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1.  Effects of a mindfulness‐based weight loss intervention in adults with obesity: A randomized clinical trial 
Obesity (Silver Spring, Md.)  2016;24(4):794-804.
Objective
To determine whether adding mindfulness‐based eating and stress management practices to a diet‐exercise program improves weight loss and metabolic syndrome components.
Methods
In 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.
Results
Estimated 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.
Conclusions
Mindfulness 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.
doi:10.1002/oby.21396
PMCID: PMC4898945  PMID: 26955895
2.  Putting the brakes on the "drive to eat": Pilot effects of naltrexone and reward based eating on food cravings among obese women 
Eating behaviors  2015;19:53-56.
Purpose
Obese 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).
Methods
Forty-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 25mg naltrexone dose (1 day), or a standard 50mg naltrexone dose (2 days).
Results
Craving 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 this positive association between reward-driven eating and craving intensity to non-significance.
Conclusions
Opioidergic 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.
doi:10.1016/j.eatbeh.2015.06.008
PMCID: PMC4644449  PMID: 26164674
Obesity; craving intensity; reward based eating drive; naltrexone; opioidergic blockade
3.  Adjunctive acupuncture for pain and symptom management in the inpatient setting: Protocol for a pilot hybrid effectiveness-implementation study 
Journal of integrative medicine  2016;14(3):228-238.
Background
Effective pain management among hospitalized patients is an important aspect of providing quality care and achieving optimal clinical outcomes and patient satisfaction. Common pharmacologic approaches for pain, though effective, have serious side effects and are not appropriate for all inpatients. Findings from randomized controlled trials (RCTs) support the efficacy of acupuncture for many symptoms relevant to inpatients including postoperative pain, cancer-related pain, nausea and vomiting, and withdrawal from narcotic use. However, the extent to which findings from RCTs translate to real-world implementation of acupuncture in typical hospital settings is unknown.
Methods/Design
In partnership with the launch of a clinical program offering acupuncture services to inpatients at the University of California, San Francisco’s Mount Zion Hospital, we are conducting a pilot study using a hybrid effectiveness-implementation design to: (1) assess the effectiveness of acupuncture to manage pain and other symptoms and improve patient satisfaction; and (2) evaluate the barriers and facilitators to implementing an on-going acupuncture service for inpatients. During a 2-month pre-randomization phase, we evaluated and adapted clinical scheduling and treatment protocols with acupuncturists and hospital providers and pretested study procedures including enrollment, consent, and data collection. During a 6-month randomization phase, we used a two-tiered consent process in which inpatients were first consented into a study of symptom management, randomized to be offered acupuncture, and consented for acupuncture if they accepted. We are also conducting in-depth interviews and focus groups to assess evidence, context, and facilitators of key provider and hospital administration stakeholders.
Discussion
Effectiveness research in ‘real-world’ practice settings is needed to inform clinical decision-making and guide implementation of evidence-based acupuncture practices. To successfully provide clinical acupuncture services and maintain a rigorous research design, practice-based trials of acupuncture require careful planning and attention to setting-specific, contextual factors.
Trial Registration
This trial has been registered in ClinicalTrials.gov. The identifier is NCT01988194, registered on November 5, 2013.
doi:10.1016/S2095-4964(16)60252-2
PMCID: PMC5050044  PMID: 27181130
acupuncture; integrative medicine; inpatients; effectiveness trial; hybrid trial; implementation research
4.  Perturbed CD8+ T cell TIGIT/CD226/PVR axis despite early initiation of antiretroviral treatment in HIV infected individuals 
Scientific Reports  2017;7:40354.
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.
doi:10.1038/srep40354
PMCID: PMC5233961  PMID: 28084312
5.  Longitudinal Genetic Characterization Reveals That Cell Proliferation Maintains a Persistent HIV Type 1 DNA Pool During Effective HIV Therapy 
The Journal of Infectious Diseases  2015;212(4):596-607.
Background
The stability of the human immunodeficiency virus type 1 (HIV-1) reservoir and the contribution of cellular proliferation to the maintenance of the reservoir during treatment are uncertain. Therefore, we conducted a longitudinal analysis of HIV-1 in T-cell subsets in different tissue compartments from subjects receiving effective antiretroviral therapy (ART).
Methods
Using single-proviral sequencing, we isolated intracellular HIV-1 genomes derived from defined subsets of CD4+ T cells from peripheral blood, gut-associated lymphoid tissue and lymph node tissue specimens from 8 subjects with virologic suppression during long-term ART at 2 time points (time points 1 and 2) separated by 7–9 months.
Results
DNA integrant frequencies were stable over time (<4-fold difference) and highest in memory T cells. Phylogenetic analyses showed that subjects treated during chronic infection contained viral populations with up to 73% identical sequence expansions, only 3 of which were observed in specimens obtained before therapy. At time points 1 and 2, such clonally expanded populations were found predominantly in effector memory T cells from peripheral blood and lymph node tissue specimens.
Conclusions
Memory T cells maintained a relatively constant HIV-1 DNA integrant pool that was genetically stable during long-term effective ART. These integrants appear to be maintained by cellular proliferation and longevity of infected cells, rather than by ongoing viral replication.
doi:10.1093/infdis/jiv092
PMCID: PMC4539896  PMID: 25712966
HIV-1 persistence; HIV-1 reservoir; memory T cells
6.  Effects of form-focused training on running biomechanics: A pilot randomized trial in untrained individuals 
Objective
To investigate the changes in running biomechanics after training in Form-Focused running using ChiRunning vs. Not-Form focused training and Self-Directed training in untrained individuals.
Design
Pilot study - Randomized controlled trial.
Setting
Research Institution with Tertiary Care Medical Center.
Participants
Seventeen subjects (9 males, 8 females) with pre-hypertension.
Methods
Twenty-two participants were randomized to three study arms but 17 completed the study. The study arms were: 1) group-based Form-Focused running using ChiRunning (enrolled, n =10; completed, n=7); 2) group-based conventional running (enrolled, n=6; completed, n=4); 3) self-directed training with educational materials (enrolled, n =6; completed, n=6). The training schedule was prescribed for 8 weeks with 4 weeks of follow-up. All subjects completed overground running motion analyses before and after training.
Outcomes
Ankle, knee, hip joint peak moments and powers; Average vertical loading rate (AVLR), impact peak, cadence, stride length, strike index, and stride reach. Paired T-tests were used to compare differences with-in groups over-time.
Results
Form-Focused group reduced their Stride Reach (P = .047) after the training but not the other groups. Form-Focused group showed a close to significant reduction in knee adduction moment (P = .051) and a reduction in the peak ankle eversion moment (P = .027). Self-Directed group showed an increase in the running speed, (P =.056) and increases in ankle and knee joint powers and moments.
Conclusions
There are differences in the changes in running biomechanics between individuals trained in running form that emphazies mid-foot strike, higher cadence, and shorter stride compared to those not trained in the thise technique. These differences may be associated with reduced lower extremity stress in individuals trained in this running form but future studies are needed to confirm these findings in larger samples.
doi:10.1016/j.pmrj.2015.01.010
PMCID: PMC4515408  PMID: 25633634
ChiRunning; Knee adduction moment; loading rate; strike index; stride reach; Kinetics
7.  Acute responses to opioidergic blockade as a biomarker of hedonic eating among obese women enrolled in a mindfulness-based weight loss intervention trial 
Appetite  2015;91:311-320.
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.
doi:10.1016/j.appet.2015.04.062
PMCID: PMC4485926  PMID: 25931433
Hedonic Eating; Mindfulness Intervention; Naltrexone; Cortisol; Nausea
9.  CD4+ T Cells Expressing PD-1, TIGIT and LAG-3 Contribute to HIV Persistence during ART 
PLoS Pathogens  2016;12(7):e1005761.
HIV persists in a small pool of latently infected cells despite antiretroviral therapy (ART). Identifying cellular markers expressed at the surface of these cells may lead to novel therapeutic strategies to reduce the size of the HIV reservoir. We hypothesized that CD4+ T cells expressing immune checkpoint molecules would be enriched in HIV-infected cells in individuals receiving suppressive ART. Expression levels of 7 immune checkpoint molecules (PD-1, CTLA-4, LAG-3, TIGIT, TIM-3, CD160 and 2B4) as well as 4 markers of HIV persistence (integrated and total HIV DNA, 2-LTR circles and cell-associated unspliced HIV RNA) were measured in PBMCs from 48 virally suppressed individuals. Using negative binomial regression models, we identified PD-1, TIGIT and LAG-3 as immune checkpoint molecules positively associated with the frequency of CD4+ T cells harboring integrated HIV DNA. The frequency of CD4+ T cells co-expressing PD-1, TIGIT and LAG-3 independently predicted the frequency of cells harboring integrated HIV DNA. Quantification of HIV genomes in highly purified cell subsets from blood further revealed that expressions of PD-1, TIGIT and LAG-3 were associated with HIV-infected cells in distinct memory CD4+ T cell subsets. CD4+ T cells co-expressing the three markers were highly enriched for integrated viral genomes (median of 8.2 fold compared to total CD4+ T cells). Importantly, most cells carrying inducible HIV genomes expressed at least one of these markers (median contribution of cells expressing LAG-3, PD-1 or TIGIT to the inducible reservoir = 76%). Our data provide evidence that CD4+ T cells expressing PD-1, TIGIT and LAG-3 alone or in combination are enriched for persistent HIV during ART and suggest that immune checkpoint blockers directed against these receptors may represent valuable tools to target latently infected cells in virally suppressed individuals.
Author Summary
The persistence of HIV in a small pool of long-lived latently infected resting CD4+ T cells is a major barrier to viral eradication. Identifying cellular markers that are preferentially expressed at the surface of latently infected cells may lead to novel therapeutic strategies to cure HIV infection. We identified PD-1, TIGIT and LAG-3 as markers preferentially expressed at the surface of infected cells in individuals receiving ART. CD4+ T cells co-expressing these markers were highly enriched for cells carrying HIV. Our results suggest that PD-1, TIGIT and LAG-3 may represent new molecular targets to interfere with HIV persistence during ART.
doi:10.1371/journal.ppat.1005761
PMCID: PMC4944956  PMID: 27415008
10.  Tired Telomeres: poor global sleep quality, perceived stress, and telomere length in immune cell subsets in obese men and women 
Brain, behavior, and immunity  2014;47:155-162.
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.
doi:10.1016/j.bbi.2014.12.011
PMCID: PMC4468027  PMID: 25535858
sleep quality; sleep duration; telomere length; stress; obesity
11.  Clinical decision rule for primary care patient with acute low back pain at risk of developing chronic pain 
Background Context
Primary care clinicians need to identify candidates for early interventions to prevent patients with acute pain from developing chronic pain.
Purpose
We 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/Setting
Prospective cohort study in primary care.
Patient Sample
Patients with acute low back pain (LBP; ≤30 days duration)
Outcome measures
Self-reported perceived non-recovery and chronic pain.
Methods
Patients 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. This study was supported by NIH/NCCAM grants K23 AT002298, R21 AT004467, NIH/NCCAM K24 AT007827, the Research Evaluation and Allocation Committee (REAC) of the University of California San Francisco, and the Mount Zion Health Fund, San Francisco. The funding agencies played no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. The authors report no conflict of interests.
Results
605 patients enrolled. 13% had chronic pain at 6 months, 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 <5% probability of chronic pain as the cutoff for low risk and a >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.
Conclusions
A 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.
doi:10.1016/j.spinee.2015.03.003
PMCID: PMC4475413  PMID: 25771757
Low back pain; chronic pain; acute pain; clinical decision rule; prediction; primary care
12.  Factors related to telomere length 
doi:10.1016/j.bbi.2015.12.001
PMCID: PMC4869862  PMID: 26851133
13.  Gut-resident Lactobacillus abundance associates with IDO1 inhibition and Th17 dynamics in SIV-infected macaques 
Cell reports  2015;13(8):1589-1597.
Summary
Gut microbes can profoundly modulate mucosal barrier-promoting Th17 cells in mammals. A salient feature of HIV/SIV immunopathogenesis is the loss of Th17 cells, which has been linked to increased activity of the immunomodulatory enzyme, indoleamine 2,3-dioxygenase 1 (IDO 1). The role of gut microbes in this system remains unknown, and the SIV-infected rhesus macaque provides a well-described model for HIV-associated Th17 loss and mucosal immune disruption. We observed a specific depletion of gut-resident Lactobacillus during acute and chronic SIV infection of rhesus macaques, which was also seen in early HIV-infected humans. This depletion in rhesus macaques correlated with increased IDO1 activity and Th17 loss. Macaques supplemented with a Lactobacillus-containing probiotic exhibited decreased IDO1 activity during chronic SIV infection. We propose that Lactobacillus species inhibit mammalian IDO1 and thus may help to preserve Th17 cells during pathogenic SIV infection, providing support for Lactobacillus species as modulators of mucosal immune homeostasis.
Graphical Abstract
doi:10.1016/j.celrep.2015.10.026
PMCID: PMC4782968  PMID: 26586432
14.  Select Host Restriction Factors Are Associated with HIV Persistence During Antiretroviral Therapy 
AIDS (London, England)  2015;29(4):411-420.
Objective
The eradication of HIV necessitates elimination of the HIV latent reservoir. Identifying host determinants governing latency and reservoir size in the setting of antiretroviral therapy (ART) is an important step in developing strategies to cure HIV infection. We sought to determine the impact of cell-intrinsic immunity on the HIV latent reservoir.
Design
We investigated the relevance of a comprehensive panel of established anti-HIV-1 host restriction factors to multiple established virologic and immunologic measures of viral persistence in HIV-1-infected, ART-suppressed individuals.
Methods
We measured the mRNA expression of 42 anti-HIV-1 host restriction factors, levels of cell-associated HIV-1 RNA, levels of total pol and 2-LTR circle HIV-1 DNA, and immunophenotypes of CD4+ T cells in 72 HIV-1-infected subjects on suppressive ART (23 subjects initiated ART <1 year post-infection, and 49 subjects initiated ART >1 year post-infection). Correlations were analyzed using non-parametric tests.
Results
The enhanced expression of a few select host restriction factors, p21, schlafen 11, and PAF1, was strongly associated with reduced CD4+ T cell-associated HIV RNA during ART (p<0.001). In addition, our data suggested that ART perturbs the regulatory relationship between CD4+ T cell activation and restriction factor expression. Lastly, cell-intrinsic immune responses were significantly enhanced in subjects who initiated ART during early versus chronic infection, and may contribute to the reduced reservoir size observed in these individuals.
Conclusions
Intrinsic immune responses modulate HIV persistence during suppressive ART, and may be manipulated to enhance the efficacy of ART and promote viral eradication through reversal of latency in vivo.
doi:10.1097/QAD.0000000000000572
PMCID: PMC4385712  PMID: 25602681
HIV latency; antiretroviral therapy; intrinsic immunity; host restriction factors; p21; schlafen 11; PAF1 complex
15.  Deep sequencing of HIV-1 variants from paired plasma and cerebrospinal fluid during primary HIV infection 
Journal of virus eradication  2015;1(4):264-268.
Background
Limited data exist comparing viral quasispecies between cerebrospinal fluid (CSF) and plasma compartments during primary HIV infection. Deep sequencing is a new method to examine the HIV plasma and CSF quasispecies.
Methods
In this pilot study, deep sequencing of protease (PR) and reverse transcriptase (RT) was performed in plasma and CSF from participants during primary HIV infection. Estimated mutational load was calculated by mutant variant frequency multiplied by HIV-RNA level.
Results
Paired plasma and CSF samples were studied from five antiretroviral therapy-naïve male participants with median 109 days post estimated transmission, age 32 years, CD4 cell count 580 cells/μL, HIV-RNA 5.18 log10 copies/mL in plasma and 3.67 log10 copies/mL in CSF. Plasma samples averaged 7,124 reads of PR and 2,448 reads of RT, whereas CSF samples averaged 7,082 and 2,792 reads, respectively. A distinct drug-resistance pattern with linked mutations present at significant levels (5–10%) was detected in one participant in CSF. Other low abundance variants (>0.2%) were detected in plasma and CSF of four out of five participants.
Conclusions
Deep sequencing of CSF HIV is technically possible with sufficient HIV-RNA levels. Differences between the quasispecies in the two compartments detected in one participant, which were present with a high mutational load in CSF at an estimated 3.6 months after HIV infection, suggest that early CNS compartmentalisation may be revealed by sensitive deep-sequencing methods. The presence of distinct low abundance (<1%) resistance variants in plasma and CSF of three other subjects may be significant, but further investigation is needed.
PMCID: PMC4743659  PMID: 26855971
HIV-1; resistance mutations; cerebrospinal fluid; compartmentalisation; HIV-associated neurocognitive disorder; primary HIV infection
16.  TIGIT Marks Exhausted T Cells, Correlates with Disease Progression, and Serves as a Target for Immune Restoration in HIV and SIV Infection 
PLoS Pathogens  2016;12(1):e1005349.
HIV infection induces phenotypic and functional changes to CD8+ T cells defined by the coordinated upregulation of a series of negative checkpoint receptors that eventually result in T cell exhaustion and failure to control viral replication. We report that effector CD8+ T cells during HIV infection in blood and SIV infection in lymphoid tissue exhibit higher levels of the negative checkpoint receptor TIGIT. Increased frequencies of TIGIT+ and TIGIT+ PD-1+ CD8+ T cells correlated with parameters of HIV and SIV disease progression. TIGIT remained elevated despite viral suppression in those with either pharmacological antiretroviral control or immunologically in elite controllers. HIV and SIV-specific CD8+ T cells were dysfunctional and expressed high levels of TIGIT and PD-1. Ex-vivo single or combinational antibody blockade of TIGIT and/or PD-L1 restored viral-specific CD8+ T cell effector responses. The frequency of TIGIT+ CD4+ T cells correlated with the CD4+ T cell total HIV DNA. These findings identify TIGIT as a novel marker of dysfunctional HIV-specific T cells and suggest TIGIT along with other checkpoint receptors may be novel curative HIV targets to reverse T cell exhaustion.
Author Summary
HIV-1 infection contributes substantially to global morbidity and mortality, with no immediate promise of an effective vaccine. One major obstacle to vaccine development and therapy is to understand why HIV-1 replication persists in a person despite the presence of viral specific immune responses. The emerging consensus has been that these immune cells are functionally ‘exhausted’ or anergic, and thus, although they can recognize HIV-1 specific target cells, they are unable to effectively keep up with rapid and dynamic viral replication in an individual. We have identified a novel combination pathway that can be targeted, TIGIT and PD-L1which may be responsible, at least in part, for making these immune cells dysfunctional and exhausted and thus unable to control the virus. We show that by blocking the TIGIT and PD-L1 pathway, we can reverse the defects of these viral specific immune cells. Our findings will give new directions to vaccines and therapies that will potentially reverse these dysfunctional cells and allow them to control HIV-1 replication, but also serve in “Shock and Kill” HIV curative strategies.
doi:10.1371/journal.ppat.1005349
PMCID: PMC4704737  PMID: 26741490
17.  Decreased HIV Type 1 Transcription in CCR5-Δ32 Heterozygotes During Suppressive Antiretroviral Therapy 
The Journal of Infectious Diseases  2014;210(11):1838-1843.
Individuals who are heterozygous for the CCR5-Δ32 mutation provide a natural model to examine the effects of reduced CCR5 expression on human immunodeficiency virus (HIV) persistence. We evaluated the HIV reservoir in 18 CCR5-Δ32 heterozygotes and 54 CCR5 wild-type individuals during suppressive antiretroviral therapy. Cell-associated HIV RNA levels (P = .035), RNA to DNA transcriptional ratios (P = .013), and frequency of detectable HIV 2–long terminal repeat circular DNA (P = .013) were significantly lower in CD4+ T cells from CCR5-Δ32 heterozygotes. Cell-associated HIV RNA was significantly correlated with CCR5 surface expression on CD4+ T cells (r2 = 0.136; P = .002). Our findings suggest that curative strategies should further explore manipulation of CCR5.
doi:10.1093/infdis/jiu338
PMCID: PMC4271057  PMID: 24935955
HIV; CCR5; Δ32; coreceptor; reservoir; latency; eradication; NF-κB; HIV transcription; HIV replication
18.  Efficient Identification of HIV Serodiscordant Couples by Existing HIV Testing Programs in South Brazil 
PLoS ONE  2015;10(11):e0142638.
Objective
To examine the feasibility of identifying HIV negative at risk individuals in HIV serodiscordant couples, during voluntary HIV testing in South Brazil.
Methods
We 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.
Results
Among 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).
Conclusion
It 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.
doi:10.1371/journal.pone.0142638
PMCID: PMC4642994  PMID: 26562436
19.  Experiences with food insecurity and risky sex among low-income people living with HIV/AIDS in a resource-rich setting 
Background
Forty-nine million individuals are food insecure in the United States, where food insecurity and HIV/AIDS are prevalent among the urban poor. Food insecurity is associated with risky sexual behaviours among people living with HIV/AIDS (PLHIV). No qualitative studies, however, have investigated the mechanisms underlying this relationship either in a resource-rich setting or among populations that include men who have sex with men (MSM).
Methods
Semi-structured in-depth interviews were conducted with 34 low-income PLHIV receiving food assistance in the San Francisco Bay Area. The interviews explored experiences with food insecurity and perceived associations with sexual risk behaviours. Interviews were conducted in English, audio-recorded and transcribed verbatim. Transcripts were coded and analyzed according to content analysis methods using an inductive-deductive approach.
Results
Food insecurity was reported to be a strong contributor to risky sexual practices among MSM and female participants. Individuals described engaging in transactional sex for food or money to buy food, often during times of destitution. Participants also explained how food insecurity could lead to condomless sex despite knowledge of and desire to use safe sexual practices, largely because the need to obtain food in the short term was prioritized over the desire to use barrier protection.
Conclusions
Our data extend previous research by demonstrating that food insecurity contributes to transactional and unprotected sex among urban poor individuals in a resource-rich setting, including among MSM. These findings underscore the importance of public health and social intervention efforts focused on structural inequalities.
doi:10.7448/IAS.18.1.20293
PMCID: PMC4636859  PMID: 26546789
food insecurity; sexual behaviour; HIV; men who have sex with men; resource-rich; San Francisco Bay Area; homeless; marginally housed
20.  Training in ChiRunning to reduce blood pressure: a randomized controlled pilot study 
Background
People with prehypertension (120–130/80–90 mmHg) are at increased risk of progressing to hypertension. Recommendations for prehypertension include engaging in regular physical activity. We aimed to assess feasibility and acceptability and collect preliminary outcome data on ChiRunning for people with elevated blood pressure. ChiRunning is a commercially available running program based on the mindful movements of Tai Chi, which is aimed at decreasing injury by both increasing body awareness and modifying running form.
Methods
We enrolled adults with elevated systolic (130–150 mmHg) or diastolic (80–100 mmHg) blood pressure in a 12-week pilot trial. Participants were randomized 2:1:1 to 8 weeks of: 1) intervention—a trainer-led ChiRunning group (n = 10); 2) active control—a trainer-led running group (n = 6); or 3) educational control—a self-directed running group (n = 6) and followed for 4 more weeks. The active control and educational control groups were combined for analysis.
Results
This study was feasible, meeting recruitment, retention and adherence goals, and acceptable to participants. Systolic and diastolic blood pressure did not change significantly over the study for either the ChiRunning or control groups. Changes in BMI over time were significantly different from zero in the ChiRunning group (p = 0.04) but not in the control group (slope for ChiRunning −0.05 [−0.1 to −0.002] vs. control −0.01 [−0.06 to 0.04], between slope difference, p = 0.22). Self-reported running-related injury (i.e. discomfort leading to a decrease in running) was similar between groups (ChiRunning, 4 [1.2 to 8.4] vs. control, 3 [0.7 to 7.1] injuries per 100 h of running, p = 0.72) although self-reported running-related discomfort (i.e. discomfort that does not lead to changes in running) trended higher in the ChiRunning group (ChiRunning, 10 [5.4 to 16.8] vs. control, 4 [1.5 to 9] reports of discomfort per 100 h of running, p = 0.06).
Conclusion
ChiRunning appears to be a feasible and acceptable exercise program for people with elevated blood pressure. We did not find that ChiRunning had a significant impact on blood pressure or self reported injury, but did see a positive change in BMI over time. ChiRunning warrants further investigation in a larger trial.
Trial registration
ClinicalTrials.gov Identifier: NCT01587183
doi:10.1186/s12906-015-0895-x
PMCID: PMC4608185  PMID: 26471194
21.  Deep sequencing of HIV-1 variants from paired plasma and cerebrospinal fluid during primary HIV infection 
Journal of Virus Eradication  null;1(4):264-268.
Abstract
Background: 
Limited data exist comparing viral quasispecies between cerebrospinal fluid (CSF) and plasma compartments during primary HIV infection. Deep sequencing is a new method to examine the HIV plasma and CSF quasispecies.
Methods: 
In this pilot study, deep sequencing of protease (PR) and reverse transcriptase (RT) was performed in plasma and CSF from participants during primary HIV infection. Estimated mutational load was calculated by mutant variant frequency multiplied by HIV-RNA level.
Results: 
Paired plasma and CSF samples were studied from five antiretroviral therapy-naïve male participants with median 109 days post estimated transmission, age 32 years, CD4 cell count 580 cells/μL, HIV-RNA 5.18 log10 copies/mL in plasma and 3.67 log10 copies/mL in CSF. Plasma samples averaged 7,124 reads of PR and 2,448 reads of RT, whereas CSF samples averaged 7,082 and 2,792 reads, respectively. A distinct drug-resistance pattern with linked mutations present at significant levels (5–10%) was detected in one participant in CSF. Other low abundance variants (>0.2%) were detected in plasma and CSF of four out of five participants.
Conclusions: 
Deep sequencing of CSF HIV is technically possible with sufficient HIV-RNA levels. Differences between the quasispecies in the two compartments detected in one participant, which were present with a high mutational load in CSF at an estimated 3.6 months after HIV infection, suggest that early CNS compartmentalisation may be revealed by sensitive deep-sequencing methods. The presence of distinct low abundance (<1%) resistance variants in plasma and CSF of three other subjects may be significant, but further investigation is needed.
PMCID: PMC4743659  PMID: 26855971
HIV-1; resistance mutations; cerebrospinal fluid; compartmentalisation; HIV-associated neurocognitive disorder; primary HIV infection
22.  Low Proportions of CD28− CD8+ T cells Expressing CD57 Can Be Reversed by Early ART Initiation and Predict Mortality in Treated HIV Infection 
The Journal of Infectious Diseases  2014;210(3):374-382.
Background. Unlike 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.
Methods. We sampled recently HIV-infected individuals (<6 months) and HIV-uninfected controls and compared longitudinal changes in the proportion of CD28−CD8+ T cells expressing CD57 between those who initiated ART early (<6 months) vs later (≥2 years). We also assessed the relationship between this phenotype and mortality in a nested case-control study of ART-suppressed chronically infected individuals.
Results. Compared to HIV-uninfected controls (n = 15), individuals who were recently infected with HIV had lower proportions of CD28−CD8+ T cells expressing CD57 (P < .001), and these proportions increased during ART. The early ART group (n = 33) achieved normal levels, whereas the later ART group (n = 30) continued to have lower levels than HIV-uninfected controls (P = .02). Among 141 ART-suppressed participants in the SOCA study, those in the lowest quartile of CD28−CD8+ T cells expressing CD57 had 5-fold higher odds of mortality than those in the highest quartile (95% CI, 1.6–15.9, P = .007).
Conclusions. Abnormally low proportions of CD28−CD8+ T cells expressing CD57 predict increased mortality during treated HIV infection and may be reversed with early ART initiation.
doi:10.1093/infdis/jiu109
PMCID: PMC4110459  PMID: 24585893
HIV; CD57; CD28; Immunosenescence; aging; mortality; antiretroviral therapy; immune activation
23.  A Novel Assay to Measure the Magnitude of the Inducible Viral Reservoir in HIV-infected Individuals 
EBioMedicine  2015;2(8):874-883.
Background
Quantifying 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.
Methods
We 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.
Findings
In 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.
Interpretations
Our 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 context
In 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.
Highlights
•We developed TILDA (Tat/rev Induced Limiting Dilution Assay) to measure the frequency of cells with inducible multiply-spliced HIV RNA in HIV-infected individuals on suppressive ART.•Our results suggest that TILDA is a reproducible and sensitive approach to measure the frequency of productively and latently infected cells in clinical settings.•Using TILDA, We demonstrate that the latent reservoir represents a substantial fraction of all infected cells prior to ART initiation.
doi:10.1016/j.ebiom.2015.06.019
PMCID: PMC4563128  PMID: 26425694
HIV; Latency; Inducible virus; Reservoir; Multiply spliced RNA; Eradication; TILDA
24.  Functional avidity and IL-2/perforin production is linked to the emergence of mutations within HLA-B*5701-restricted epitopes and HIV-1 disease progression 
Viral escape from HIV-1-specific CD8+ T cells has been demonstrated in numerous studies previously. However, the qualitative features driving the emergence of mutations within epitopes are still unclear. In this study, we aimed to distinguish whether specific functional characteristics of HLA-B*5701-restricted CD8+ T cells influence the emergence of mutations in high-risk progressors (HRPs) versus low-risk progressors (LRPs). Single genome sequencing was performed to detect viral mutations (variants) within seven HLA-B*5701-restricted epitopes in Gag (n = 4) and Nef (n = 3) in six untreated HLA-B*5701 subjects followed from early infection up to seven years. Several well-characterized effector markers (IFN-γ, IL-2, MIP-1β, TNF, CD107a and perforin) were identified by flow cytometry following autologous (initial and emerging variant/s) epitope stimulations. This study demonstrates that specific functional attributes may facilitate the outgrowth of mutations within HLA-B*5701-restricted epitopes. A significantly lower fraction of IL-2 producing cells and a decrease in functional avidity and polyfunctional sensitivity were evident in emerging epitope variants compared to the initial autologous epitopes. Interestingly, the HRPs mainly drove these differences, while the LRPs maintained a directed and maintained functional response against emerging epitope variants. In addition, LRPs induced improved cell cycle progression and perforin up-regulation after autologous and emerging epitope variant stimulations in contrast to HRPs. The maintained quantitative and qualitative features of the CD8+ T cell responses in LRPs toward emerging epitope variants provide insights into why HLA-B*5701 subjects have different risks of HIV-1 disease progression.
doi:10.4049/jimmunol.1302253
PMCID: PMC4046013  PMID: 24740510
HIV-1; Immunity; cellular; CD8-Positive T-Lymphocytes; HLA-B57 Antigen; Disease progression
25.  Correlating Traditional Ayurvedic and Modern Medical Perspectives on Cancer: Results of a Qualitative Study 
Abstract
Objective: To characterize Ayurvedic perspectives on the etiopathogenesis and supportive treatments for a biomedical diagnosis of cancer.
Methods: Hour-long, digitally recorded interviews were conducted with 10 experienced Ayurvedic clinicians, transcribed verbatim, and analyzed using techniques of qualitative thematic analysis.
Results: Four major themes were identified. The Ayurvedic description of the pathophysiology of cancer uses traditional concepts translated into a modern context. Although the biomedical treatment of cancer is considered valuable, from an Ayurvedic perspective it results in degeneration and depletion. In cases where biomedical treatment of cancer is not feasible, an Ayurvedic approach focusing on strengthening digestion, eliminating toxins, reducing tumor growth, and improving tissue metabolism is useful. An Ayurvedic approach to cancer supportive care focuses on restoring equilibrium, building strength, and rejuvenation.
Conclusion: Ayurvedic medicine offers a unique perspective on the biomedical diagnosis of cancer that emphasizes restoring wholeness, uses natural remedies, includes a focus on emotional health, and emphasizes prevention strategies.
doi:10.1089/acm.2013.0259
PMCID: PMC4011424  PMID: 24341342

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