Search

Interleukin 32 (IL-32) is a potent multi-isoform proinflammatory cytokine, which is upregulated in people with HIV (PWH) and is associated with cardiovascular disease (CVD) risk. However, the impact of IL-32 isoforms on CD4 T-cell cardiotropism, a mechanism potentially contributing to heart inflammation, remains unknown. Here we show that IL-32 isoforms β and γ induce the generation of CCR4+CXCR3+ double positive (DP) memory CD4 T-cell subpopulation expressing the tyrosine kinase receptor c-Met, a phenotype associated with heart-homing of T cells. Our ex vivo studies on PWH show that the frequency of DP CD4 T cells is significantly higher in individuals with, compared to individuals without, subclinical atherosclerosis and that DP cells from antiretroviral-naive and treated individuals are highly enriched with HIV DNA. Together, these data demonstrate that IL-32 isoforms have the potential to induce heart-homing of HIV-infected CD4 T cells, which may further aggravate heart inflammation and CVD in PWH. [ABSTRACT FROM AUTHOR]

Background Although cell surface immune checkpoint proteins (ICPs) such as PD-1 expressed on T cells are associated with T-cell exhaustion, HIV disease progression, and AIDS events, they have shown limited utility in predicting non-AIDS morbidity. Given that ICPs also exist in soluble forms and are elevated in ART-treated HIV infection, we tested the hypothesis that soluble ICPs may be predictive of non-AIDS events in adults initiating ART. Methods Utilizing a nested case–control study from the AIDS Clinical Trials Group ALLRT cohort, we measured plasma levels of 15 soluble inhibitory and activating ICPs by Luminex. Participants (134 cases, 292 matched controls) were evaluated pre-ART, a year post-ART, and immediately preceding a non-AIDS event, which included myocardial infarction (MI)/stroke, malignancy, serious bacterial infection, and nonaccidental death. Results Conditional logistic regression analysis determined that higher levels of soluble CD27 were associated with increased risk of non-AIDS events at all time points. Higher levels of CD40 at baseline and pre-event and CD80 at pre-event were associated with increased risk of non-AIDS events. Examining specific non-AIDS events, multiple ICPs were associated with malignancy at baseline and pre-event, whereas only higher CD27 levels were associated with increased risk of MI/stroke at year 1 and pre-event. Conclusions While select soluble ICPs were associated with non-AIDS events, CD27 emerged as a consistent marker irrespective of ART. Our data may offer guidance on new targets for early clinical monitoring in people with HIV who remain at greater risk of specific non-AIDS events. [ABSTRACT FROM AUTHOR]

Background Development of human immunodeficiency virus (HIV) remission strategies requires precise information on time to HIV rebound after treatment interruption, but there is uncertainty regarding whether modern antiretroviral therapy (ART) regimens and timing of ART initiation may affect this outcome. Methods AIDS Clinical Trials Group (ACTG) A5345 enrolled individuals who initiated ART during chronic or early HIV infection and on suppressive ART for ≥2 years. Participants underwent carefully monitored antiretroviral interruption. ART was restarted upon 2 successive viral loads ≥1000 copies/mL. We compared participants of A5345 with participants of 6 historic ACTG treatment interruption studies. Results Thirty-three chronic-treated and 12 early-treated participants interrupted ART with evaluable time to viral rebound. Median time to viral rebound ≥1000 HIV RNA copies/mL was 22 days. Acute retroviral rebound syndrome was diagnosed in 9% of the chronic-treated and none of the early-treated individuals. All participants of the historic studies were on older protease inhibitor-based regimens, whereas 97% of A5345 participants were on integrase inhibitor-based ART. There were no differences in the timing of viral rebound comparing A5345 versus historic studies. In a combined analysis, a higher percentage of early-treated participants remained off ART at posttreatment interruption week 12 (chronic vs early: 2% vs 9%, P  = .0496). One chronic-treated and one early-treated A5345 participant remained off ART for >24 weeks. All participants resuppressed after ART reinitiation. Conclusions Early ART initiation, using either older or newer ART regimens, was associated with a significant delay in the time to HIV rebound after ART interruption, lowering the barrier for HIV remission. [ABSTRACT FROM AUTHOR]

Background: Persistent immune activation due to gut barrier dysfunction is a suspected cause of morbidity in HIV, but the impact of menopause on this pathway is unknown.Methods: In 350 women with HIV from the Women's Interagency HIV Study, plasma biomarkers of gut barrier dysfunction (intestinal fatty acid binding protein; IFAB), innate immune activation (soluble CD14 and CD163; sCD14, sCD163), and systemic inflammation (interleukin-6 and tumor necrosis factor receptor 1; IL-6, TNFR1) were measured at 674 person-visits spanning ≤2 years.Results: Menopause (post- vs premenopausal status) was associated with higher plasma sCD14 and sCD163 in linear mixed-effects regression adjusting for age and other covariates (β = 161.89 ng/mL; 95% confidence interval [CI], 18.37-305.41 and 65.48 ng/mL, 95% CI, 6.64-124.33, respectively); but not with plasma IFAB, IL-6, or TNFR1. In piece-wise linear mixed-effects regression of biomarkers on years before/after the final menstrual period, sCD14 increased during the menopausal transition by 250.71 ng/mL per year (95% CI, 16.63-484.79; P = .04), but not in premenopausal or postmenopausal periods.Conclusions: In women with HIV, menopause may increase innate immune activation, but data did not support an influence on the gut barrier or inflammation. Clinical implications of immune activation during menopausal transition warrant further investigation. [ABSTRACT FROM AUTHOR]

Background Neurocognitive impairment (NCI) is associated with monocyte activation in people with HIV (PWH). Activated monocytes increase glycolysis, reduce oxidative phosphorylation, and accumulate citrate and succinate, tricarboxylic acid (TCA) cycle metabolites that promote inflammation—this metabolic shift may contribute to NCI and slowed gait speed in PWH. Methods Plasma citrate and succinate were assayed by liquid chromatography–mass spectrometry from 957 participants upon entry to a multicenter, prospective cohort of older PWH. Logistic, linear, and mixed-effects linear regression models were used to examine associations between entry/baseline TCA cycle metabolites and cross-sectional and longitudinal NCI, neuropsychological test scores (NPZ-4), and gait speed. Results Median age was 51 (range 40–78) years. Each 1 standard deviation (SD) citrate increment was associated with 1.18 higher odds of prevalent NCI at baseline (P =.03), 0.07 SD lower time-updated NPZ-4 score (P =.01), and 0.02 m/s slower time-updated gait speed (P <.0001). Age accentuated these effects. In the oldest age-quartile, higher citrate was associated with 1.64 higher odds of prevalent NCI, 0.17 SD lower NPZ-4, and 0.04 m/s slower gait speed (P ≤.01 for each). Similar associations were apparent with succinate in the oldest age-quintile, but not with gait speed. In participants without NCI at entry, higher citrate predicted a faster rate of neurocognitive decline. Conclusions Higher plasma citrate and succinate are associated with worse cross-sectional and longitudinal measures of neurocognitive function and gait speed that are age-dependent, supporting the importance of altered bioenergetic metabolism in the pathogenesis of NCI in older PWH. [ABSTRACT FROM AUTHOR]

Background Food insecurity is associated with increased morbidity and mortality in people with human immunodeficiency virus (HIV) on antiretroviral therapy, but its relationship with immune dysregulation, a hallmark of HIV infection and comorbidity, is unknown. Methods In 241 women participating in the Women's Interagency HIV Study, peripheral blood mononuclear cells were characterized by flow cytometry to identify cell subsets, comprising surface markers of activation (%CD38+HLADR+), senescence (%CD57+CD28−), exhaustion (%PD-1+), and co-stimulation (%CD57− CD28+) on CD4+ and CD8+ T cells. Mixed-effects linear regression models were used to assess the relationships of food insecurity with immune outcomes, accounting for repeated measures at ≤3 study visits and adjusting for sociodemographic and clinical factors. Results At the baseline study visit, 71% of participants identified as non-Hispanic Black, 75% were virally suppressed, and 43% experienced food insecurity. Food insecurity was associated with increased activation of CD4+ and CD8+ T cells, increased senescence of CD8+ T cells, and decreased co-stimulation of CD4+ and CD8+ T cells (all P  < .05), adjusting for age, race/ethnicity, income, education, substance use, smoking, HIV viral load, and CD4 count. In stratified analyses, the association of food insecurity with CD4+ T-cell activation was more pronounced in women with uncontrolled HIV (viral load >40 copies/mL and CD4 <500 cells/mm3) but remained statistically significant in those with controlled HIV. Conclusions Food insecurity may contribute to the persistent immune activation and senescence in women with HIV on antiretroviral therapy, independently of HIV control. Reducing food insecurity may be important for decreasing non–AIDS-related disease risk in this population. [ABSTRACT FROM AUTHOR]

AIDS Clinical Trials Group study A5308 found reduced T-cell activation and exhaustion in human immunodeficiency virus (HIV) controllers start antiretroviral therapy (ART). We further assessed HIV-specific T-cell responses and post-ART viral loads. Before ART, the 31% of participants with persistently undetectable viremia had more robust HIV-specific T-cell responses. During ART, significant decreases were observed in a broad range of T-cell responses. Eight controllers in A5308 and the Study of the Consequences of the Protease Inhibitor Era (SCOPE) cohort showed no viremia above the level of quantification in the first 12 weeks after ART discontinuation. ART significantly reduced HIV-specific T-cell responses in HIV controllers but did not adversely affect controller status after ART discontinuation. [ABSTRACT FROM AUTHOR]

Background Alterations in gut microbiota (GMB) and host metabolites have been noted in individuals with HIV. However, it remains unclear whether alterations in GMB and related functional groups contribute to disrupted host metabolite profiles in these individuals. Methods This study included 185 women (128 with longstanding HIV infection, 88% under antiretroviral therapy; and 57 women without HIV from the same geographic location with comparable characteristics). Stool samples were analyzed by 16S rRNA V4 region sequencing, and GMB function was inferred by PICRUSt. Plasma metabolomic profiling was performed using liquid chromatography–tandem mass spectrometry, and 133 metabolites (amino acids, biogenic amines, acylcarnitines, and lipids) were analyzed. Results Four predominant bacterial genera were identified as associated with HIV infection, with higher abundances of Ruminococcus and Oscillospira and lower abundances of Bifidobacterium and Collinsella in women with HIV than in those without. Women with HIV showed a distinct plasma metabolite profile, which featured elevated glycerophospholipid levels compared with those without HIV. Functional analyses also indicated that GMB lipid metabolism was enriched in women with HIV. Ruminococcus and Oscillospira were among the top bacterial genera contributing to the GMB glycerophospholipid metabolism pathway and showed positive correlations with host plasma glycerophospholipid levels. One bacterial functional capacity in the acetate and propionate biosynthesis pathway was identified to be mainly contributed by Bifidobacterium ; this functional capacity was lower in women with HIV than in women without HIV. Conclusions Our integrative analyses identified altered GMB with related functional capacities that might be associated with disrupted plasma metabolite profiles in women with HIV. [ABSTRACT FROM AUTHOR]

Background: A higher proportion of circulating memory CD4+ T cells is associated with prevalent diabetes mellitus in the general population. Given the broad changes in adaptive immunity, including memory T-cell expansion, and rising prevalence of diabetes in the human immunodeficiency virus (HIV) population, we assessed whether similar relationships were present in persons with HIV (PWH).Methods: Multiple CD4+ and CD8+ T-cell subsets were measured by flow cytometry, and prevalent diabetes cases were adjudicated by 2 physicians for PWH and HIV-negative participants in the Veterans Aging Cohort Study. Multivariable logistic regression models evaluated the association of T-cell subsets and diabetes stratified by HIV status, adjusted for cytomegalovirus serostatus and traditional risk factors.Results: Among 2385 participants (65% PWH, 95% male, 68% African American), higher CD45RO+ memory CD4+ T cells and lower CD38+ CD4+ T cells were associated with prevalent diabetes, and had a similar effect size, in both the PWH and HIV-negative (P ≤ .05 for all). Lower CD38+CD8+ T cells were also associated with diabetes in both groups.Conclusions: The CD4+ and CD8+ T-cell subsets associated with diabetes are similar in PWH and HIV-negative individuals, suggesting that diabetes in PWH may be related to chronic immune activation. [ABSTRACT FROM AUTHOR]

Aims To test whether human immunodeficiency virus (HIV) infection and subclinical cardiovascular disease (sCVD) are associated with expression of CXCR4 and other surface markers on classical, intermediate, and non-classical monocytes in women. Methods and results sCVD was defined as presence of atherosclerotic lesions in the carotid artery in 92 participants of the Women's Interagency HIV Study (WIHS). Participants were stratified into four sets (n  = 23 each) by HIV and sCVD status (HIV−/sCVD−, HIV−/sCVD+, HIV+/sCVD−, and HIV+/sCVD+) matched by age, race/ethnicity, and smoking status. Three subsets of monocytes were determined from archived peripheral blood mononuclear cells. Flow cytometry was used to count and phenotype surface markers. We tested for differences by HIV and sCVD status accounting for multiple comparisons. We found no differences in monocyte subset size among the four groups. Expression of seven surface markers differed significantly across the three monocyte subsets. CXCR4 expression [median fluorescence intensity (MFI)] in non-classical monocytes was highest among HIV−/CVD− [628, interquartile range (IQR) (295–1389)], followed by HIV+/CVD− [486, IQR (248–699)], HIV−/CVD+ (398, IQR (89–901)), and lowest in HIV+/CVD+ women [226, IQR (73–519)), P  = 0.006 in ANOVA. After accounting for multiple comparison (Tukey) the difference between HIV−/CVD− vs. HIV+/CVD+ remained significant with P  = 0.005 (HIV−/CVD− vs. HIV+/CVD− P  = 0.04, HIV−/CVD− vs. HIV−/CVD+ P  = 0.06, HIV+/CVD+ vs. HIV+/CVD− P  = 0.88, HIV+/CVD+ vs. HIV−/CVD+ P  = 0.81, HIV+/CVD− vs. HIV−/CVD+, P  = 0.99). All pairwise comparisons with HIV−/CVD− were individually significant (P  = 0.050 vs. HIV−/CVD+, P  = 0.028 vs. HIV+/CVD−, P  = 0.009 vs. HIV+/CVD+). CXCR4 expression on non-classical monocytes was significantly higher in CVD− (501.5, IQR (249.5–887.3)) vs. CVD+ (297, IQR (81.75–626.8) individuals (P  = 0.028, n  = 46 per group). CXCR4 expression on non-classical monocytes significantly correlated with cardiovascular and HIV−related risk factors including systolic blood pressure, platelet and T cell counts along with duration of antiretroviral therapy (P  < 0.05). In regression analyses, adjusted for education level, study site, and injection drug use, presence of HIV infection and sCVD remained significantly associated with lower CXCR4 expression on non-classical monocytes (P  = 0.003), but did not differ in classical or intermediate monocytes. Conclusion CXCR4 expression in non-classical monocytes was significantly lower among women with both HIV infection and sCVD, suggesting a potential atheroprotective role of CXCR4 in non-classical monocytes. [ABSTRACT FROM AUTHOR]

Background: Chronic inflammation is associated with AIDS-defining and non-AIDS-defining conditions. Limited research has considered how food insecurity influences chronic inflammation among people living with human immunodeficiency virus (HIV). We examined whether food insecurity was associated with higher levels of inflammation among women living with HIV (WWH) in the United States.Methods: We analyzed cross-sectional data collected in 2015 from 421 participants on antiretroviral therapy from the Women's Interagency HIV Study. The exposure was any food insecurity. The outcome was inflammation, measured by proinflammatory cytokine interleukin-6 (IL-6) and tumor necroses factor receptor 1 (TNFR1) levels. We conducted multivariable linear regressions, adjusting for sociodemographic, clinical, and nutritional factors.Results: Nearly one-third of participants (31%) were food insecure and 79% were virally suppressed (<20 copies/mL). In adjusted analyses, food insecurity was associated with 1.23 times the level of IL-6 (95% confidence interval [CI], 1.06-1.44) and 1.13 times the level of TNFR1 (95% CI, 1.05-1.21). Findings did not differ by HIV control (virally suppressed with CD4 counts ≥500 cells/mm3 or not) in adjusted stratified analyses.Conclusion: Food insecurity was associated with elevated inflammation among WWH regardless of HIV control. Findings support the need for programs that address food insecurity among WWH. [ABSTRACT FROM AUTHOR]

Abstract: Global antibody glycosylation is dynamic and plays critical roles in shaping different immunological outcomes and direct antibody functionality during HIV infection. However, the relevance of global antibody or plasma glycosylation patterns to HIV persistence after antiretroviral therapy (ART) has not been characterized. First, we compared glycomes of total plasma and isolated immunoglobulin G (IgG) from HIV+ ART‐suppressed, HIV+ viremic, and HIV‐negative individuals. Second, in ART‐suppressed individuals, we examined the associations between glycomes and (1) levels of cell‐associated HIV DNA and RNA in PBMCs and isolated CD4+ T cells, (2) CD4 count and CD4%, and (3) expression of CD4+ T‐cell activation markers. HIV infection is associated with persistent alterations in the IgG glycome including decreased levels of disialylated glycans, which is associated with a lower anti‐inflammatory activity, and increased levels of fucosylated glycans, which is associated with lower antibody‐dependent cell‐mediated cytotoxicity (ADCC). We also show that levels of certain mono‐ and digalactosylated nonfucosylated glycomic traits (A2G1, A2G2, and A2BG2), which have been reported to be associated with higher ADCC and higher anti‐inflammatory activities, exhibit significant negative correlations with levels of cell‐associated total HIV DNA and HIV RNA in ART‐suppressed individuals. Finally, levels of certain circulating anti‐inflammatory glycans are associated with higher levels of CD4 T cells and lower levels of T‐cell activation. Our findings represent the first proof‐of‐concept evidence that glycomic alterations, known to be associated with differential states of inflammation and ADCC activities, are also associated with levels of HIV persistence in the setting of ART suppression. [ABSTRACT FROM AUTHOR]

Background: We examined changes in soluble inflammatory cytokines and T-cell activation after antiretroviral therapy (ART) initiation in an AIDS Clinical Trials Group (ACTG) nested case-control study.Methods: Cases were 143 human immunodeficiency virus (HIV)-infected adults who developed a non-AIDS event; 315 controls remained event-free. Specimens were tested pre-ART, year 1 post-ART, and at the visit preceding the event. Conditional logistic regression evaluated the associations of biomarker changes with non-AIDS events.Results: Inflammatory and most activation biomarkers declined from pre-ART to year 1 for cases and controls. Subsequently, inflammatory biomarkers remained mostly stable in controls but not cases. Cellular activation markers generally declined for both cases and controls between year 1 and the pre-event sampling. Controls with greater pre-ART RNA levels or lower CD4+ levels had higher biomarker levels while also experiencing greater biomarker declines in the first year of ART. Changes in biomarkers to year 1 showed no significant associations with non-AIDS events. Cases, however, had significantly greater increases in all plasma biomarkers (but not cellular activation) from year 1 to the visit preceding the event.Conclusions: Inflammation increases prior to non-AIDS events in treated HIV-infected adults. These biomarker changes may reflect subclinical disease processes or other alterations in the inflammatory environment that causally contribute to disease.Clinical Trials Registration: NCT00001137. [ABSTRACT FROM AUTHOR]

IL‐7‐dependent NK cell activation and effector function to be impaired in viral infections. Several lines of evidence support the concept that NK cells play an important role in control of hepatitis C virus (HCV) infection via cytokine secretion and cytotoxicity. IL‐7 is a homeostatic cytokine with a role in T cell development, activation, proliferation, and cytokine secretion. The IL‐7Rα chain [cluster of differentiation (CD)127] is expressed on NK cells, with greatest abundance on the CD56brightCD16dim/− (CD56bright) subset. Here, we measured CD127 expression on CD56bright, CD56dimCD16+ (CD56dim), or CD56negCD16+ (CD56neg) NK cell subsets of 25 uninfected donors (UD); 34 chronic HCV‐infected, treatment‐naiüve; 25 HIV‐infected, virally suppressed on antiretroviral therapy (ART); and 42 HCV–HIV‐coinfected subjects on ART. Interestingly, CD127 expression on CD56bright NK cells negatively correlated with HCV plasma levels in HCV monoinfection and HCV–HIV coinfection. IL‐7 induced CD69 expression, as well as IFN‐γ production, in CD56bright NK cells and also enhanced the IFN‐α‐induced CD69 expression on these cells. The latter was impaired in HIV infection. Furthermore, IL‐7 induced B cell lymphoma 2 (BCL‐2) expression and cell cycling of CD56bright NK cells, and this effect was impaired in HCV‐ and HIV‐infected subjects. Whereas IL‐7‐stimulated CD56bright NK cell degranulation appeared intact in all cohorts, we observed impaired IL‐7‐activated NK cell cytolytic function in HCV‐ and HIV‐infected subjects. Finally, IL‐7‐induced phosphorylation of STAT‐5 (pSTAT‐5) signaling was impaired in NK cells of subjects with chronic viral infection, and this was reversible upon 6 mo of viral suppression with IFN‐free HCV therapy. These results implicate that IL‐7‐dependent NK cell activation and effector function may be other host immune surveillance mechanisms that are impaired in viral infections. [ABSTRACT FROM AUTHOR]

Background: Monocytes and monocyte-derived macrophages promote atherosclerosis through increased inflammation and vascular remodeling. This may be especially true in chronic human immunodeficiency virus (HIV) infection.Methods: We examined 778 women (74% HIV+) in the Women's Interagency HIV Study and 503 men (65% HIV+) in the Multicenter AIDS Cohort Study who underwent repeated B-mode carotid artery ultrasound imaging in 2004-2013. We assessed baseline associations of the serum macrophage inflammation markers soluble (s)CD163, sCD14, galectin-3 (Gal-3), and Gal-3 binding protein (Gal-3BP) with carotid plaque formation (focal intima-media thickness >1.5 mm) over 7 years.Results: Marker levels were higher in HIV+ persons versus HIV- persons. Presence of focal plaque increased over time: from 8% to 15% in women, and 24% to 34% in men. After adjustment for demographic, behavioral, and cardiometabolic factors, and CRP and interleukin-6, each standard deviation increase in sCD14 was associated with increased plaque formation (risk ratio [RR] 1.24, 95% confidence interval [CI] 1.07-1.43). This pattern was consistentby sex. sCD163 was associated with plaque formation in virally suppressed HIV+ men (RR 1.52, 95% CI 1.04-2.22); Gal-3BP and Gal-3 were not associated with increased plaque.Conclusions: sCD14 and sCD163 may play important roles in atherogenesis among HIV+ persons. [ABSTRACT FROM AUTHOR]

Background. Individuals infected with human immunodeficiency virus (HIV) live longer as a result of effective treatment, but long-term consequences of infection, treatment, and immunological dysfunction are poorly understood. Methods. We prospectively examined 1011 women (74% HIV-infected) in theWomen's Interagency HIV Study and 811 men (65% HIV-infected) in the Multicenter AIDS Cohort Study who underwent repeated B-mode carotid artery ultrasound imaging in 2004-2013. Outcomes included changes in right common carotid artery intima-media thickness (CCA-IMT) and new focal carotid artery plaque formation (IMT >1.5 mm) over median 7 years. We assessed the association between HIV serostatus and progression of subclinical atherosclerosis, adjusting for demographic, behavioral, and cardiometabolic risk factors. Results. Unadjusted mean CCA-IMT increased (725 to 752 µm in women, 757 to 790 µm in men), but CCAIMT progression did not differ by HIV serostatus, either in combined or sex-specific analyses. Focal plaque prevalence increased from 8% to 15% in women and 25% to 34% in men over 7 years. HIV-infected individuals had 1.6-fold greater risk of new plaque formation compared with HIV-uninfected individuals (relative risk [RR] 1.61, 95% CI, 1.12-2.32), adjusting for cardiometabolic factors; the association was similar by sex. Increased plaque occurred even among persistently virologically suppressed HIV-infected individuals compared with uninfected individuals (RR 1.56, 95% CI, 1.07-2.27). HIV-infected individuals with baseline CD4+ ≥500 cells/μL had plaque risk not statistically different from uninfected individuals. Conclusions. HIV infection is associated with greater increases in focal plaque among women and men, potentially mediated by factors associated with immunodeficiency or HIV replication at levels below current limits of detection. [ABSTRACT FROM AUTHOR]

Background: Rifaximin, a nonabsorbable antibiotic that decreases lipopolysaccharide (LPS) in cirrhotics, may decrease the elevated levels of microbial translocation, T-cell activation and inflammation in human immunodeficiency virus (HIV)-positive immune nonresponders to antiretroviral therapy (ART).Methods: HIV-positive adults receiving ART for ≥96 weeks with undetectable viremia for ≥48 weeks and CD4(+) T-cell counts <350 cells/mm(3) were randomized 2:1 to rifaximin versus no study treatment for 4 weeks. T-cell activation, LPS, and soluble CD14 were measured at baseline and at weeks 2, 4, and 8. Wilcoxon rank sum tests compared changes between arms.Results: Compared with no study treatment (n = 22), rifaximin (n = 43) use was associated with a significant difference between study arms in the change from baseline to week 4 for CD8(+)T-cell activation (median change, 0.0% with rifaximin vs +0.6% with no treatment; P = .03). This difference was driven by an increase in the no-study-treatment arm because there was no significant change within the rifaximin arm. Similarly, although there were significant differences between study arms in change from baseline to week 2 for LPS and soluble CD14, there were no significant changes within the rifaximin arm.Conclusions: In immune nonresponders to ART, rifaximin minimally affected microbial translocation and CD8(+)T-cell activation. Trial registration number. NCT01466595. [ABSTRACT FROM AUTHOR]

Abnormal levels of inflammation are associated with cardiovascular disease and mortality in human immunodeficiency virus (HIV)–infected patients. Microbial translocation, which may cause inflammation, is decreased by sevelamer in patients undergoing hemodialysis. In this single-arm study, we evaluated the effects of 8 weeks of sevelamer therapy on 36 HIV-infected subjects who were not receiving antiretroviral therapy. Sevelamer did not significantly change markers of microbial translocation, inflammation, or T-cell activation. During sevelamer treatment, however, levels of soluble tissue factor, low-density lipoprotein (LDL) cholesterol, and oxidized LDL cholesterol decreased significantly, whereas D-dimer levels increased. Thus, in this study population, sevelamer did not reduce microbial translocation but may have yielded cardiovascular benefits.Clinical Trials Registration. NCT 01543958. [ABSTRACT FROM AUTHOR]

Background: Defining the association of non-AIDS-defining events with inflammation and immune activation among human immunodeficiency virus (HIV)-infected persons with antiretroviral therapy (ART)-associated virological suppression is critical to identifying interventions to decrease the occurrence of these events.Methods: We conducted a case-control study of HIV-infected subjects who had achieved virological suppression within 1 year after ART initiation. Cases were patients who experienced non-AIDS-defining events, defined as myocardial infarction, stroke, non-AIDS-defining cancer, non-AIDS-defining serious bacterial infection, or death. Controls were matched to cases on the basis of age, sex, pre-ART CD4(+) T-cell count, and ART regimen. Peripheral blood mononuclear cells and plasma specimens obtained at the visit before ART initiation (hereafter, baseline), the visit approximately 1 year after ART initiation (hereafter, year 1), and the visit immediately preceding the non-AIDS-defining event (hereafter, pre-event) were analyzed for activated CD4(+) and CD8(+) T cells, plasma interleukin 6 (IL-6) level, soluble tumor necrosis factor receptor I (sTNFR-I) level, sTNFR-II level, soluble CD14 level, kynurenine-to-tryptophan (KT) ratio, and D-dimer level. Conditional logistic regression analysis was used to study the association between biomarkers and outcomes, with adjustment for potential confounders.Results: Higher IL-6 level, sTNFR-I level, sTNFR-II level, KT ratio, and D-dimer level at year 1 were associated with the occurrence of a non-AIDS-defining event. Significant associations were also seen between non-AIDS-defining events and values of these biomarkers in specimens obtained at baseline and the pre-event time points. Effects remained significant after control for confounders. T-cell activation was not significantly related to outcomes.Conclusions: Interventional trials to decrease the incidence of non-AIDS-defining events among HIV-infected persons with virological suppression should consider targeting the pathways represented by these soluble markers. Clinical Trials Registration. NCT00001137. [ABSTRACT FROM AUTHOR]

Background. Antiretroviral therapy has reduced the incidence of adverse events and early mortality in HIV-infected persons. Despite these benefits, important comorbidities that increase with age (eg, diabetes, cardiovascular disease, cancer, liver disease, and neurocognitive impairment) are more prevalent in HIV-infected persons than in HIV-uninfected persons at every age, and geriatric syndromes such as falls and frailty occur earlier in HIV-infected persons. This raises a critical research question: Does HIV accelerate aging through pathways and mechanisms common to the aging process or is HIV simply an additional risk factor for a wide number of chronic conditions, thus accentuating aging? Methods. Extensive literature review. Results. The purpose of this review is to briefly outline the evidence that age-related clinical syndromes are exacerbated by HIV, examine the ways in which HIV is similar, and dissimilar from natural aging, and assess the validity of HIV as a model of premature aging. Specific biomarkers of aging are limited in HIV-infected hosts and impacted by antiretroviral therapy, and a high rate of modifiable life style confounders (eg, smoking, substance abuse, alcohol) and coinfections (eg, hepatitis) in HIV-infected participants. Conclusions. There is a need for validated biomarkers of aging in the context of HIV. Despite these differences, welldesigned studies of HIV-infected participants are likely to provide new opportunities to better understand the mechanisms that lead to aging and age-related diseases. [ABSTRACT FROM PUBLISHER]

Background The Short Physical Performance Battery (SPPB) is a well regarded physical functioning assessment including balance, gait speed, and chair-stand tests. Its use has not been widely assessed in human immunodeficiency virus (HIV) care. We evaluated the feasibility of integrating the SPPB into care of aging people living with HIV (PLWH) and compared SPPB performance with aged HIV-uninfected individuals. Methods We enrolled PLWH aged ≥50 at 3 HIV clinics and compared their SPPB scores and subscores with older HIV-uninfected adults in the Health, Aging, and Body Composition (Health ABC) study. We conducted regression analyses on age stratified by sex and adjusting for site, and we calculated percentage variance explained by age among PLWH and HIV-uninfected adults. Results The SPPB was feasible to implement in clinical care and did not require licensed professionals; 176 PLWH completed it with a mean completion time of 7.0 minutes (standard deviation = 2.6). Overall mean SPPB score among PLWH was 10.3 (median 11.0, 25th percentile 9.0, 75th percentile 12.0). People living with HIV were younger than HIV-uninfected individuals (55 vs 74 years old). Mean SPPB scores and most subscores were similar among PLWH and older HIV-uninfected individuals despite the ~20-year age difference. Regression analyses of gait speed revealed similar slopes in PLWH and HIV-uninfected individuals; however, separate intercepts were needed for PLWH. Mean gait speeds were faster in older HIV-uninfected men and women (P <.01), yet relationships with age within PLWH and HIV uninfected were similar. Conclusions The SPPB can be implemented into busy HIV clinics. Despite the ~20-year age difference, mean scores were similar among PLWH and older HIV-uninfected individuals, although gait speed was faster among HIV-uninfected individuals. [ABSTRACT FROM AUTHOR]

We examined associations of 5 plasma choline metabolites with carotid plaque among 520 HIV-infected and 217 HIV-uninfected participants (112 incident plaque cases) over 7 years. After multivariable adjustment, higher gut microbiota-related metabolite trimethylamine-N-oxide (TMAO) was associated with an increased risk of carotid plaque in HIV-infected participants (risk ratio = 1.25 per standard deviation increment; 95% confidence interval, 1.05-1.50; P = .01). TMAO was positively correlated with biomarkers of monocyte activation and inflammation (sCD14, sCD163). Further adjustment for these biomarkers attenuated the association between TMAO and carotid plaque (P = .08). Among HIV-infected individuals, plasma TMAO was associated with carotid atherosclerosis progression, partially through immune activation and inflammation. [ABSTRACT FROM AUTHOR]