] = 14.6?122.1), BMH (aOR = 12.6, CI = 3.9?40.3), and LPH (aOR = 6.6, CI = 2.1?21.1) but decreased odds of PCP at BMH (aOR = 0.1, CI = 0.04?0.2) and LPH (aOR = 0.2, CI = 0.1?0.4) compared with those at NMC. The cryptococcosis risk was increased at LPH (aOR = 6.2, CI = 0.9?41.0) compared with that at NMC. Cytomegalovirus (CMV) retinitis prevalences were similar in all countries. OI prevalence remained high among ART-naive patients in our cohort. The risks of TB, PCP, and cryptococcosis, but not CMV retinitis, differed between countries. Improved early HIV detection is warranted

The brain-liver cholinergic anti-inflammatory pathway and viral infections

Abstract Efferent cholinergic signaling is a critical and targetable source of immunoregulation. The vagus nerve (VN) is the primary source of cholinergic signaling in the body, and partially innervates hepatic functionality through the liver-brain axis. Virus-induced disruption of cholinergic signaling may promote pathogenesis in hepatotropic and neurotropic viruses. Therefore, restoring VN functionality could be a novel therapeutic strategy to alleviate pathogenic inflammation in hepatotropic and neurotropic viral infections alike. In this minireview, we discuss the physiological importance of cholinergic signaling in maintaining liver-brain axis homeostasis. Next, we explore mechanisms by which the VN is perturbed by viral infections, and how non-invasive restoration of cholinergic signaling pathways with bioelectronic medicine (BEM) might ameliorate hepatic inflammation and neuroinflammation in certain viral infections

Plasma galectin-3 is associated with decreased glomerular filtration rate in chronic HIV

Background People living with HIV (PLWH) have higher rates of chronic kidney disease (CKD) compared with HIV-uninfected individuals. The pathogenesis of CKD in HIV remains poorly understood but is likely from a combination of various factors, such as traditional comorbidities, prolonged antiretroviral therapy, immune dysregulation, and direct HIV effect on the kidneys. We evaluated plasma galectin-3 (Gal-3), a circulating marker of fibrosis, and its association with renal function. Methods Estimated glomerular filtration rate (eGFR) was assessed by CKD-EPI. Plasma galectin-3 was obtained from banked specimens by ELISA. Factors associated with eGFR were analyzed using step-wise multiple linear regression. Results A total of 45 PLWH and 58 HIV-uninfected participants were included with similar demographic parameters. Among PLWH, majority had undetectable plasma HIV RNA (82.2%). Gal-3 was significantly higher in PLWH than in HIV-uninfected participants (6.4 [IQR 4.0, 8.5] ng/mL and 4.5 [IQR 2.3, 6.5] ng/mL, respectively; p = 0.020) while a trend towards lower eGFR was found in PLWH compared to the HIV-uninfected cohort (86.8 [IQR 71.3, 91.8] and 89.0 [IQR 78.6, 97.4] mL/min/1.73 m2, respectively; p = 0.071). In univariable analysis, HIV status was marginally associated with decreased eGFR (β coefficient= −0.035, p = 0.051). In the final multivariable regression model adjusted for traditional risk factors of CKD, Gal-3 independently predicted a decrease in eGFR (unstandardized B= −0.008, p < 0.001) while HIV status did not demonstrate any significant association. Conclusion Gal-3 was higher in PLWH compared with HIV-uninfected participants. In multivariable adjusted analyses, Gal-3, but not HIV status, was associated with decreased eGFR. The role of Gal-3 as a biomarker of kidney function needs to be further elucidated

Plasma monocyte chemoattractant protein-1 and tumor necrosis factor-α levels predict the presence of coronary artery calcium in HIV-infected individuals independent of traditional cardiovascular risk factors.

Coronary artery calcium (CAC) is a validated subclinical measure of atherosclerosis. Studies in the general population have linked blood inflammatory biomarkers including monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor (TNF)-α with the burden of CAC, but this relationship is often lost following correction for traditional cardiovascular risk factors. We assessed the relationship of various biomarkers to CAC, specifically in HIV-infected individuals on potent antiretroviral therapy (ART). Analyses utilized entry data from participants in the Hawaii Aging with HIV-Cardiovascular (HAHC-CVD) study. Computerized tomography examinations for CAC were obtained locally and analyzed by a central reading center in blinded fashion. Plasma biomarkers were assessed by multiplexing using Milliplex Human Cardiovascular Disease panels. Among a cohort of 130 subjects [88% male, median (IQR) age of 51 (46-57) years, CD4 count of 492 (341-635) cells/mm(3), 86.9% with HIV RNA ≤50 copies/ml], CAC was present in 46.9% of subjects. In univariate analyses higher levels of log-transformed MCP-1 and TNF-α were associated with the presence of CAC (p&lt;0.05). In multivariate logistic regression models, MCP-1 and TNF-α remained significant after adjustment for traditional cardiovascular (CVD) risk factors. Similar results were found when analyses were assessed by Framingham risk score categories or when restricted to subjects with plasma HIV RNA ≤50 copies/ml. In contrast to findings in the general population, higher MCP-1 and TNF-α predict the presence of CAC independent of traditional CVD risk factors in HIV-infected subjects fully suppressed on ART, suggesting that HIV-mediated immune activation may play a role in CVD risk

Mitochondrial oxidative phosphorylation in peripheral blood mononuclear cells is decreased in chronic HIV and correlates with immune dysregulation.

BackgroundCellular immunometabolism among people living with HIV (PLWH) on antiretroviral therapy (ART) remains under investigated. We assessed the relationships between mitochondrial oxidative phosphorylation (OXPHOS) in peripheral blood mononuclear cells (PBMCs) and blood parameters associated with HIV immune dysregulation.MethodsPLWH ≥40 years old and on stable ART ≥3 months were enrolled (N = 149). OXPHOS complex I (CI, NADH dehydrogenase) and complex IV (CIV, cytochrome c oxidase) protein levels in PBMCs were quantified using immunoassays. Monocyte subsets and markers of T-cell activation, senescence, and exhaustion were measured on PBMC by flow cytometry. Plasma inflammatory mediators were quantified using a multiplex assay. HIV-uninfected group (N = 44) of similar age, gender, and ethnicity had available OXPHOS levels.ResultsPLWH had a median age of 51 years. Majority were male (88.6%), Caucasian (57.7%), and with undetectable plasma HIV RNA ConclusionCI PBMC protein levels were decreased in PLWH on ART. Decreased OXPHOS correlated with disease severity and inflammation. Further studies on the relationship between immunometabolism and immune dysregulation in HIV are warranted

Plasma Monocyte Chemoattractant Protein-1 and Tumor Necrosis Factor-α Levels Predict the Presence of Coronary Artery Calcium in HIV-Infected Individuals Independent of Traditional Cardiovascular Risk Factors

Coronary artery calcium (CAC) is a validated subclinical measure of atherosclerosis. Studies in the general population have linked blood inflammatory biomarkers including monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor (TNF)-α with the burden of CAC, but this relationship is often lost following correction for traditional cardiovascular risk factors. We assessed the relationship of various biomarkers to CAC, specifically in HIV-infected individuals on potent antiretroviral therapy (ART). Analyses utilized entry data from participants in the Hawaii Aging with HIV–Cardiovascular (HAHC-CVD) study. Computerized tomography examinations for CAC were obtained locally and analyzed by a central reading center in blinded fashion. Plasma biomarkers were assessed by multiplexing using Milliplex Human Cardiovascular Disease panels. Among a cohort of 130 subjects [88% male, median (IQR) age of 51 (46–57) years, CD4 count of 492 (341–635) cells/mm(3), 86.9% with HIV RNA ≤50 copies/ml], CAC was present in 46.9% of subjects. In univariate analyses higher levels of log-transformed MCP-1 and TNF-α were associated with the presence of CAC (p<0.05). In multivariate logistic regression models, MCP-1 and TNF-α remained significant after adjustment for traditional cardiovascular (CVD) risk factors. Similar results were found when analyses were assessed by Framingham risk score categories or when restricted to subjects with plasma HIV RNA ≤50 copies/ml. In contrast to findings in the general population, higher MCP-1 and TNF-α predict the presence of CAC independent of traditional CVD risk factors in HIV-infected subjects fully suppressed on ART, suggesting that HIV-mediated immune activation may play a role in CVD risk

Monocytes expand with immune dysregulation and is associated with insulin resistance in older individuals with chronic HIV.

Rates of insulin resistance are increased in HIV-infected patients on stable antiretroviral therapy (ART). Such increase may partially be due to HIV-induced immune dysregulation involving monocytes (MO) and its subsets.Cross-sectional analysis of 141 HIV-infected subjects age ≥ 40 years on stable ART. Homeostatic model assessment-insulin resistance (HOMA-IR) and rates of metabolic syndrome were calculated. Subjects were classified by fasting glucose and oral glucose tolerance test (OGTT) into clinical diabetes categories. Multi-parametric flow cytometry was used to determine MO subset percentages: [classical (CD14(++)CD16(-)), intermediate (CD14(++)CD16(+)), non-classical (CD14(low/+)CD16(++)), and a recently identified fourth (CD14(low/+)CD16(-)) 'transitional' MO subset] and percentage of activated (CD38(+)HLA-DR(+)) CD8 T cells. Absolute levels of cells were calculated using clinical CBC and T cell subset data. Multiple plasma soluble biomarkers were assessed by Luminex technology.Median age 50 years, CD4 count (percent) 505 cells/µL (29%), and 89% male. Total MO (r=-0.23, p=0.006) and classical and non-classical MO subsets correlated negatively with CD4 percent. No correlations were seen with CD4 count as absolute values. Log-total MO and log-classical MO predicted HOMA-IR independently of HIV immuno-virologic and diabetes risk factors (β=0.42, p=0.02 and β=0.35, p=0.02, respectively) and were increased in subjects with metabolic syndrome (p=0.03 and p=0.05 respectively). Total and/or subset MO levels correlated with multiple soluble plasma biomarkers including CRP, IL-6, MMP-9, MPO, SAA, SAP and tPAI-1, with tPAI-1 independently predicting HOMA-IR (β=0.74, p<0.001).MO levels increase with worsening HIV immune dysregulation as assessed by CD4 percent. CD4 percent may provide additional information about MO and metabolic risk in this population beyond absolute values. MO, and specifically classical MO, may contribute to insulin resistance and metabolic syndrome during chronic HIV infection. Multiple soluble plasma biomarkers including tPAI-1 increase with increase in MO. Levels of tPAI-1 independently predict the development of insulin resistance