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BackgroundOptimal carbohydrate intake is an important and controversial area in the nutritional management of type 2 diabetes. Some evidence indicates that reducing overall carbohydrate intake with a low- or very low-carbohydrate eating plan can improve glycemic control compared to following eating plans that involve greater carbohydrate intake. However, critical knowledge gaps currently prevent clear recommendations about carbohydrate intake levels.MethodsThe LEGEND (Lifestyle Education about Nutrition for Diabetes) Trial aims to compare a very low-carbohydrate diet to a moderate-carbohydrate plate-method diet for glycemic control in adults with type 2 diabetes. This two-site trial plans to recruit 180 adults with type 2 diabetes. We will randomize participants to either a 20-session group-based diet and lifestyle intervention that teaches either a very low-carbohydrate diet or a moderate-carbohydrate plate-method diet. We will assess participants at study entry and 4 and 12 months later. The primary outcome is HbA1c, and secondary outcomes include inflammation (high sensitivity C-reactive protein), body weight, changes in diabetes medications, lipids (small particle LDL, HDL, triglycerides), skeletal metabolism (bone mineral density from dual-energy x-ray absorptiometry and bone turnover markers serum procollagen type I N propeptide and serum C-terminal telopeptide of type I collagen), and body composition (percent body fat, percent lean body mass).DiscussionThe LEGEND trial is a randomized controlled trial to assess optimal carbohydrate intake in type 2 diabetes by evaluating the effects of a very low-carbohydrate diet vs. a moderate-carbohydrate plate-method diet over a year-long period. The research addresses important gaps in the evidence base for the nutritional management of type 2 diabetes by providing data on potential benefits and adverse effects of different levels of carbohydrate intake.Trial registrationClinicalTrials.gov NCT05237128. Registered on February 11, 2022.

Early detection of diseases such as COVID-19 could be a critical tool in reducing disease transmission by helping individuals recognize when they should self-isolate, seek testing, and obtain early medical intervention. Consumer wearable devices that continuously measure physiological metrics hold promise as tools for early illness detection. We gathered daily questionnaire data and physiological data using a consumer wearable (Oura Ring) from 63,153 participants, of whom 704 self-reported possible COVID-19 disease. We selected 73 of these 704 participants with reliable confirmation of COVID-19 by PCR testing and high-quality physiological data for algorithm training to identify onset of COVID-19 using machine learning classification. The algorithm identified COVID-19 an average of 2.75 days before participants sought diagnostic testing with a sensitivity of 82% and specificity of 63%. The receiving operating characteristic (ROC) area under the curve (AUC) was 0.819 (95% CI [0.809, 0.830]). Including continuous temperature yielded an AUC 4.9% higher than without this feature. For further validation, we obtained SARS CoV-2 antibody in a subset of participants and identified 10 additional participants who self-reported COVID-19 disease with antibody confirmation. The algorithm had an overall ROC AUC of 0.819 (95% CI [0.809, 0.830]), with a sensitivity of 90% and specificity of 80% in these additional participants. Finally, we observed substantial variation in accuracy based on age and biological sex. Findings highlight the importance of including temperature assessment, using continuous physiological features for alignment, and including diverse populations in algorithm development to optimize accuracy in COVID-19 detection from wearables.

Future HIV-1 curative therapies require a thorough understanding of the distribution of genetically-intact HIV-1 within T-cell subsets during antiretroviral therapy (ART) and the cellular mechanisms that maintain this reservoir. Therefore, we sequenced near-full-length HIV-1 genomes and identified genetically-intact and genetically-defective genomes from resting naive, stem-cell memory, central memory, transitional memory, effector memory, and terminally-differentiated CD4+ T-cells with known cellular half-lives from 11 participants on ART. We find that a higher infection frequency with any HIV-1 genome was significantly associated with a shorter cellular half-life, such as transitional and effector memory cells. A similar enrichment of genetically-intact provirus was observed in these cells with relatively shorter half-lives. We found that effector memory and terminally-differentiated cells also had significantly higher levels of expansions of genetically-identical sequences, while only transitional and effector memory cells contained genetically-intact proviruses that were part of a cluster of identical sequences. Expansions of identical sequences were used to infer cellular proliferation from clonal expansion. Altogether, this indicates that specific cellular mechanisms such as short half-life and proliferative potential contribute to the persistence of genetically-intact HIV-1. IMPORTANCE The design of future HIV-1 curative therapies requires a more thorough understanding of the distribution of genetically-intact HIV-1 within T-cell subsets as well as the cellular mechanisms that maintain this reservoir. These genetically-intact and presumably replication-competent proviruses make up the latent HIV-1 reservoir. Our investigations into the possible cellular mechanisms maintaining the HIV-1 reservoir in different T-cell subsets have revealed a link between the half-lives of T-cells and the level of proviruses they contain. Taken together, we believe our study shows that more differentiated and proliferative cells, such as transitional and effector memory T-cells, contain the highest levels of genetically-intact proviruses, and the rapid turnover rate of these cells contributes to the expansion of genetically-intact proviruses within them. Therefore, our study delivers an in-depth assessment of the cellular mechanisms, such as cellular proliferation and half-life, that contribute to and maintain the latent HIV-1 reservoir.

ObjectiveTo determine the effects of ESRT (an iteratively adapted and tailored MBI) on perceived stress, executive cognitive function, psychosocial well-being (ie, burnout, mindfulness), and pro-inflammatory gene expression in surgical (ESRT-1) and mixed specialty (ESRT-2) PGY-1 volunteers.Summary of background and dataTailored MBIs have proven beneficial in multiple high-stress and high-performance populations. In surgeons, tailored MBIs have been shown to be feasible and potentially beneficial, but whether mindfulness-based cognitive training can improve perceived stress, executive function, well-being or physiological distress in surgical and nonsurgical trainees is unknown.MethodsIn 2 small single-institution randomized clinical trials, ESRT, a tailored mindfulness-based cognitive training program, was administered and iteratively adapted for first-year surgical (ESRT-1, 8 weekly, 2-hour classes, n = 44) and mixed specialty (ESRT-2, 6 weekly, 90-minute classes, n = 45) resident trainees. Primary and secondary outcomes were, respectively, perceived stress and executive function. Other prespecified outcomes were burnout (assessed via Maslach Burnout Inventory), mindfulness (assessed via Cognitive Affective Mindfulness Scale - Revised), and pro-inflammatory gene expression (assessed through the leukocyte transcriptome profile "conserved transcriptional response to adversity").ResultsNeither version of ESRT appeared to affect perceived stress. Higher executive function and mindfulness scores were seen in ESRT-1, and lower emotional exhaustion and depersonalization scores in ESRT-2, at pre-/postintervention and/or 50-week follow-up (ESRT-1) or at 32-week follow-up (ESRT-2), compared to controls. Pooled analysis of both trials found ESRT-treated participants had reduced pro-inflammatory RNA expression compared to controls.ConclusionsThis pilot work suggests ESRT can variably benefit executive function, burnout, and physiologic distress in PGY-1 trainees, with potential for tailoring to optimize effects.

Although many HIV cure strategies seek to expand HIV-specific CD8+ T cells to control the virus, all are likely to fail if cellular exhaustion is not prevented. A loss in stem-like memory properties (i.e., the ability to proliferate and generate secondary effector cells) is a key feature of exhaustion; little is known, however, about how these properties are regulated in human virus-specific CD8+ T cells. We found that virus-specific CD8+ T cells from humans and nonhuman primates naturally controlling HIV/SIV infection express more of the transcription factor TCF-1 than noncontrollers. HIV-specific CD8+ T cell TCF-1 expression correlated with memory marker expression and expansion capacity and declined with antigenic stimulation. CRISPR-Cas9 editing of TCF-1 in human primary T cells demonstrated a direct role in regulating expansion capacity. Collectively, these data suggest that TCF-1 contributes to the regulation of the stem-like memory property of secondary expansion capacity of HIV-specific CD8+ T cells, and they provide a rationale for exploring the enhancement of this pathway in T cell-based therapeutic strategies for HIV.

The precise role of CD4 T cell turnover in maintaining HIV persistence during antiretroviral therapy (ART) has not yet been well characterized. In resting CD4 T cell subpopulations from 24 HIV-infected ART-suppressed and 6 HIV-uninfected individuals, we directly measured cellular turnover by heavy water labeling, HIV reservoir size by integrated HIV-DNA (intDNA) and cell-associated HIV-RNA (caRNA), and HIV reservoir clonality by proviral integration site sequencing. Compared to HIV-negatives, ART-suppressed individuals had similar fractional replacement rates in all subpopulations, but lower absolute proliferation rates of all subpopulations other than effector memory (TEM) cells, and lower plasma IL-7 levels (p = 0.0004). Median CD4 T cell half-lives decreased with cell differentiation from naïve to TEM cells (3 years to 3 months, p

Elevated core temperature constitutes an important biomarker for COVID-19 infection; however, no standards currently exist to monitor fever using wearable peripheral temperature sensors. Evidence that sensors could be used to develop fever monitoring capabilities would enable large-scale health-monitoring research and provide high-temporal resolution data on fever responses across heterogeneous populations. We launched the TemPredict study in March of 2020 to capture continuous physiological data, including peripheral temperature, from a commercially available wearable device during the novel coronavirus pandemic. We coupled these data with symptom reports and COVID-19 diagnosis data. Here we report findings from the first 50 subjects who reported COVID-19 infections. These cases provide the first evidence that illness-associated elevations in peripheral temperature are observable using wearable devices and correlate with self-reported fever. Our analyses support the hypothesis that wearable sensors can detect illnesses in the absence of symptom recognition. Finally, these data support the hypothesis that prediction of illness onset is possible using continuously generated physiological data collected by wearable sensors. Our findings should encourage further research into the role of wearable sensors in public health efforts aimed at illness detection, and underscore the importance of integrating temperature sensors into commercially available wearables.

Proliferation of CD4+ T cells harboring HIV-1 proviruses is a major contributor to viral persistence in people on antiretroviral therapy (ART). To determine whether differential rates of clonal proliferation or HIV-1-specific cytotoxic T lymphocyte (CTL) pressure shape the provirus landscape, we performed an intact proviral DNA assay (IPDA) and obtained 661 near-full-length provirus sequences from 8 individuals with suppressed viral loads on ART at time points 7 years apart. We observed slow decay of intact proviruses but no changes in the proportions of various types of defective proviruses. The proportion of intact proviruses in expanded clones was similar to that of defective proviruses in clones. Intact proviruses observed in clones did not have more escaped CTL epitopes than intact proviruses observed as singlets. Concordantly, total proviruses at later time points or observed in clones were not enriched in escaped or unrecognized epitopes. Three individuals with natural control of HIV-1 infection (controllers) on ART, included because controllers have strong HIV-1-specific CTL responses, had a smaller proportion of intact proviruses but a distribution of defective provirus types and escaped or unrecognized epitopes similar to that of the other individuals. This work suggests that CTL selection does not significantly check clonal proliferation of infected cells or greatly alter the provirus landscape in people on ART.

While the relationship of protective human leukocyte antigen (HLA) class I alleles and HIV progression is well defined, the interaction of HLA-mediated protection and CD8 T-cell exhaustion is less well characterized. To gain insight into the influence of HLA-B*57:01 on the deterioration of CD8 T-cell responses during HIV infection in the absence of antiretroviral treatment, we compared HLA-B*57:01-restricted HIV-specific CD8 T-cell responses to responses restricted by other HLA class I alleles longitudinally after control of peak viremia. Detailed characterization of polyfunctionality, differentiation phenotypes, transcription factor, and inhibitory receptor expression revealed progression of CD8 T-cell exhaustion over the course of the infection in both patient groups. However, early effects on the phenotype of the total CD8 T-cell population were apparent only in HLA-B*57-negative patients. The HLA-B*57:01-restricted, HIV epitope-specific CD8 T-cell responses showed beneficial functional patterns and significantly lower frequencies of inhibitory receptor expression, i.e., PD-1 and coexpression of PD-1 and TIGIT, within the first year of infection. Coexpression of PD-1 and TIGIT was correlated with clinical markers of disease progression and declining percentages of the T-bethi Eomesdim CD8 T-cell population. In accordance with clinical and immunological deterioration in the HLA-B*57:01 group, the difference in PD-1 and TIGIT receptor expression did not persist to later stages of the disease.IMPORTANCE Given the synergistic nature of TIGIT and PD-1, the coexpression of those inhibitory receptors should be considered when evaluating T-cell pathogenesis, developing immunomodulatory therapies or vaccines for HIV, and when using immunotherapy or vaccination for other causes in HIV-infected patients. HIV-mediated T-cell exhaustion influences the patient´s disease progression, immune system and subsequently non-AIDS complications, and efficacy of vaccinations against other pathogens. Consequently, the possibilities of interfering with exhaustion are numerous. Expanding the use of immunomodulatory therapies to include HIV treatment depends on information about possible targets and their role in the deterioration of the immune system. Furthermore, the rise of immunotherapies against cancer and elevated cancer incidence in HIV-infected patients together increase the need for detailed knowledge of T-cell exhaustion and possible interactions. A broader approach to counteract immune exhaustion to alleviate complications and improve efficacy of other vaccines also promises to increase patients' health and quality of life.

ObjectiveThe contribution of HLA-DR+ memory CD4 T cells to the HIV reservoir during prolonged antiretroviral therapy is unclear as these cells are commonly excluded when assessing for replication-competent HIV. To address this issue, we examined the distribution of genetically intact HIV DNA within HLA-DR- and HLA-DR+ memory CD4 T cells and the RNA transcriptional profile of these cells during antiretroviral therapy.Design/methodsFull-length DNA sequencing was used to examine the HIV DNA landscape within HLA-DR+ and HLA-DR- memory CD4 T cells. RNA quantification and sequencing was used to interrogate the relationship between HLA-DR status and HIV RNA transcription.ResultsHLA-DR+ CD4 T cells contained a high frequency of genetically intact HIV genomes, contributing over half of the genetically intact viral sequences to the reservoir. Expansions of genetically identical sequences were identified in all T-cell subsets, indicating that cellular proliferation maintains genetically intact and defective viral DNA during therapy. Intracellular HIV RNA levels in HLA-DR+ and HLA-DR- T cells were not statistically different by either long terminal repeat quantitative PCR quantification or single-genome RNA sequencing of the p6-RT region.ConclusionThe high proportion of intact viral DNA sequences in the proliferative HLA-DR+ subset suggests they are critical in maintaining HIV infection during effective therapy. As such, these cells should be included in any immune intervention targeting HIV during effective therapy.

ObjectiveWe aimed to understand the associations of compulsive eating (CE) and stress eating (SE) with metabolic health among adults with obesity and whether mindfulness-based weight loss training may buffer these associations.MethodWe used data from a trial in which we randomized 194 participants with obesity to a diet-exercise weight loss intervention with either mindful eating training plus mindfulness-based eating awareness and stress management training (n = 100) or active control components (n = 94). We measured CE, SE, weight, and fasting blood glucose (FBG) at baseline, and 6, 12 months, and 18 months. We tested CE and SE as both moderators and mediators of intervention effects on changes in metabolic health.ResultsParticipants higher (+ 1 SD) in CE at baseline randomized to the mindfulness (vs. control) intervention had greater improvements in FBG at 18 months (p = .05). Twelve-month reductions in CE mediated the effect of the intervention on changes in FBG and weight at 12 and 18 months postbaseline (p ≤ .05). Furthermore, those higher (+ 1 SD) in SE at baseline were nearly 2 BMI points higher than those lower (-1 SD) in SE (p < .01). Decreases in SE (B = 3.42; p < .001; 95% CI [2.55, 4.30]) and CE (B = 0.45; p < .001; 95% CI [0.36, 0.54]) in all participants at 6 months were associated with greater weight loss at 18 months.ConclusionsThose with greater compulsive eating may reduce risk for metabolic decline by participating in a mindfulness-based weight loss program. Future obesity interventions should consider tailoring treatment toward trait-level characteristics, such as compulsive eating. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

ObjectiveExisting pharmacologic approaches for painful diabetic neuropathy (PDN) are limited in efficacy and have side effects. We examined the feasibility, acceptability, and effects of group acupuncture for PDN.Design and settingWe randomized patients with PDN from a public safety net hospital to 1) usual care, 2) usual care plus 12 weeks of group acupuncture once weekly, or 3) usual care plus 12 weeks of group acupuncture twice weekly.MethodsThe primary outcome was change in weekly pain intensity (daily 0-10 numerical rating scale [NRS] averaged over seven days) from baseline to week 12. We also assessed health-related quality of life and related symptoms at baseline and weeks 6, 12, and 18.ResultsWe enrolled 40 patients with PDN (baseline pain = 5.3). Among participants randomized to acupuncture, 92% attended at least one treatment (mean treatments = 10.1). We observed no significant differences between once- vs twice-weekly acupuncture and combined those groups for the main analyses. Compared with usual care, participants randomized to acupuncture experienced greater decreases in pain during the 12-week intervention period (between-group differences from baseline = -2.06, 95% confidence interval [CI] = -3.01 to -1.10), but benefits were not maintained after acupuncture ended (baseline to week 18 = -0.61, 95% CI = -1.46 to 0.24). Quality of life improved for acupuncture participants (baseline to week 12 difference = 11.79, 95% CI = 1.92 to 21.66), but group differences were not significant compared with usual care (25.58, 95% CI = -3.90 to 55.06).ConclusionsGroup acupuncture is feasible and acceptable among linguistically and racially diverse safety net patients. Findings suggest clinically relevant reduction in pain from PDN and quality of life improvements associated with acupuncture, with no differences based on frequency.

BackgroundHIV posttreatment controllers are rare individuals who start antiretroviral therapy (ART), but maintain HIV suppression after treatment interruption. The frequency of posttreatment control and posttreatment interruption viral dynamics have not been well characterized.MethodsPosttreatment controllers were identified from 14 studies and defined as individuals who underwent treatment interruption with viral loads ≤400 copies/mL at two-thirds or more of time points for ≥24 weeks. Viral load and CD4+ cell dynamics were compared between posttreatment controllers and noncontrollers.ResultsOf the 67 posttreatment controllers identified, 38 initiated ART during early HIV infection. Posttreatment controllers were more frequently identified in those treated during early versus chronic infection (13% vs 4%, P < .001). In posttreatment controllers with weekly viral load monitoring, 45% had a peak posttreatment interruption viral load of ≥1000 copies/mL and 33% had a peak viral load ≥10000 copies/mL. Of posttreatment controllers, 55% maintained HIV control for 2 years, with approximately 20% maintaining control for ≥5 years.ConclusionsPosttreatment control was more commonly identified amongst early treated individuals, frequently characterized by early transient viral rebound and heterogeneous durability of HIV remission. These results may provide mechanistic insights and have implications for the design of trials aimed at achieving HIV remission.

ObjectiveEvidence links depression and stress to more rapid progression of HIV-1 disease. We conducted a randomized controlled trial to test whether an intervention aimed at improving stress management and emotion regulation, mindfulness-based stress reduction (MBSR), would improve immunological (i.e. CD4+ T-cell counts) and psychological outcomes in persons with HIV-1 infection.MethodsWe randomly assigned participants with HIV-1 infection and CD4 T-cell counts >350 cells/μl who were not on antiretroviral therapy in a 1:1 ratio to either an MBSR group (n = 89) or an HIV disease self-management skills group (n = 88). The study was conducted at the University of California at San Francisco. We assessed immunologic (CD4, c-reactive protein, IL-6, and d-dimer) and psychological measures (Beck Depression Inventory for depression, modified Differential Emotions Scale for positive and negative affect, Perceived stress-scale, and mindfulness) at 3, 6 and 12 months after initiation of the intervention; we used multiple imputation to address missing values.ResultsWe observed statistically significant improvements from baseline to 3-months within the MBSR group in depression, positive and negative affect, perceived stress, and mindfulness; between group differences in change were significantly greater in the MBSR group only for positive affect (per item difference on DES-positive 0.25, 95% CI 0.049, 0.44, p = .015). By 12 months the between group difference in positive affect was not statistically significant, although both groups had trends toward improvements compared to baseline in several psychological outcomes that were maintained at 12-months; these improvements were only statistically significant for depression and negative affect in the MBSR group and perceived stress for the control group. The groups did not differ significantly on rates of antiretroviral therapy initiation (MBSR = 39%, control = 29%, p = .22). After 12 months, the mean decrease in CD4+ T-cell count was 49.6 cells/μl in participants in the MBSR arm, compared to 54.2 cells/μl in the control group, a difference of 4.6 cells favoring the MBSR group (95% CI, -44.6, 53.7, p = .85). The between group differences in other immunologic-related outcomes (c-reactive protein, IL-6, HIV-1 viral load, and d-dimer) were not statistically significant at any time point.ConclusionsMBSR improved positive affect more than an active control arm in the 3 months following the start of the intervention. However, this difference was not maintained over the 12-month follow-up and there were no significant differences in immunologic outcomes between intervention groups. These results emphasize the need for further carefully designed research if we are to translate evidence linking psychological states to immunological outcomes into evidence-based clinical practices.

ObjectiveThe aim of the study was to determine, within a weight loss clinical trial for obesity, the impact of intervention arm, weight change, and weight loss maintenance on telomere length (TL).MethodsAdults (N = 194) with a body mass index between 30 and 45 were randomized to a 5.5-month weight loss program with (n = 100) or without (n = 94) mindfulness training and identical diet-exercise guidelines. We assessed TL at baseline and 3-, 6-, and 12-month postbaseline in immune cell populations (primarily in peripheral blood mononuclear cells [PBMCs], but also in granulocytes and T and B lymphocytes). We defined weight loss maintenance as having lost at least 5% or 10% of body weight (tested in separate models) from preintervention to postintervention, and having maintained this loss at 12 months. We predicted that greater weight loss and weight loss maintenance would be associated with TL lengthening.ResultsNeither weight loss intervention significantly predicted TL change nor did amount of weight change, at any time point. Across all participants, weight loss maintenance of at least 10% was associated with longer PBMC TL (b = 239.08, 95% CI = 0.92 to 477.25, p = .049), CD8+ TL (b = 417.26, 95% CI = 58.95 to 775.57, p = .023), and longer granulocyte TL (b = 191.56, 95% CI = -4.23 to 387.35, p = .055) at 12 months after accounting for baseline TL. Weight loss maintenance of 5% or more was associated with longer PBMC TL (b = 163.32, 95% CI = 4.00 to 320.62, p = .045) at 12 months after accounting for baseline TL. These tests should be interpreted in light of corrections for multiple tests.ConclusionsAmong individuals with obesity, losing and maintaining a weight loss of 10% or more may lead to TL lengthening, which may portend improved immune and metabolic function. TL lengthening in this study is of unknown duration beyond 12 months and requires further study.Trial registrationClinicaltrials.govidentifierNCT00960414; Open Science Framework (OSF) preregistration: https://osf.io/t3r2g/.

While negative emotions are associated with risk behaviors and risk avoidance among people with HIV, emerging evidence indicates that negative self-conscious emotions, those evoked by self-reflection or self-evaluation (e.g., shame, guilt, and embarrassment), may differentially influence health-risk behaviors by producing avoidance or, conversely, pro-social behaviors. Positive emotions are associated with beneficial health behaviors, and may account for inconsistent findings related to negative self-conscious emotions. Using multinomial logistic regression, we tested whether positive emotion moderated the relationships between negative emotion and negative self-conscious emotions and level of condomless sex risk: (1) seroconcordant; (2) serodiscordant with undetectable viral load; and (3) serodiscordant with detectable viral load [potentially amplified transmission (PAT)] among people recently diagnosed with HIV (n = 276). While positive emotion did not moderate the relationship between negative emotion and condomless sex, it did moderate the relationship between negative self-conscious emotion and PAT (AOR = 0.60; 95% CI 0.41, 0.87); high negative self-conscious and high positive emotion were associated with lower PAT risk. Acknowledgment of both positive and negative self-conscious emotion may reduce transmission risk behavior among people with HIV.

Dietary treatment is important in management of type 2 diabetes or prediabetes, but uncertainty exists about the optimal diet. We randomized adults (n = 34) with glycated hemoglobin (HbA1c) > 6.0% and elevated body weight (BMI > 25) to a very low-carbohydrate ketogenic (LCK) diet (n = 16) or a moderate-carbohydrate, calorie-restricted, low-fat (MCCR) diet (n = 18). All participants were encouraged to be physically active, get sufficient sleep, and practice behavioral adherence strategies based on positive affect and mindful eating. At 12 months, participants in the LCK group had greater reductions in HbA1c levels (estimated marginal mean (EMM) at baseline = 6.6%, at 12 mos = 6.1%) than participants in MCCR group (EMM at baseline = 6.9%, at 12 mos = 6.7%), p = .007. Participants in the LCK group lost more weight (EMM at baseline = 99.9 kg, at 12 mos = 92.0 kg) than participants in the MCCR group (EMM at baseline = 97.5 kg, at 12 mos = 95.8 kg), p

Latent replication-competent HIV-1 persists in individuals on long-term antiretroviral therapy (ART). We developed the Full-Length Individual Proviral Sequencing (FLIPS) assay to determine the distribution of latent replication-competent HIV-1 within memory CD4+ T cell subsets in six individuals on long-term ART. FLIPS is an efficient, high-throughput assay that amplifies and sequences near full-length (∼9 kb) HIV-1 proviral genomes and determines potential replication competency through genetic characterization. FLIPS provides a genome-scale perspective that addresses the limitations of other methods that also genetically characterize the latent reservoir. Using FLIPS, we identified 5% of proviruses as intact and potentially replication competent. Intact proviruses were unequally distributed between T cell subsets, with effector memory cells containing the largest proportion of genetically intact HIV-1 proviruses. We identified multiple identical intact proviruses, suggesting a role for cellular proliferation in the maintenance of the latent HIV-1 reservoir.

In untreated HIV infection, CD8+ T cell exhaustion (i.e., decreased proliferative and effector capacity) is associated with high levels of expression of coinhibitory receptors, including PD-1, T cell immunoreceptor with Ig and ITIM domains (TIGIT), CD160, and 2B4. This is evident for both HIV-specific and non-HIV-specific CD8+ T cells. Antiretroviral therapy (ART) initiated during chronic infection decreases but may not completely normalize the expression of such "exhaustion markers." Compared to initiation of ART later in the course of disease, initiation soon after infection reduces some parameters of chronic inflammation and adaptive immune dysfunction. However, it is not known if Early ART (e.g., initiated within the first 6 months after HIV infection) versus Delayed ART (e.g., initiated during chronic infection) preferentially reduces expression of exhaustion markers. We evaluated exhaustion marker expression on subsets of circulating effector and memory CD8+ T cells at longitudinal pre- and post-ART (2 and 5 years on ART) time points from n = 19 (Early ART) and n = 23 (Delayed ART) individuals. Before ART, TIGIT and CD160 were expressed on a statistically significantly higher proportion of effector and transitional memory cells from individuals in the Delayed ART group: the timing of ART initiation, however, did not consistently affect the expression of the exhaustion markers once viral suppression was achieved. Understanding which factors do and do not regulate aspects of CD8+ T cell exhaustion, including the expression of exhaustion markers, is critical to inform the rational design of CD8+ T cell-based therapies to treat HIV, for which CD8+ T cell exhaustion remains an important barrier to efficacy.

Background and objectiveSleep disturbance is a common problem among adults with obesity. Mindfulness interventions have been shown to improve sleep quality in various populations but have not been investigated in adults with obesity. The aim of this study was to compare the effects of a mindfulness-based weight-loss intervention with an active control on self-reported sleep quality among adults with obesity.MethodThis study was a secondary analysis of a randomized controlled trial and included 194 adults with a body mass index in the range 30-45 kg/m2. The treatment intervention included mindfulness-based eating and stress-management practices, and the active control intervention included training in progressive muscle relaxation (PMR). Both groups received identical diet and exercise guidelines in 17 group sessions conducted over 5.5 months that were matched for time, attention, and social support. The primary outcome of this analysis was between-group change in self-reported sleep quality, which was assessed using the Pittsburgh Sleep Quality Index (PSQI) global score at baseline and at 6, 12, and 18 months.ResultsBetween-group differences in mean PSQI change scores in the mindfulness group (n = 100) compared to the control group (n = 94) were -0.27 (-0.68, 1.22; p = 0.58) at 6 months, -0.57 (-0.35, 1.50; p = 0.22) at 12 months, and -0.50 (-0.53, 1.53; p = 0.34) at 18 months, all in the direction of more sleep improvement in the mindfulness group but none reaching statistical significance. In the mindfulness group, average weekly minutes of meditation practice time was associated with improved sleep quality from baseline to 6 months.ConclusionsNo statistically significant evidence was found that a weight-loss program that incorporates mindfulness improves self-reported sleep quality compared to a control diet/exercise intervention that included PMR. Within the mindfulness group, average weekly minutes of mindfulness practice was associated with improved sleep quality.

Human evolution has resulted in selection for genetic polymorphisms beneficial in the defense against pathogens. However, such polymorphisms may have the potential to heighten the risk of autoimmune disease. Here, we investigated whether psoriasis-associated single nucleotide polymorphisms influence host control of HIV-1 infection. We studied psoriasis and viral immune response variants in three HIV-positive cohorts: (1) HIV-1 controllers and non-controllers in the Study of the Consequences of the Protease Inhibitor Era (SCOPE) cohort (n=366), (2) Individuals with primary HIV infection in the Options cohort (n=675), and (3) HIV-positive injection drug users from the Urban Health Study (UHS) (n=987). We found a strong association of two psoriasis MHC variants, rs9264942 and rs3021366, with both HIV-1 controller status and viral load, and identified another Class III MHC variant rs9368699 to be strongly associated with viral load. A number of genetic variants outside the MHC (SOX5, TLR9, SDC4, PROX1, IL12B, TLR4, MBL-2, TYK2, IFIH1) demonstrated nominal significance. Overall, our data suggest that several psoriasis variants within the MHC have a robust impact on HIV-1 control, while variants outside the MHC require further investigation.

HIV-specific CD8+ T cells demonstrate an exhausted phenotype associated with increased expression of inhibitory receptors, decreased functional capacity, and a skewed transcriptional profile, which are only partially restored by antiretroviral treatment (ART). Expression levels of the inhibitory receptor, T cell immunoglobulin and ITIM domain (TIGIT), the co-stimulatory receptor CD226 and their ligand PVR are altered in viral infections and cancer. However, the extent to which the TIGIT/CD226/PVR-axis is affected by HIV-infection has not been characterized. Here, we report that TIGIT expression increased over time despite early initiation of ART. HIV-specific CD8+ T cells were almost exclusively TIGIT+, had an inverse expression of the transcription factors T-bet and Eomes and co-expressed PD-1, CD160 and 2B4. HIV-specific TIGIThi cells were negatively correlated with polyfunctionality and displayed a diminished expression of CD226. Furthermore, expression of PVR was increased on CD4+ T cells, especially T follicular helper (Tfh) cells, in HIV-infected lymph nodes. These results depict a skewing of the TIGIT/CD226 axis from CD226 co-stimulation towards TIGIT-mediated inhibition of CD8+ T cells, despite early ART. These findings highlight the importance of the TIGIT/CD226/PVR axis as an immune checkpoint barrier that could hinder future "cure" strategies requiring potent HIV-specific CD8+ T cells.

ObjectivePrior hypothesis-driven studies identified immunophenotypic characteristics associated with the control of HIV replication without antiretroviral therapy (HIV controllers) as well as with the degree of CD4 T-cell recovery during ART. We hypothesized that an unbiased 'discovery-based' approach might identify novel immunologic characteristics of these phenotypes.DesignWe performed immunophenotyping on four 'aviremic' patient groups: HIV controllers (n = 98), antiretroviral-treated immunologic nonresponders (CD4  350, n = 142), and as a control group HIV-negative adults (n = 43). We measured levels of T-cell maturation, activation, dysfunction, senescence, functionality, and proliferation.MethodsSupervised learning assessed the relative importance of immune parameters in predicting clinical phenotypes (controller, immunologic responder, or immunologic nonresponder). Unsupervised learning clustered immune parameters and examined if these clusters corresponded to clinical phenotypes.ResultsHIV controllers were characterized by high percentages of HIV-specific T-cell responses and decreased percentages of cells expressing human leukocytic antigen-antigen D related in naive, central memory, and effector T-cell subsets. Immunologic nonresponders were characterized by higher percentages of CD4 T cells that were TNFα+ or INFγ+, higher percentages of activated naive and central memory T cells, and higher percentages of cells expressing programmed cell death protein 1. Unsupervised learning found two distinct clusters of controllers and two distinct clusters of immunologic nonresponders, perhaps suggesting different mechanisms for the clinical outcomes.ConclusionOur discovery-based approach confirmed previously reported characteristics that distinguish aviremic individuals, but also identified novel immunologic phenotypes and distinct clinical subpopulations that should lead to more focused pathogenesis studies that might identify targets for novel therapeutic interventions.

Many individuals with obesity report over eating despite intentions to maintain or lose weight. Two barriers to long-term weight loss are reward-driven eating, which is characterized by a lack of control over eating, a preoccupation with food, and a lack of satiety; and psychological stress. Mindfulness training may address these barriers by promoting awareness of hunger and satiety cues, self-regulatory control, and stress reduction. We examined these two barriers as potential mediators of weight loss in the Supporting Health by Integrating Nutrition and Exercise (SHINE) randomized controlled trial, which compared the effects of a 5.5-month diet and exercise intervention with or without mindfulness training on weight loss among adults with obesity. Intention-to-treat multiple mediation models tested whether post-intervention reward-driven eating and psychological stress mediated the impact of intervention arm on weight loss at 12- and 18-months post-baseline among 194 adults with obesity (BMI: 30-45). Mindfulness (relative to control) participants had significant reductions in reward-driven eating at 6 months (post-intervention), which, in turn, predicted weight loss at 12 months. Post-intervention reward-driven eating mediated 47.1% of the total intervention arm effect on weight loss at 12 months [β = -0.06, SE(β) = 0.03, p = .030, 95% CI (-0.12, -0.01)]. This mediated effect was reduced when predicting weight loss at 18 months (p = .396), accounting for 23.0% of the total intervention effect, despite similar weight loss at 12 months. Psychological stress did not mediate the effect of intervention arm on weight loss at 12 or 18 months. In conclusion, reducing reward-driven eating, which can be achieved using a diet and exercise intervention that includes mindfulness training, may promote weight loss (clinicaltrials.gov registration: NCT00960414).

ObjectiveTo determine whether adding mindfulness-based eating and stress management practices to a diet-exercise program improves weight loss and metabolic syndrome components.MethodsIn this study 194 adults with obesity were randomized to a 5.5-month program with or without mindfulness training and identical diet-exercise guidelines. Intention-to-treat analyses with multiple imputation were used for missing data. The primary outcome was 18-month weight change.ResultsEstimated effects comparing the mindfulness to control arm favored the mindfulness arm in (a) weight loss at 12 months, -1.9 kg (95% CI: -4.5, 0.8; P = 0.17), and 18 months, -1.7 kg (95% CI: -4.7, 1.2; P = 0.24), though not statistically significant; (b) changes in fasting glucose at 12 months, -3.1 mg/dl (95% CI: -6.3, 0.1; P = 0.06), and 18 months, -4.1 mg/dl (95% CI: -7.3, -0.9; P = 0.01); and (c) changes in triglyceride/HDL ratio at 12 months, -0.57 (95% CI: -0.95, -0.18; P = 0.004), and 18 months, -0.36 (95% CI: -0.74, 0.03; P = 0.07). Estimates for other metabolic risk factors were not statistically significant, including waist circumference, blood pressure, and C-reactive protein.ConclusionsMindfulness enhancements to a diet-exercise program did not show substantial weight loss benefit but may promote long-term improvement in some aspects of metabolic health in obesity that requires further study.

We evaluated changes in mindful eating as a potential mechanism underlying the effects of a mindfulness-based intervention for weight loss on eating of sweet foods and fasting glucose levels. We randomized 194 obese individuals (M age = 47.0 ± 12.7 years; BMI = 35.5 ± 3.6; 78% women) to a 5.5-month diet-exercise program with or without mindfulness training. The mindfulness group, relative to the active control group, evidenced increases in mindful eating and maintenance of fasting glucose from baseline to 12-month assessment. Increases in mindful eating were associated with decreased eating of sweets and fasting glucose levels among mindfulness group participants, but this association was not statistically significant among active control group participants. Twelve-month increases in mindful eating partially mediated the effect of intervention arm on changes in fasting glucose levels from baseline to 12-month assessment. Increases in mindful eating may contribute to the effects of mindfulness-based weight loss interventions on eating of sweets and fasting glucose levels.

ObjectivesTo describe cancer inpatients' prior-year use of complementary and integrative health (CIH) therapies and interest in receiving CIH therapies while in the hospital.DesignObservational, cross-sectional survey of prior-year use of 12 different CIH approaches and interest in receiving any of 7 CIH services in the hospital.SettingSurgical oncology ward of an academic medical center.Participants166 hospitalized oncology patients, with an average age of 54 years.ResultsThe most commonly used CIH approach was vitamins/nutritional supplements (67%), followed by use of a special diet (42%) and manual therapies (39%). More than 40% of patients expressed interest in each of the therapies if it was offered during their hospital stay, and 95% of patients were interested in at least one. More than 75% expressed interest in nutritional counseling and in massage. CIH use and interest varied somewhat by demographic and clinical characteristics.ConclusionRates of CIH use among patients with cancer were high, as were their preferences to have these services available in the inpatient setting. Hospitals have the opportunity to provide patient-centered care by developing capacity to provide inpatient CIH services.

PurposeObese individuals vary in their experience of food cravings and tendency to engage in reward-driven eating, both of which can be modulated by the neural reward system rather than physiological hunger. We examined two predictions in a sample of obese women: (1) whether opioidergic blockade reduced food-craving intensity, and (2) whether opioidergic blockade reduced an association between food-craving intensity and reward-driven eating, which is a trait-like index of three factors (lack of control over eating, lack of satiation, preoccupation with food).MethodsForty-four obese, pre-menopausal women completed the Reward-Based Eating Drive (RED) scale at study start and daily food-craving intensity on 5 days on which they ingested either a pill-placebo (2 days), a 25 mg naltrexone dose (1 day), or a standard 50mg naltrexone dose (2 days).ResultsCraving intensity was similar under naltrexone and placebo doses. The association between food-craving intensity and reward-driven eating significantly differed between placebo and 50mg naltrexone doses. Reward-driven eating and craving intensity were significantly positively associated under both placebo doses. As predicted, opioidergic blockade (for both doses 25mg and 50mg naltrexone) reduced the positive association between reward-driven eating and craving intensity to non-significance.ConclusionsOpioidergic blockade did not reduce craving intensity; however, blockade reduced an association between trait-like reward-driven eating and daily food-craving intensity, and may help identify an important endophenotype within obesity.

There are currently no commonly used or easily accessible 'biomarkers' of hedonic eating. Physiologic responses to acute opioidergic blockade, indexed by cortisol changes and nausea, may represent indirect functional measures of opioid-mediated hedonic eating drive and predict weight loss following a mindfulness-based intervention for stress eating. In the current study, we tested whether cortisol and nausea responses induced by oral ingestion of an opioidergic antagonist (naltrexone) correlated with weight and self-report measures of hedonic eating and predicted changes in these measures following a mindfulness-based weight loss intervention. Obese women (N = 88; age = 46.7 ± 13.2 years; BMI = 35.8 ± 3.8) elected to complete an optional sub-study prior to a 5.5-month weight loss intervention with or without mindfulness training. On two separate days, participants ingested naltrexone and placebo pills, collected saliva samples, and reported nausea levels. Supporting previous findings, naltrexone-induced cortisol increases were associated with greater hedonic eating (greater food addiction symptoms and reward-driven eating) and less mindful eating. Among participants with larger cortisol increases (+1 SD above mean), mindfulness participants (relative to control participants) reported greater reductions in food addiction symptoms, b = -0.95, SE(b) = 0.40, 95% CI [-1.74, -0.15], p = .021. Naltrexone-induced nausea was marginally associated with reward-based eating. Among participants who endorsed naltrexone-induced nausea (n = 38), mindfulness participants (relative to control participants) reported greater reductions in food addiction symptoms, b = -1.00, 95% CI [-1.85, -0.77], p = .024, and trended toward reduced reward-based eating, binge eating, and weight, post-intervention. Single assessments of naltrexone-induced cortisol increases and nausea responses may be useful time- and cost-effective biological markers to identify obese individuals with greater opioid-mediated hedonic eating drive who may benefit from weight loss interventions with adjuvant mindfulness training that targets hedonic eating.

BackgroundQuantifying latently infected cells is critical to evaluate the efficacy of therapeutic strategies aimed at reducing the size of the long-lived viral reservoir, but the low frequency of these cells makes this very challenging.MethodsWe developed TILDA (Tat/rev Induced Limiting Dilution Assay) to measure the frequency of cells with inducible multiply-spliced HIV RNA, as these transcripts are usually absent in latently infected cells but induced upon viral reactivation. TILDA requires less than a million cells, does not require RNA extraction and can be completed in two days.FindingsIn suppressed individuals on ART, we found the median frequency of latently infected CD4 + T cells as estimated by TILDA to be 24 cells/million, which was 48 times more than the frequency measured by the quantitative viral outgrowth assay, and 6-27 times less than the frequencies of cells harbouring viral DNA measured by PCR-based assays. TILDA measurements strongly correlated with most HIV DNA assays. The size of the latent reservoir measured by TILDA was lower in subjects who initiated ART during the early compared to late stage of infection (p = 0.011). In untreated HIV disease, the frequency of CD4 + cells carrying latent but inducible HIV largely exceeded the frequency of actively producing cells, demonstrating that the majority of infected cells are transcriptionally silent even in the absence of ART.InterpretationsOur results suggest that TILDA is a reproducible and sensitive approach to measure the frequency of productively and latently infected cells in clinical settings. We demonstrate that the latent reservoir represents a substantial fraction of all infected cells prior to ART initiation.Research in contextIn this manuscript, we describe the development of a novel assay that measures the magnitude of the latent HIV reservoir, the main barrier to HIV eradication. This novel assay, termed TILDA for Tat/rev Induced Limiting Dilution Assay, requires only 10 ml of blood, does not necessitate extraction of viral nucleic acids, is highly reproducible, covers a wide dynamic range of reservoir sizes and can be completed in two days. As such, TILDA may represent an alternative to existing assays used to evaluate the efficacy of therapeutic strategies aimed at reducing the size of the latent HIV reservoir.

Background contextPrimary care clinicians need to identify candidates for early interventions to prevent patients with acute pain from developing chronic pain.PurposeWe conducted a 2-year prospective cohort study of risk factors for the progression to chronic pain and developed and internally validated a clinical decision rule (CDR) that stratifies patients into low-, medium-, and high-risk groups for chronic pain.Study design/settingThis is a prospective cohort study in primary care.Patient samplePatients with acute low back pain (LBP, ≤30 days duration) were included.Outcome measuresOutcome measures were self-reported perceived nonrecovery and chronic pain.MethodsPatients were surveyed at baseline, 6 months, and 2 years. We conducted bivariate and multivariate regression analyses of demographic, clinical, and psychosocial variables for chronic pain outcomes, developed a CDR, and assessed its performance by calculating the bootstrapped areas under the receiver-operating characteristic curve (AUC) and likelihood ratios.ResultsSix hundred five patients enrolled: 13% had chronic pain at 6 months and 19% at 2 years. An eight-item CDR was most parsimonious for classifying patients into three risk levels. Bootstrapped AUC was 0.76 (0.70-0.82) for the 6-month CDR. Each 10-point score increase (60-point range) was associated with an odds ratio of 11.1 (10.8-11.4) for developing chronic pain. Using a less than 5% probability of chronic pain as the cutoff for low risk and a greater than 40% probability for high risk, likelihood ratios were 0.26 (0.14-0.48) and 4.4 (3.0-6.3) for these groups, respectively.ConclusionsA CDR was developed that may help primary care clinicians classify patients with strictly defined acute LBP into low-, moderate-, and high-risk groups for developing chronic pain and performed acceptably in 1,000 bootstrapped replications. Validation in a separate sample is needed.

Poor sleep quality and short sleep duration are associated with increased incidence and progression of a number of chronic health conditions observed at greater frequency among the obese and those experiencing high levels of stress. Accelerated cellular aging, as indexed by telomere attrition in immune cells, is a plausible pathway linking sleep and disease risk. Prior studies linking sleep and telomere length are mixed. One factor may be reliance on leukocytes, which are composed of varied immune cell types, as the sole measure of telomere length. To better clarify these associations, we investigated the relationships of global sleep quality, measured by the Pittsburgh Sleep Quality Index (PSQI), and diary-reported sleep duration with telomere length in different immune cell subsets, including granulocytes, peripheral blood mononuclear cells (PBMCs), CD8+ and CD4+ T lymphocytes, and B lymphocytes in a sample of 87 obese men and women (BMI mean=35.4, SD=3.6; 81.6% women; 62.8% Caucasian). Multiple linear regression analyses were performed adjusting for age, gender, race, education, BMI, sleep apnea risk, and perceived stress. Poorer PSQI global sleep quality was associated with statistically significantly shorter telomere length in lymphocytes but not granulocytes and in particular CD8+ T cells (b=-56.8 base pairs per one point increase in PSQI, SE=20.4, p=0.007) and CD4+ T cells (b=-37.2, SE=15.9, p=0.022). Among separate aspects of global sleep quality, low perceived sleep quality and decrements in daytime function were most related to shorter telomeres. In addition, perceived stress moderated the sleep-CD8+ telomere association. Poorer global sleep quality predicted shorter telomere length in CD8+ T cells among those with high perceived stress but not in low stress participants. These findings provide preliminary evidence that poorer global sleep quality is related to telomere length in several immune cell types, which may serve as a pathway linking sleep and disease risk in obese individuals.

ObjectiveTo examine the feasibility of identifying HIV negative at risk individuals in HIV serodiscordant couples, during voluntary HIV testing in South Brazil.MethodsWe surveyed HIV testers at 4 public testing sites in Rio Grande do Sul. We obtained information on risk behaviors and sexual partnerships. HIV testing and testing for recent infection were performed; HIV prevalence and risk behaviors were assessed among subjects who reported having a steady partner who was HIV positive (serodiscordant group) and compared with the general testing population.ResultsAmong 3100 patients, 490 (15.8%) reported being in a steady relationship with an HIV positive partner. New HIV infections were diagnosed in 23% of the serodiscordant group (vs. 13% in the general population, p = 0.01); among newly positive subjects, recent HIV infections were more frequent (23/86, 26.7%) among testers with positive partners than among the general testing group (52/334; 15.6%; p = 0.016). Less than half of the serodiscordant testers reported having used a condom during the last sexual intercourse with their HIV-positive partner. Participants with inconsistent condom use with steady partner were four times more likely to test positive for HIV compared to those who reported always using condoms with the steady partner (OR: 4.2; 95% CI: 2.3 to 7.5).ConclusionIt is highly feasible to identify large numbers of HIV susceptible individuals who are in HIV serodiscordant relationships in South Brazil testing sites. Condom use within HIV serodiscordant couples is low in this setting, suggesting urgent need for biomedical prevention strategies to reduce HIV transmission.

BackgroundHuman Endogenous Retroviruses (HERVs) comprise about 8% of the human genome and have lost their ability to replicate or to produce infectious particles after having accumulated mutations over time. We assessed the kinetics of expression of HERV-K (HML-2) Envelope mRNA transcript and surface unit (SU) and transmembrane (TM) subunit proteins during HIV-1 infection. We also mapped the specificity of the humoral response to HERV-K (HML-2) Envelope protein in HIV-1 infected subjects at different stages of disease, and correlated the response with plasma viral load.ResultsWe found that HIV-1 modified HERV-K (HML-2) Env mRNA expression, resulting in the expression of a fully N-glycosylated HERV-K (HML-2) envelope protein on the cell surface. Serological mapping of HERV-K (HML-2) envelope protein linear epitopes revealed two major immunogenic domains, one on SU and another on the ectodomain of TM. The titers of HERV-K (HML-2) TM antibodies were dramatically increased in HIV-1 infected subjects (p

BackgroundType 2 diabetes is a major health problem in many countries including India. Yoga may be an effective type 2 diabetes prevention strategy in India, particularly given its cultural familiarity.MethodsThis was a parallel, randomized controlled pilot study to collect feasibility and preliminary efficacy data on yoga for diabetes risk factors among people at high risk of diabetes. Primary outcomes included: changes in BMI, waist circumference, fasting blood glucose, postprandial blood glucose, insulin, insulin resistance, blood pressure, and cholesterol. We also looked at measures of psychological well-being including changes in depression, anxiety, positive and negative affect and perceived stress. Forty-one participants with elevated fasting blood glucose in Bangalore, India were randomized to either yoga (n = 21) or a walking control (n = 20). Participants were asked to either attend yoga classes or complete monitored walking 3-6 days per week for eight weeks. Randomization and allocation was performed using computer-generated random numbers and group assignments delivered in sealed, opaque envelopes generated by off-site study staff. Data were analyzed based on intention to treat.ResultsThis study was feasible in terms of recruitment, retention and adherence. In addition, yoga participants had significantly greater reductions in weight, waist circumference and BMI versus control (weight -0.8 ± 2.1 vs. 1.4 ± 3.6, p = 0.02; waist circumference -4.2 ± 4.8 vs. 0.7 ± 4.2, p

In this study, we investigated the expression levels of host restriction factors in six untreated HIV-1-positive patients over the course of infection. We found that the host restriction factor gene expression profile consistently increased over time and was significantly associated with CD4+ T cell activation and viral load. Our data are among the first to demonstrate the dynamic nature of host restriction factors in vivo over time.

BackgroundUnlike cytomegalovirus (CMV) infection and aging, human immunodeficiency virus (HIV) decreases the proportion of CD28(-)CD8(+) T cells expressing CD57. Whether this abnormality predicts mortality in treated HIV infection and can be reversed by early antiretroviral therapy (ART) remains unknown.MethodsWe sampled recently HIV-infected individuals (

BackgroundThere is intense interest in the role of programmed death 1 (PD-1) in causing persistent T-cell dysfunction in HIV infection. However, the impact of HIV infection and antiretroviral treatment (ART) on the expression of PD-1 on T cells is still poorly defined.MethodsPD-1 was measured longitudinally in a cohort of recently HIV-infected individuals (n = 121) who started ART early (

Though depression is known to frequently afflict those with chronic HIV, mood during the early course of HIV is not well characterized. In a prospective study we assessed mood during primary HIV infection [primary HIV infection (PHI),

A low CD4/CD8 ratio in elderly HIV-uninfected adults is associated with increased morbidity and mortality. A subset of HIV-infected adults receiving effective antiretroviral therapy (ART) fails to normalize this ratio, even after they achieve normal CD4+ T cell counts. The immunologic and clinical characteristics of this clinical phenotype remain undefined. Using data from four distinct clinical cohorts and three clinical trials, we show that a low CD4/CD8 ratio in HIV-infected adults during otherwise effective ART (after CD4 count recovery above 500 cells/mm3) is associated with a number of immunological abnormalities, including a skewed T cell phenotype from naïve toward terminally differentiated CD8+ T cells, higher levels of CD8+ T cell activation (HLADR+CD38+) and senescence (CD28- and CD57+CD28-), and higher kynurenine/tryptophan ratio. Changes in the peripheral CD4/CD8 ratio are also reflective of changes in gut mucosa, but not in lymph nodes. In a longitudinal study, individuals who initiated ART within six months of infection had greater CD4/CD8 ratio increase compared to later initiators (>2 years). After controlling for age, gender, ART duration, nadir and CD4 count, the CD4/CD8 ratio predicted increased risk of morbidity and mortality. Hence, a persistently low CD4/CD8 ratio during otherwise effective ART is associated with increased innate and adaptive immune activation, an immunosenescent phenotype, and higher risk of morbidity/mortality. This ratio may prove useful in monitoring response to ART and could identify a unique subset of individuals needed of novel therapeutic interventions.

Overweight and obese individuals differ in their degree of hedonic eating. This may reflect adaptations in reward-related neural circuits, regulated in part by opioidergic activity. We examined an indirect, functional measure of central opioidergic activity by assessing cortisol and nausea responses to acute opioid blockade using the opioid antagonist naltrexone in overweight/obese women (mean BMI=31.1±4.8) prior to the start of a mindfulness-based intervention to reduce stress eating. In addition, we assessed indices of hedonic-related eating, including eating behaviors (binge eating, emotional eating, external eating, restraint) and intake of sweets/desserts and carbohydrates (Block Food Frequency); interoceptive awareness (which is associated with dysregulated eating behavior); and level of adiposity at baseline. Naltrexone-induced increases in cortisol were associated with greater emotional and restrained eating and lower interoceptive awareness. Naltrexone-induced nausea was associated with binge eating and higher adiposity. Furthermore, in a small exploratory analysis, naltrexone-induced nausea predicted treatment response to the mindfulness intervention, as participants with more severe nausea at baseline maintained weight whereas those with little or no nausea responses tended to gain weight. These preliminary data suggest that naltrexone-induced cortisol release and nausea may help identify individuals who have greater underlying food reward dependence, which leads to an excessive drive to eat. Future research is needed to confirm this finding and to test if these markers of opioidergic tone might help predict success in certain types of weight management programs.

BackgroundChronic antigenic stimulation by cytomegalovirus (CMV) is thought to increase "immunosenesence" of aging, characterized by accumulation of terminally differentiated CD28- CD8+ T cells and increased CD57, a marker of proliferative history. Whether chronic HIV infection causes similar effects is currently unclear.MethodsWe compared markers of CD8+ T cell differentiation (e.g., CD28, CD27, CCR7, CD45RA) and CD57 expression on CD28- CD8+ T cells in healthy HIV-uninfected adults with and without CMV infection and in both untreated and antiretroviral therapy (ART)-suppressed HIV-infected adults with asymptomatic CMV infection.ResultsCompared to HIV-uninfected adults without CMV (n=12), those with asymptomatic CMV infection (n=31) had a higher proportion of CD28-CD8+ T cells expressing CD57 (P=0.005). Older age was also associated with greater proportions of CD28-CD8+ T cells expressing CD57 (rho: 0.47, P=0.007). In contrast, untreated HIV-infected CMV+ participants (n=55) had much lower proportions of CD28- CD8+ cells expressing CD57 than HIV-uninfected CMV+ participants (P

The association between the host immune environment and the size of the HIV reservoir during effective antiretroviral therapy is not clear. Progress has also been limited by the lack of a well-accepted assay for quantifying HIV during therapy. We examined the association between multiple measurements of HIV and T cell activation (as defined by markers including CD38, HLA-DR, CCR5 and PD-1) in 30 antiretroviral-treated HIV-infected adults. We found a consistent association between the frequency of CD4+ and CD8+ T cells expressing HLA-DR and the frequency of resting CD4+ T cells containing HIV DNA. This study highlights the need to further examine this relationship and to better characterize the biology of markers commonly used in HIV studies. These results may also have implications for reactivation strategies.

Background. CD4(+)/CD8(+) T-cell activation levels often remain elevated in chronic human immunodeficiency virus (HIV) infection despite initiation of antiretroviral therapy (ART). T-cell activation predicts early death and blunted CD4+ T-cell recovery during ART and may affect persistent HIV reservoir size. We investigated whether very early ART initiation is associated with lower on-therapy immune activation and HIV persistence. Methods. From a cohort of patients with early HIV infection (

ObjectiveThe level of T cell activation in untreated HIV disease is strongly and independently associated with risk of immunologic and clinical progression. The factors that influence the level of activation, however, are not fully defined. Since endogenous glucocorticoids are important in regulating inflammation, we sought to determine whether less optimal diurnal cortisol patterns are associated with greater T cell activation.MethodsWe studied 128 HIV-infected adults who were not on treatment and had a CD4(+) T cell count above 250 cells/µl. We assessed T cell activation by CD38 expression using flow cytometry, and diurnal cortisol was assessed with salivary measurements.ResultsLower waking cortisol levels correlated with greater T cell immune activation, measured by CD38 mean fluorescent intensity, on CD4(+) T cells (r = -0.26, p = 0.006). Participants with lower waking cortisol also showed a trend toward greater activation on CD8(+) T cells (r = -0.17, p = 0.08). A greater diurnal decline in cortisol, usually considered a healthy pattern, correlated with less CD4(+) (r = 0.24, p = 0.018) and CD8(+) (r = 0.24, p = 0.017) activation.ConclusionsThese data suggest that the hypothalamic-pituitary-adrenal (HPA) axis contributes to the regulation of T cell activation in HIV. This may represent an important pathway through which psychological states and the HPA axis influence progression of HIV.

BackgroundPsychological distress and metabolic dysregulation are associated with markers of accelerated cellular aging, including reduced telomerase activity and shortened telomere length. We examined whether participation in a mindfulness-based intervention, and, secondarily, improvements in psychological distress, eating behavior, and metabolic factors are associated with increases in telomerase activity in peripheral blood mononuclear cells (PBMCs).MethodsWe enrolled 47 overweight/obese women in a randomized waitlist-controlled pilot trial (n=47) of a mindfulness-based intervention for stress eating and examined changes in telomerase activity from pre- to post-intervention. In secondary analyses, changes in telomerase activity across the sample were examined in relation to pre- to post-intervention changes in psychological distress, eating behavior, and metabolic factors (weight, serum cortisol, fasting glucose and insulin, and insulin resistance).ResultsBoth groups increased in mean telomerase activity over 4 months in intent-to-treat and treatment efficacy analyses (p

ObjectiveHIV-infected individuals are at high risk of developing cardiovascular disease. Whether earlier initiation of HIV therapy at higher CD4 cell counts has any effect on cardiovascular risk as assessed by endothelial function is unknown.DesignCross-sectional study of 74 antiretroviral-treated men with undetectable plasma HIV RNA levels.MethodsParticipants underwent noninvasive assessment of endothelial function using brachial artery flow-mediated dilation (FMD). The association of nadir and current CD4 T-cell count with FMD was assessed using multivariable linear regression.ResultsThe median age was 47 years [interquartile range (IQR) 42-55], median current CD4 T-cell count was 659 cells/μl (IQR 542-845), and nadir CD4 cell count was 314 cells/μl (IQR 150-490). Twenty-eight percent had hypertension, and 32% hyperlipidemia. Nadir CD4 T-cell count less than 350 cells/μl was associated with lower FMD in age-adjusted and race-adjusted analyses and remained an independent predictor of FMD after adjustment for cardiovascular risk factors (hypertension, diabetes, smoking, hyperlipidemia) and HIV-related characteristics (HIV duration, HAART duration). After multivariable adjustment, individuals with nadir CD4 T-cell count less than 350 cells/μl had a 1.22% lower FMD compared with those with higher T-cell counts [95% confidence interval (CI) -2.20 to -0.19, P=0.02]. Proximal CD4 T-cell count showed little association with FMD.ConclusionAmong treated HIV-infected individuals, nadir CD4 T-cell count less than 350 cells/μl is independently associated with lower FMD, suggesting that delayed therapy results in sustained harm to endothelial function. Our data support future prospective studies evaluating cardiovascular effects of HAART initiation at higher CD4 cell counts.

BackgroundTransmitted HIV-1 drug resistance (TDR) is an ongoing public health problem, representing 10-20% of new HIV infections in many geographic areas. TDR usually arises from two main sources: individuals on antiretroviral therapy (ART) who are failing to achieve virologic suppression, and individuals who acquired TDR and transmit it while still ART-naïve. TDR rates can be impacted when novel antiretroviral medications are introduced that allow for greater virologic suppression of source patients. Although several new HIV medications were introduced starting in late 2007, including raltegravir, maraviroc, and etravirine, it is not known whether the prevalence of TDR was subsequently affected in 2008-2009.Methodology/principal findingsWe performed population sequence genotyping on individuals who were diagnosed with acute or early HIV (

Little is known about the manipulation of IL-17 producing CD4+ T cells (T(H)17) on a per-cell basis in humans in vivo. Previous studies on the effects of IL-2 on IL-17 secretion in non-HIV models have shown divergent results. We hypothesized that IL-2 would mediate changes in IL-17 levels among recently HIV-1-infected adults receiving anti-retroviral therapy. We measured cytokine T cell responses to CD3/CD28, HIV-1 Gag, and CMV pp65 stimulation, and changes in multiple CD4+ T cell subsets. Those who received IL-2 showed a robust expansion of naive and total CD4+ T cell counts and T-reg counts. However, after IL-2 treatment, the frequency of T(H)17 cells declined, while counts of T(H)17 cells did not change due to an expansion of the CD4+ naïve T cell population (CD27+CD45RA+). Counts of HIV-1 Gag-specific T cells declined modestly, but CMV pp65 and CD3/CD28 stimulated populations did not change. Hence, in contrast with recent studies, our results suggest IL-2 is not a potent in vivo regulator of T(H)17 cell populations in HIV-1 disease. However, IL-2-mediated T-reg expansions may selectively reduce responses to certain antigen-specific populations, such as HIV-1 Gag.

BackgroundThe relationship of elevated T cell activation to altered T cell differentiation profiles, each defining features of HIV-1 infection, has not been extensively explored. We hypothesized that anti-retroviral suppression of T cell activation levels would lead to alterations in the T cell differentiation of total and HIV-1 specific CD8+ T cell responses among recently HIV-1 infected adults.Methodology/principal findingsWe performed a longitudinal study simultaneously measuring T cell activation and maturation markers on both total and antigen-specific T cells in recently infected adults: prior to treatment; after the initiation of HAART; and after treatment was halted. Prior to treatment, HIV-1 Gag-specific CD8+ T cells were predominantly of a highly activated, intermediate memory (CD27+CD28-) phenotype, while CMV pp65-specific CD8+ T cells showed a late memory (CD27-CD28-), low activation phenotype. Participants with the highest fraction of late memory (CD27-CD28-) HIV-1-specific CD8+ T cells had higher CD4+ T cell counts (rho = +0.74, p = 0.004). In turn, those with the highest fraction of intermediate memory (CD27+ CD28-) HIV-1 specific CD8+ T cells had high total CD8+ T cell activation (rho = +0.68, p = 0.01), indicating poorer long-term clinical outcomes. The HIV-1 specific T cell differentiation profile was not readily altered by suppression of T cell activation following HAART treatment.Conclusions/significanceA more differentiated, less activated HIV-1 specific CD8+ T cell response may be clinically protective. Anti-retroviral treatment initiated two to four months after infection lowered T cell activation but had no effect on the differentiation profile of the HIV-1-specific response. Intervention during the first month of acute infection may be required to shift the differentiation phenotype of HIV-1 specific responses to a more clinically favorable profile.