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1.  CD4+ and CD8+ T Cell Activation Are Associated with HIV DNA in Resting CD4+ T Cells 
PLoS ONE  2014;9(10):e110731.
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.
doi:10.1371/journal.pone.0110731
PMCID: PMC4207702  PMID: 25340755
2.  Programmed death-1 expression on CD4+ and CD8+ T cells in treated and untreated HIV disease 
AIDS (London, England)  2014;28(12):1749-1758.
Background
There 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.
Methods
PD-1 was measured longitudinally in a cohort of recently HIV-infected individuals (n = 121) who started ART early (<6 months after infection) vs. later (≥2 years after infection). PD-1 was also measured cross-sectionally in a diverse cohort of chronically HIV-infected adults (n = 206).
Results
PD-1 expression levels were high on CD8+ T cells during early HIV infection. PD-1 levels increased on both CD4+ and CD8+ T cells populations in those who delayed therapy (11 and 10%/year, respectively). PD-1 levels declined and were similar in those treated early vs. late after 1 year of ART. In both cohorts, PD-1 expression on CD4+ T cells was associated with CD4+ T-cell activation (CD38+HLA-DR+) and inversely with CD4+ cell count. In contrast, PD-1 expression on CD8+ T cells was most strongly associated with CD8+ T-cell activation and with plasma viral load in viremic individuals.
Conclusion
Across two large cohorts of untreated and treated individuals, we found consistent associations between HIV RNA levels, CD8+ T-cell activation and PD-1 expression on CD8+ T cells. In contrast, CD4+ T-cell counts and CD4+ T-cell activation were more consistent correlates of PD-1 expression on CD4+ T cells. PD-1 expression appears to be driven by both direct antigen and homeostatic pathways.
doi:10.1097/QAD.0000000000000314
PMCID: PMC4206412  PMID: 24871455
CD4+ lymphocyte count; early antiretroviral therapy; HIV antiretroviral therapy; HIV-1/immunology/*physiology; humans; programmed death-1; T-cell activation; T lymphocytes/immunology/*physiology; virus replication/physiology
3.  Antiretroviral Therapy Initiated Within 6 Months of HIV Infection Is Associated With Lower T-Cell Activation and Smaller HIV Reservoir Size 
The Journal of Infectious Diseases  2013;208(8):1202-1211.
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 (<6 months duration since infection) we identified persons who started ART early (<6 months after infection) or later (≥2 years after infection) and maintained ≥2 years of virologic suppression; at-risk HIV-negative persons were controls. We measured CD4+/CD8+ T-cell activation (percent CD38+/HLA-DR+) and HIV reservoir size (based on HIV DNA and cell-associated RNA levels).
Results. In unadjusted analyses, early ART predicted lower on-therapy CD8+ T-cell activation (n = 34; mean, 22.1%) than achieved with later ART (n = 32; mean, 28.8%; P = .009), although levels in early ART remained elevated relative to HIV-negative controls (P = .02). Early ART also predicted lower CD4+ T-cell activation than with later ART (5.3% vs 7.5%; P = .06). Early ART predicted 4.8-fold lower DNA levels than achieved with later ART (P = .005), and lower cell-associated RNA levels (difference in signal-to-cutoff ratio (S/Co), 3.2; P = .035).
Conclusions. ART initiation <6 months after infection is associated with lower levels of T-cell activation and smaller HIV DNA and RNA reservoir size during long-term therapy.
doi:10.1093/infdis/jit311
PMCID: PMC3778965  PMID: 23852127
HIV antiretroviral therapy; early ART; T-cell activation; inflammation; HIVreservoir; HIV eradication; HIV cure
4.  Baseline CD4+ T Cell Counts Correlates with HIV-1 Synonymous Rate in HLA-B*5701 Subjects with Different Risk of Disease Progression 
PLoS Computational Biology  2014;10(9):e1003830.
HLA-B*5701 is the host factor most strongly associated with slow HIV-1 disease progression, although risk of progression may vary among patients carrying this allele. The interplay between HIV-1 evolutionary rate variation and risk of progression to AIDS in HLA-B*5701 subjects was studied using longitudinal viral sequences from high-risk progressors (HRPs) and low-risk progressors (LRPs). Posterior distributions of HIV-1 genealogies assuming a Bayesian relaxed molecular clock were used to estimate the absolute rates of nonsynonymous and synonymous substitutions for different set of branches. Rates of viral evolution, as well as in vitro viral replication capacity assessed using a novel phenotypic assay, were correlated with various clinical parameters. HIV-1 synonymous substitution rates were significantly lower in LRPs than HRPs, especially for sets of internal branches. The viral population infecting LRPs was also characterized by a slower increase in synonymous divergence over time. This pattern did not correlate to differences in viral fitness, as measured by in vitro replication capacity, nor could be explained by differences among subjects in T cell activation or selection pressure. Interestingly, a significant inverse correlation was found between baseline CD4+ T cell counts and mean HIV-1 synonymous rate (which is proportional to the viral replication rate) along branches representing viral lineages successfully propagating through time up to the last sampled time point. The observed lower replication rate in HLA-B*5701 subjects with higher baseline CD4+ T cell counts provides a potential model to explain differences in risk of disease progression among individuals carrying this allele.
Author Summary
The clinical course of HIV-1 infection is characterized by considerable variability in the rate of progression to acquired immunodeficiency syndrome (AIDS) among patients with different genetic background. The human leukocyte antigen (HLA) B*5701 is the host factor most strongly associated with slow HIV-1 disease progression. However, the risk of progression to AIDS also varies among patients carrying this specific allele. To gain a better understanding of the interplay between HIV-1 evolutionary rate variation and risk of disease progression, we followed untreated HLA-B*5701 subjects from early infection up to the onset of AIDS. The analysis of longitudinal viral sequences with advanced computational biology techniques based on coalescent Bayesian methods showed a highly significant association between lower synonymous substitution rates and higher baseline CD4+ T cell counts in HLA-B*5701 subjects. The finding provides a potential model to explain differences in risk of disease progression among individuals carrying this allele and might have translational impact on clinical practice, since synonymous rates, which are proportional to in vivo viral replication rates, could be used as a novel evolutionary marker of disease progression.
doi:10.1371/journal.pcbi.1003830
PMCID: PMC4154639  PMID: 25187947
5.  Limited HIV Infection of Central Memory and Stem Cell Memory CD4+ T Cells Is Associated with Lack of Progression in Viremic Individuals 
PLoS Pathogens  2014;10(8):e1004345.
A rare subset of HIV-infected individuals, designated viremic non-progressors (VNP), remain asymptomatic and maintain normal levels of CD4+ T-cells despite persistently high viremia. To identify mechanisms potentially responsible for the VNP phenotype, we compared VNPs (average >9 years of HIV infection) to HIV-infected individuals who have similar CD4+ T-cell counts and viral load, but who are likely to progress if left untreated (“putative progressors”, PP), thus avoiding the confounding effect of differences related to substantial CD4+ T cell depletion. We found that VNPs, compared to PPs, had preserved levels of CD4+ stem cell memory cells (TSCM (p<0.0001), which was associated with decreased HIV infection of these cells in VNPs (r = −0.649, p = 0.019). In addition, VNPs had decreased HIV infection in CD4+ central memory (TCM) cells (p = 0.035), and the total number of TCM cells was associated with increased proliferation of memory CD4+ T cells (r = 0.733, p = 0.01). Our results suggest that, in HIV-infected VNPs, decreased infection of CD4+ TCM and TSCM, cells are involved in preservation of CD4+ T cell homeostasis and lack of disease progression despite high viremia.
Author Summary
Here we assessed correlates of protection from disease progression in a rare subset of HIV-infected individuals, viremic non-progressors (VNP). These individuals have high viral load for several years. In contrast to the majority of infected individuals, however, these individuals do not progress to AIDS. Here we found this lack of progression was associated with selective preservation of two critical subsets of memory CD4+ T cells, central memory (TCM) and stem-cell memory (TSCM) cells. Compared to HIV-infected putative progressors, VNPs had higher proliferation of these indispensable subsets of memory cells. In addition, the long-lived CD4+ TCM and TSCM cells in VNPs had decreased HIV infection compared to the less critical effector memory CD4+ T cells, which indicates a possible mechanism by which VNPs maintain their CD4+ T cell pool after several years of infection, and remain free from AIDS progression.
doi:10.1371/journal.ppat.1004345
PMCID: PMC4148445  PMID: 25167059
6.  A yoga intervention for type 2 diabetes risk reduction: a pilot randomized controlled trial 
Background
Type 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.
Methods
This 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.
Results
This 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 < 0.01; BMI −0.2 ± 0.8 vs. 0.6 ± 1.6, p = 0.05). There were no between group differences in fasting blood glucose, postprandial blood glucose, insulin resistance or any other factors related to diabetes risk or psychological well-being. There were significant reductions in systolic and diastolic blood pressure, total cholesterol, anxiety, depression, negative affect and perceived stress in both the yoga intervention and walking control over the course of the study.
Conclusion
Among Indians with elevated fasting blood glucose, we found that participation in an 8-week yoga intervention was feasible and resulted in greater weight loss and reduction in waist circumference when compared to a walking control. Yoga offers a promising lifestyle intervention for decreasing weight-related type 2 diabetes risk factors and potentially increasing psychological well-being.
Trial registration
ClinicalTrials.gov Identified NCT00090506.
doi:10.1186/1472-6882-14-212
PMCID: PMC4096416  PMID: 24980650
Yoga; Prediabetes; Type 2 diabetes; India; Randomized controlled pilot
7.  Immune Reconstitution of CD56dim NK Cells in Individuals with Primary HIV-1 Infection Treated with Interleukin-2 
The Journal of infectious diseases  2008;197(1):117-125.
Natural killer (NK) cells are believed to play a role in human immunodeficiency virus type 1 (HIV-1) disease progression, and NK cell levels are reduced in individuals with chronic HIV-1 infection. Interleukin (IL)–2 therapy results in an expansion of CD4+ T cells as well as NK cells; however, little is known about the detailed effects of IL-2 therapy on NK cells in HIV-1 infection in general and in early infection in particular. Here, we investigated the effects of combined IL-2 therapy and antiretroviral therapy (ART) on the number, frequency, phenotype, and interferon (IFN)–γ production of NK cells in individuals with early HIV-1 infection. Patients randomized to receive combined ART and IL-2 therapy predominantly expanded CD56dim NK cells, and the expansion was greater than in patients randomized to receive ART alone. Importantly, NK cell receptor expression and IFN-γ production were maintained over time. This reconstitution of NK cells may be useful in helping contain viremia if patients discontinue therapy or develop drug resistance.
doi:10.1086/524141
PMCID: PMC4061976  PMID: 18171294
8.  Identifying the Early Post-HIV Antibody Seroconversion Period 
The Journal of Infectious Diseases  2011;204(4):526-533.
Background. Identifying persons with recent human immunodeficiency virus (HIV) antibody seroconversion is useful for treatment, research, and prevention, but the sensitivity and specificity of tests for this purpose are uncertain.
Methods. We used longitudinal specimens panels from 155 persons identified prior to HIV seroconversion to assess antibody-based methods for classifying persons as within 30, 60, or 90 days of seroconversion, including 2 incidence assays, a less-sensitive (LS) enzyme immunoassay (EIA), and the BED assay.
Results. Sensitivity and specificity, respectively, for identifying persons within 30 days of seroconversion were: 34%–57% and 98%–100% for 2 standard EIAs (employing a signal-to-cutoff ≤4.0; ≥1.0 defines HIV positive), 84% and 73% for the LS-EIA (≤0.2 cutoff), 88% and 72% for the BED (≤0.2 cutoff), and 43%–58% and 98% (≤3 bands) for 2 Western blot (WB) assays. By area under the receiver operator curves, the best test for identifying persons within 30 days of seroconversion was the number of bands on the Bio-Rad WB (0.90); within 60 days, the LS-EIA and BED (both 0.85); and for persons within 90 days the BED (0.86).
Conclusions. Standard EIAs, Western blots, and HIV incidence assays provide useful information for identifying persons 30 to 90 days after seroconversion.
doi:10.1093/infdis/jir304
PMCID: PMC3144168  PMID: 21791654
9.  HIV-Infected Individuals with Low CD4/CD8 Ratio despite Effective Antiretroviral Therapy Exhibit Altered T Cell Subsets, Heightened CD8+ T Cell Activation, and Increased Risk of Non-AIDS Morbidity and Mortality 
PLoS Pathogens  2014;10(5):e1004078.
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.
Author Summary
The CD4/CD8 ratio, a hallmark of the collection of T cell defects related to aging –“immunosenescence”- and a predictor of mortality in the general population, often fails to normalize in an important proportion of HIV-infected individuals with adequate CD4+ T cell recovery after ART initiation. However, the immunological and clinical characteristics of this clinical phenotype have not been elucidated. Herein we show that during treated HIV infection, expansion of CD8+ T cells, reflected as a low CD4/CD8 ratio, identifies a subgroup of individuals with a number of immunological abnormalities and a poor prognosis. These subjects exhibit increased innate and adaptive immune activation, an immunosenescent phenotype, CD4+ and CD8+ imbalance in the gut mucosa and higher risk of morbidity and mortality. In contrast, those who normalize the CD4/CD8 ratio have traits of a healthy immune system. We observed that early ART initiation might contribute to more rapid and robust CD4/CD8 ratio normalization compared to later initiation. Hence, the CD4/CD8 ratio might help to further discriminate the risk of disease progression of successfully treated HIV-infected individuals, and a successful response to ART may require both normalization of the peripheral CD4+ T cell count and the ratio of CD4+ to CD8+ T cell counts.
doi:10.1371/journal.ppat.1004078
PMCID: PMC4022662  PMID: 24831517
10.  Differential Persistence of Transmitted HIV-1 Drug Resistance Mutation Classes 
The Journal of Infectious Diseases  2011;203(8):1174-1181.
Background. Transmitted human immunodeficiency virus type 1 (HIV-1) drug resistance (TDR) mutations can become replaced over time by emerging wild-type viral variants with improved fitness. The impact of class-specific mutations on this rate of mutation replacement is uncertain.
Methods. We studied participants with acute and/or early HIV infection and TDR in 2 cohorts (San Francisco, California, and São Paulo, Brazil). We followed baseline mutations longitudinally and compared replacement rates between mutation classes with use of a parametric proportional hazards model.
Results. Among 75 individuals with 195 TDR mutations, M184V/I became undetectable markedly faster than did nonnucleoside reverse-transcriptase inhibitor (NNRTI) mutations (hazard ratio, 77.5; 95% confidence interval [CI], 14.7–408.2; P < .0001), while protease inhibitor and NNRTI replacement rates were similar. Higher plasma HIV-1 RNA level predicted faster mutation replacement, but this was not statistically significant (hazard ratio, 1.71 log10 copies/mL; 95% CI, .90–3.25 log10 copies/mL; P = .11). We found substantial person-to-person variability in mutation replacement rates not accounted for by viral load or mutation class (P < .0001).
Conclusions. The rapid replacement of M184V/I mutations is consistent with known fitness costs. The long-term persistence of NNRTI and protease inhibitor mutations suggests a risk for person-to-person propagation. Host and/or viral factors not accounted for by viral load or mutation class are likely influencing mutation replacement and warrant further study.
doi:10.1093/infdis/jiq167
PMCID: PMC3107558  PMID: 21451005
11.  Environmental Enrichment Alters Splenic Immune Cell Composition and Enhances Secondary Influenza Vaccine Responses in Mice 
Molecular Medicine  2014;20(1):179-190.
Chronic stress has deleterious effects on immune function, which can lead to adverse health outcomes. However, studies investigating the impact of stress reduction interventions on immunity in clinical research have yielded divergent results, potentially stemming from differences in study design and genetic heterogeneity, among other clinical research challenges. To test the hypothesis that reducing glucocorticoid levels enhances certain immune functions, we administered influenza vaccine once (prime) or twice (boost) to mice housed in either standard control caging or environmental enrichment (EE) caging. We have shown that this approach reduces mouse corticosterone production. Compared with controls, EE mice had significantly lower levels of fecal corticosterone metabolites (FCMs) and increased splenic B and T lymphocyte numbers. Corticosterone levels were negatively associated with the numbers of CD19+ (r2 = 0.43, p = 0.0017), CD4+ (r2 = 0.28, p = 0.0154) and CD8+ cells (r2 = 0.20, p = 0.0503). Vaccinated mice showed nonsignificant differences in immunoglobulin G (IgG) titer between caging groups, although EE mice tended to exhibit larger increases in titer from prime to boost than controls; the interaction between the caging group (control versus EE) and vaccine group (prime versus boost) showed a strong statistical trend (cage-group*vaccine-group, F = 4.27, p = 0.0555), suggesting that there may be distinct effects of EE caging on primary versus secondary IgG vaccine responses. Vaccine-stimulated splenocytes from boosted EE mice had a significantly greater frequency of interleukin 5 (IL-5)-secreting cells than boosted controls (mean difference 7.7, IL-5 spot-forming units/106 splenocytes, 95% confidence interval 0.24–135.1, p = 0.0493) and showed a greater increase in the frequency of IL-5–secreting cells from prime to boost. Our results suggest that corticosterone reduction via EE caging was associated with enhanced secondary vaccine responses, but had little effect on primary responses in mice. These findings help identify differences in primary and secondary vaccine responses in relationship to stress mediators that may be relevant in clinical studies.
doi:10.2119/molmed.2013.00158
PMCID: PMC4002849  PMID: 24687160
12.  Targeting of Conserved Gag-Epitopes in Early HIV Infection Is Associated with Lower Plasma Viral Load and Slower CD4+ T Cell Depletion 
Abstract
We aimed to investigate whether the character of the immunodominant HIV-Gag peptide (variable or conserved) targeted by CD8+ T cells in early HIV infection would influence the quality and quantity of T cell responses, and whether this would affect the rate of disease progression. Treatment-naive HIV-infected study subjects within the OPTIONS cohort at the University of California, San Francisco, were monitored from an estimated 44 days postinfection for up to 6 years. CD8+ T cells responses targeting HLA-matched HIV-Gag-epitopes were identified and characterized by multicolor flow cytometry. The autologous HIV gag sequences were obtained. We demonstrate that patients targeting a conserved HIV-Gag-epitope in early infection maintained their epitope-specific CD8+ T cell response throughout the study period. Patients targeting a variable epitope showed decreased immune responses over time, although there was no limitation of the functional profile, and they were likely to target additional variable epitopes. Maintained immune responses to conserved epitopes were associated with no or limited sequence evolution within the targeted epitope. Patients with immune responses targeting conserved epitopes had a significantly lower median viral load over time compared to patients with responses targeting a variable epitope (0.63 log10 difference). Furthermore, the rate of CD4+ T cell decline was slower for subjects targeting a conserved epitope (0.85% per month) compared to subjects targeting a variable epitope (1.85% per month). Previous studies have shown that targeting of antigens based on specific HLA types is associated with a better disease course. In this study we show that categorizing epitopes based on their variability is associated with clinical outcome.
doi:10.1089/aid.2012.0171
PMCID: PMC3581067  PMID: 23140171
13.  Impact of HIV on CD8+ T Cell CD57 Expression Is Distinct from That of CMV and Aging 
PLoS ONE  2014;9(2):e89444.
Background
Chronic 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.
Methods
We 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.
Results
Compared 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<0.0001) and were enriched for less well-differentiated CD28- transitional memory (TTR) CD8+ T cells (P<0.0001). Chronically HIV-infected adults maintaining ART-mediated viral suppression (n = 96) had higher proportions of CD28-CD8+ T cells expressing CD57 than untreated patients (P<0.0001), but continued to have significantly lower levels than HIV-uninfected controls (P = 0.001). Among 45 HIV-infected individuals initiating their first ART regimen, the proportion of CD28-CD8+ T cells expressing CD57 declined (P<0.0001), which correlated with a decline in percent of transitional memory CD8+ T cells, and appeared to be largely explained by a decline in CD28-CD57- CD8+ T cell counts rather than an expansion of CD28-CD57+ CD8+ T cell counts.
Conclusions
Unlike CMV and aging, which are associated with terminal differentiation and proliferation of effector memory CD8+ T cells, HIV inhibits this process, expanding less well-differentiated CD28- CD8+ T cells and decreasing the proportion of CD28- CD8+ T cells that express CD57.
doi:10.1371/journal.pone.0089444
PMCID: PMC3937334  PMID: 24586783
14.  HIV RNA level in early infection is predicted by viral load in the transmission source 
AIDS (London, England)  2010;24(7):941-945.
Objective
HIV-1 viral load in early infection predicts the risk of subsequent disease progression but the factors responsible for the differences between individuals in viral load during this period have not been fully identified. We sought to determine the relationship between HIV-1 RNA levels in the source partner and recently infected recipient partners within transmission pairs.
Methods
We recruited donor partners of persons who presented with acute or recent (< 6 months) HIV infection. Transmission was confirmed by phyologenetic comparison of virus sequence in the donor and recipient partners. We compared viral load in the donor partner and the recipient in the first 6 months of HIV infection.
Results
We identified 24 transmission pairs. The median estimated time from infection to evaluation in acutely/recently infected recipient individuals was 72 days. The viral load in the donor was closely associated with viral load at presentation in the recipient case (r=0.55, P=0.006).
Conclusion
The strong correlation between HIV-1 RNA levels within HIV transmission pairs indicates that virus characteristics are an important determinant of viral load in early HIV infection.
doi:10.1097/QAD.0b013e328337b12e
PMCID: PMC2887742  PMID: 20168202
HIV-1 RNA; acute HIV-1 infection; HIV-1 transmission; viral load set-point; HIV-1 pathogenesis
15.  Trans-activation, post-transcriptional maturation, and induction of antibodies to HERV-K (HML-2) envelope transmembrane protein in HIV-1 infection 
Retrovirology  2014;11:10.
Background
Human 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.
Results
We 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 < 0.0001). HIV-1 infected adults who control HIV-1 in the absence of therapy (“elite” controllers) had a higher titer response against TM compared to antiretroviral-treated adults (p < 0.0001) and uninfected adults (p < 0.0001).
Conclusions
These data collectively suggest that HIV-1 infection induces fully glycosylated HERV-K (HML-2) envelope TM protein to which antibodies are induced. These anti-HERV-K (HML-2) TM antibodies are a potential marker of HIV-1 infection, and are at higher titer in elite controllers. HERV-K (HML-2) envelope TM protein may be a new therapeutic target in HIV-1 infection.
doi:10.1186/1742-4690-11-10
PMCID: PMC3907665  PMID: 24472118
HIV; Antibody; HERV; Endogenous retroviruses; Transmembrane; Envelope; Elite controllers; Alternative transcripts
17.  The development of an RDoC-based treatment program for adolescent depression: “Training for Awareness, Resilience, and Action” (TARA) 
Major depressive disorder (MDD) is one of the current leading causes of disability worldwide. Adolescence is a vulnerable period for the onset of depression, with MDD affecting 8–20% of all youth. Traditional treatment methods have not been sufficiently effective to slow the increasing prevalence of adolescent depression. We therefore propose a new model for the treatment of adolescent depression – Training for Awareness, Resilience, and Action (TARA) – that is based on current understanding of developmental and depression neurobiology. The TARA model is aligned with the Research Domain Criteria (RDoC) of the National Institute of Mental Health. In this article, we first address the relevance of RDoC to adolescent depression. Second, we identify the major RDoC domains of function involved in adolescent depression and organize them in a way that gives priority to domains thought to be driving the psychopathology. Third, we select therapeutic training strategies for TARA based on current scientific evidence of efficacy for the prioritized domains of function in a manner that maximizes time, resources, and feasibility. The TARA model takes into consideration the developmental limitation in top-down cognitive control in adolescence and promotes bottom-up strategies such as vagal afference to decrease limbic hyperactivation and its secondary effects. The program has been informed by mindfulness-based therapy and yoga, as well as modern psychotherapeutic techniques. The treatment program is semi-manualized, progressive, and applied in a module-based approach designed for a group setting that is to be conducted one session per week for 12 weeks. We hope that this work may form the basis for a novel and more effective treatment strategy for adolescent depression, as well as broaden the discussion on how to address this challenge.
doi:10.3389/fnhum.2014.00630
PMCID: PMC4137278  PMID: 25191250
adolescent depression; RDoC; treatment development; emotion regulation; attention training; yoga-based movement; mindfulness
18.  CD56negCD16+ NK cells are activated mature NK cells with impaired effector function during HIV-1 infection 
Retrovirology  2013;10:158.
Background
A subset of CD3negCD56negCD16+ Natural Killer (NK) cells is highly expanded during chronic HIV-1 infection. The role of this subset in HIV-1 pathogenesis remains unclear. The lack of NK cell lineage-specific markers has complicated the study of minor NK cell subpopulations.
Results
Using CD7 as an additional NK cell marker, we found that CD3negCD56negCD16+ cells are a heterogeneous population comprised of CD7+ NK cells and CD7neg non-classical myeloid cells. CD7+CD56negCD16+ NK cells are significantly expanded in HIV-1 infection. CD7+CD56negCD16+ NK cells are mature and express KIRs, the C-type lectin-like receptors NKG2A and NKG2C, and natural cytotoxicity receptors similar to CD7+CD56+CD16+ NK cells. CD7+CD56neg NK cells in healthy donors produced minimal IFNγ following K562 target cell or IL-12 plus IL-18 stimulation; however, they degranulated in response to K562 stimulation similar to CD7+CD56+ NK cells. HIV-1 infection resulted in reduced IFNγ secretion following K562 or cytokine stimulation by both NK cell subsets compared to healthy donors. Decreased granzyme B and perforin expression and increased expression of CD107a in the absence of stimulation, particularly in HIV-1-infected subjects, suggest that CD7+CD56negCD16+ NK cells may have recently engaged target cells. Furthermore, CD7+CD56negCD16+ NK cells have significantly increased expression of CD95, a marker of NK cell activation.
Conclusions
Taken together, CD7+CD56negCD16+ NK cells are activated, mature NK cells that may have recently engaged target cells.
doi:10.1186/1742-4690-10-158
PMCID: PMC3892122  PMID: 24351015
Natural killer cells; NK cells; CD7; Human immunodeficiency virus; HIV-1; HIV pathogenesis; CD56neg NK cells
19.  Performance of Rapid Point-of-Care and Laboratory Tests for Acute and Established HIV Infection in San Francisco 
PLoS ONE  2013;8(12):e80629.
Background
Current laboratory and point-of-care tests for HIV detect different analytes and use different sample types. Some have fast turnaround times (<1 hour). We investigated how HIV test choice could impact case finding by testing programs.
Methods
We analyzed 21,234 consecutive HIV tests with venous blood obtained by San Francisco HIV testing programs from 2003 to 2008. For a subset, oral fluid (n = 6446) or fingerstick blood (n = 8127) samples were also obtained for rapid testing. In all cases, HIV status was determined using an HIV antibody-plus-RNA test algorithm. We assessed how the screening antibody tests performed individually versus the gold standard of the full algorithm. We then evaluated the potential ability of other tests (including new tests) to detect more cases, by re-testing all specimens that had negative/discrepant antibody results on initial screening.
Findings
The antibody-RNA algorithm identified 58 acute and 703 established HIV infection cases. 1st-generation (Vironostika) and 3rd-generation (Genetic Systems) immunoassays had 92 and 96 percent sensitivity, respectively. The Oraquick rapid test had clinical sensitivity of only 86 percent on oral fluid samples, but 92 percent on finger-stick blood. Newer 4th-generation, antigen-antibody combo rapid immunoassay (ARCHITECT) detected HIV in 87 percent of all the acute cases that had been missed by one of the previous screening assays. A point-of-care 4th generation antigen-antibody combo rapid test (Determine) detected about 54 percent of such acute cases.
Conclusions
Our study suggests that some rapid antibody blood tests will give similar case detection to laboratory antibody tests, but that oral fluid testing greatly reduces ability to detect HIV. New 4th-generation combo tests can detect the majority of acute infections detectable by HIV RNA but with rapid results. Using these tests as a primary screening assay in high-risk HIV testing programs could reduce or eliminate the need for HIV RNA testing.
doi:10.1371/journal.pone.0080629
PMCID: PMC3861178  PMID: 24349007
20.  Cortisol Patterns Are Associated with T Cell Activation in HIV 
PLoS ONE  2013;8(7):e63429.
Objective
The 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.
Methods
We 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.
Results
Lower 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.
Conclusions
These 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.
doi:10.1371/journal.pone.0063429
PMCID: PMC3724863  PMID: 23922644
21.  Hematopoietic Precursor Cells Isolated From Patients on Long-term Suppressive HIV Therapy Did Not Contain HIV-1 DNA 
Background. We address the key emerging question of whether Lin−/CD34+ hematopoietic precursor cells (HPCs) represent an important latent reservoir of human immunodeficiency virus type 1 (HIV-1) during long-term suppressive therapy.
Methods. To estimate the frequency of HIV-1 infection in bone marrow, we sorted Lin−/CD34+ HPCs and 3 other cell types (Lin−/CD34−, Lin−/CD4+, and Lin+/CD4+) from 8 patients who had undetectable viral loads for 3–12 years. Using a single-proviral sequencing method, we extracted, amplified, and sequenced multiple single HIV-1 DNA molecules from these cells and memory CD4+ T cells from contemporaneous peripheral blood samples.
Results. We analyzed 100 000–870 000 bone marrow Lin−/CD34+ HPCs from the 8 patients and found no HIV-1 DNA. We did isolate HIV-1 DNA from their bone marrow Lin+/CD4+ cells that was genetically similar to HIV-1 DNA from lymphoid cells located in the peripheral blood, indicating an exchange of infected cells between these compartments.
Conclusions. The absence of infected HPCs provides strong evidence that the HIV-1 infection frequency of Lin−/CD34+ HPCs from bone marrow, if it occurred, was <.003% (highest upper 95% confidence interval) in all 8 patients. These results strongly suggest that Lin−/CD34+ HPCs in bone marrow are not a source of persistent HIV-1 in patients on long-term suppressive therapy.
doi:10.1093/infdis/jis301
PMCID: PMC3415927  PMID: 22536001
22.  Yoga Breathing for Cancer Chemotherapy–Associated Symptoms and Quality of Life: Results of a Pilot Randomized Controlled Trial 
Abstract
Background
Many debilitating symptoms arise from cancer and its treatment that are often unrelieved by established methods. Pranayama, a series of yogic breathing techniques, may improve cancer-related symptoms and quality of life, but it has not been studied for this purpose.
Objectives
A pilot study was performed to evaluate feasibility and to test the effects of pranayama on cancer-associated symptoms and quality of life.
Design
This was a randomized controlled clinical trial comparing pranayama to usual care.
Setting
The study was conducted at a university medical center.
Subjects
Patients receiving cancer chemotherapy were randomized to receive pranayama immediately or after a waiting period (control group).
Interventions
The pranayama intervention consisted of four breathing techniques taught in weekly classes and practiced at home. The treatment group received pranayama during two consecutive cycles of chemotherapy. The control group received usual care during their first cycle, and received pranayama during their second cycle of chemotherapy.
Outcome measures
Feasibility, cancer-associated symptoms (fatigue, sleep disturbance, anxiety, depression, stress), and quality of life were the outcomes.
Results
Class attendance was nearly 100% in both groups. Sixteen (16) participants were included in the final intent-to-treat analyses. The repeated-measures analyses demonstrated that any increase in pranayama dose, with dose measured in the number of hours practiced in class or at home, resulted in improved symptom and quality-of-life scores. Several of these associations—sleep disturbance (p=0.04), anxiety (p=0.04), and mental quality of life (p=0.05)—reached or approached statistical significance.
Conclusions
Yoga breathing was a feasible intervention among patients with cancer receiving chemotherapy. Pranayama may improve sleep disturbance, anxiety, and mental quality of life. A dose–response relationship was found between pranayama use and improvements in chemotherapy-associated symptoms and quality of life. These findings need to be confirmed in a larger study.
doi:10.1089/acm.2011.0555
PMCID: PMC3353818  PMID: 22525009
23.  The Prognosis of Acute Low Back Pain in Primary Care in the U.S. A 2-Year Prospective Cohort Study 
Spine  2012;37(8):678-684.
Study Design
Prospective cohort study
Objective
to assess the prognosis of patients presenting with acute low back pain (LBP) in a primary care setting in the U.S.
Summary of Background Data
Practice guidelines for acute LBP based on return-to-work outcomes underestimate the development of chronic pain in the primary care setting. Due to differences in inclusion criteria, chronic pain definitions and national health systems, prognostic cohort studies have reported a wide range of results limiting interpretation and generalization. Current data from carefully designed prognostic studies of acute LBP are lacking for the U.S. primary care system.
Methods
Members of a large health service organization were enrolled after seeking medical care for acute LBP, with or without sciatica, of up to 30 days duration, with no prior episode in the past 12 months and no history of spine surgery. We conducted phone interviews at baseline, six months and two years. Based on receiver operating characteristic analyses, a combination of global perceived recovery with pain intensity was used as primary outcome for chronic pain. Recurrence and multiple secondary outcomes were assessed to allow for comparison with other studies.
Results
605 patients had an average pain intensity of 5.6 (numeric rating scale 0–10) and disability of 15.8 (Roland Morris scale 0–24). Eight percent had declared sick leave between pain onset and baseline interview. 13% of 521 patients (86% follow-up) suffered from chronic pain at six months and 19% of 443 patients at 2 years. At six months, 54% had experienced at least one LBP recurrence, and 47% in the subsequent 18 months.
Conclusion
The prognosis of strictly-defined acute LBP, with or without sciatica, is less favorable than commonly stated in practice guidelines based on failure to return to work. Broad initiatives to develop new means for the primary and secondary prevention of recurrent and chronic LBP are urgently needed.
doi:10.1097/BRS.0b013e318230ab20
PMCID: PMC3335773  PMID: 22504516
Low Back Pain; Prognosis; Acute Pain; Chronic Pain
24.  Combination of Immune and Viral Factors Distinguishes Low-Risk versus High-Risk HIV-1 Disease Progression in HLA-B*5701 Subjects 
Journal of Virology  2012;86(18):9802-9816.
HLA-B*5701 is the host factor most strongly associated with slow HIV-1 disease progression, although rates can vary within this group. Underlying mechanisms are not fully understood but likely involve both immunological and virological dynamics. The present study investigated HIV-1 in vivo evolution and epitope-specific CD8+ T cell responses in six HLA-B*5701 patients who had not received antiretroviral treatment, monitored from early infection for up to 7 years. The subjects were classified as high-risk progressors (HRPs) or low-risk progressors (LRPs) based on baseline CD4+ T cell counts. Dynamics of HIV-1 Gag p24 evolution and multifunctional CD8+ T cell responses were evaluated by high-resolution phylogenetic analysis and polychromatic flow cytometry, respectively. In all subjects, substitutions occurred more frequently in flanking regions than in HLA-B*5701-restricted epitopes. In LRPs, p24 sequence diversity was significantly lower; sequences exhibited a higher degree of homoplasy and more constrained mutational patterns than HRPs. The HIV-1 intrahost evolutionary rate was also lower in LRPs and followed a strict molecular clock, suggesting neutral genetic drift rather than positive selection. Additionally, polyfunctional CD8+ T cell responses, particularly to TW10 and QW9 epitopes, were more robust in LRPs, who also showed significantly higher interleukin-2 (IL-2) production in early infection. Overall, the findings indicate that HLA-B*5701 patients with higher CD4 counts at baseline have a lower risk of HIV-1 disease progression because of the interplay between specific HLA-linked immune responses and the rate and mode of viral evolution. The study highlights the power of a multidisciplinary approach, integrating high-resolution evolutionary and immunological data, to understand mechanisms underlying HIV-1 pathogenesis.
doi:10.1128/JVI.01165-12
PMCID: PMC3446568  PMID: 22761389
25.  Mindfulness-Based Stress Reduction for HIV Treatment Side Effects: A Randomized Wait-List Controlled Trial 
Context
Advances in antiretroviral therapy (ART) for HIV offer life-extending benefit; however, the side effects associated with ART use negatively impact quality of life and medication adherence among people living with HIV.
Objectives
This study tested the efficacy of mindfulness-based stress reduction (MBSR) for reducing ART symptoms and bother/distress related to ART side effects. Secondary aims were to test the impact of MBSR on medication adherence and psychological functioning.
Methods
Seventy-six people living with HIV who were actively taking ART and reported distress from ART-related side effects were randomly assigned to MBSR or a wait-list control standard care condition. We measured side effects, ART adherence, perceived stress, depression, positive and negative affect, and mindfulness at three time points: baseline, three-month follow-up, and six-month follow-up. Side effects and related distress were assessed separately from other symptoms.
Results
Compared to a wait-list control, participants in the MBSR condition experienced a reduction in the frequency of symptoms attributable to antiretroviral therapies at three months post intervention (mean difference = 0.33; 95% confidence interval [CI] = 0.01, 0.66; t(132) = 2.04, P = 0.044) and at six months post intervention (mean difference = 0.38; 95% CI = 0.05, 0.71; t(132) = 2.27, P = 0.025). MBSR participants also experienced a reduction in distress associated with those symptoms at three months post intervention (mean difference = 0.47; 95% CI = 0.003, 0.94; t(132) = 1.99, P = 0.048) compared with the wait-list control condition.
Conclusion
Mindfulness-based stress reduction is a promising approach for reducing HIV treatment-related side effects.
doi:10.1016/j.jpainsymman.2011.04.007
PMCID: PMC3253947  PMID: 21925831
Mindfulness-based stress reduction; HIV; antiretroviral therapy; side effects; symptoms; adherence

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