Short Intracellular HIV-1 Transcripts as Biomarkers of Residual Immune Activation in Patients on Antiretroviral Therapy
Aya IshizakaHidenori SatoHitomi NakamuraMichiko KogaTadashi KikuchiNoriaki HosoyaTomohiko KoibuchiAkio NomotoAi Kawana‐TachikawaTaketoshi Mizutani
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ABSTRACT HIV-1 patients continue to remain at an abnormal immune status despite prolonged combination antiretroviral therapy (cART), which results in an increased risk of non-AIDS-related diseases. Given the growing recognition of the importance of understanding and controlling the residual virus in patients, additional virological markers to monitor infected cells are required. However, viral replication in circulating cells is much poorer than that in lymph nodes, which results in the absence of markers to distinguish these cells from uninfected cells in the blood. In this study, we identified prematurely terminated short HIV-1 transcripts (STs) in peripheral blood mononuclear cells (PBMCs) as an efficient intracellular biomarker to monitor viral activation and immune status in patients with cART-mediated full viral suppression in plasma. STs were detected in PBMCs obtained from both treated and untreated patients. ST levels in untreated patients generally increased with disease progression and decreased after treatment initiation. However, some patients exhibited sustained high levels of ST and low CD4 + cell counts despite full viral suppression by treatment. The levels of STs strongly reflected chronic immune activation defined by coexpression of HLA-DR and CD38 on CD8 + T cells, rather than circulating proviral load. These observations represent evidence for a relationship between viral persistence and host immune activation, which in turn results in the suboptimal increase in CD4 + cells despite suppressive antiretroviral therapy. This cell-based measurement of viral persistence contributes to an improved understanding of the dynamics of viral persistence in cART patients and will guide therapeutic approaches targeting viral reservoirs. IMPORTANCE Combination antiretroviral therapy (cART) suppresses HIV-1 load to below the detectable limit in plasma. However, the virus persists, and patients remain at an abnormal immune status, which results in an increased risk of non-AIDS-related complications. To achieve a functional cure for HIV-1 infection, activities of viral reservoirs must be quantified and monitored. However, latently infected cells are difficult to be monitored. Here, we identified prematurely terminated short HIV-1 transcripts (STs) as an efficient biomarker for monitoring viral activation and immune status in patients with cART-mediated full viral suppression in plasma. This cell-based measurement of viral persistence will contribute to our understanding of the impact of residual virus on chronic immune activation in HIV-1 patients during cART.Keywords:
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Ongoing HIV replication while receiving combination antiretroviral therapy (cART) may reduce survival. Viremia copy-years (VCY) has shown improved mortality risk prediction over single time-point viral load measures. However, the timing of a patient's viral load history most associated with later mortality has not been studied. Here we determined the optimal duration and temporality of viral load history for predicting mortality.Survival analysis among HIV-positive men who initiated cART in the Multicenter AIDS Cohort Study (1995-2015).VCY measures were derived from area-under-the-viral load-curve. The overall VCY based upon the complete post-cART viral load history was compared with 20 VCYs derived from viral loads assessed during different shorter time periods (the most recent 1-10 years and initial 1-10 years following cART initiation) for associations with mortality.Each 10-fold increase in VCYs based on the most recent 3-8 years was significantly associated with 23-26% decrease in survival times, a magnitude of effect greater than that of the most recent viral load (16%). These associations were independent of CD4 cell count and single time-point viral loads. In addition, the degree of pre-cART immunodeficiency did not affect the mortality prognostic value of VCY based on viral loads in the most recent 3 years. Conversely, the overall VCY and VCYs based on viral loads immediately following cART initiation were not independent predictors of mortality.Among cART-treated men, VCY based upon viral loads in the recent 3 years (six viral loads) has a mortality prognostic value greater than that of the overall VCY and single time-point viral loads, making the former a more feasible measure for use.
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Human Immunodeficiency Virus (HIV) patient management continues to be a challenge all over the world. CD4 absolute counts and viral load are the gold standard tools for monitoring of HIV-1 disease. However, the use of CD4 counts cannot be used solely to determine the overall status of immune system. It requires the additional measurement of viral load. Determination of viral load is also expensive in many places that are limited with resources. Therefore, there is need for identification of other markers for management of HIV. CD38 is one such candidate marker. The main the correlation between CD38 antibody binding capacity (ABC) and viral load. A a negative correlation was established for participants not on drugs, whereas a positive correlation was exhibited between CD4 and viral load for group on drugs. There was a significant correlation between CD38 ABC and viral load. CD38 levels for the group not on drugs was elevated the same way viral load was, whereas for the group on drugs CD38 levels were lowered the same way as viral load. There was no significant correlation between ages with the outcome from the two groups. Quantification of CD38 may therefore be an affordable test that can serve as an extra tool in HIV-1 management. However, more studies are required to justify the use of CD38 as a surrogate marker for HIV patients on ART.
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연구배경 ICT(Information and Communications Technology) 기술의 범용화 추세의 일환으로, 최근 국내외 일부 마트에서 스마트카트가 도입되고 있다. 본 논문은 저자들이 현재 개발 중인 “A” Smart Cart의 Prototype에 대한 실무진의 피드백(Feedback)을 분석하여, 향후 개발될 스마트카트에 의미 있는 인사이트(Insight)를 제시하고자 한다. 연구방법 먼저 마트 카트의 사용자 경험 및 스마트카트의 제반 기술을 간략히 고찰하였다. 다음으로, “A” Smart Cart를 설명과 함께 제시하고, 관련 업계 실무자(UX, 제품디자인, POS 개발, 제조관리 등)들을 심층 인터뷰하여 분석하였다. 연구결과 사용자의 매끄러운(Seamless) 쇼핑경험을 지원하는 “A” Smart Cart”의 구성요소 및 디자인을 실물 Prototype 사진과 함께 제시하고, 심층 인터뷰를 통해 도난방지, 안전, 고객 실수 오류대처, 사용시간, 유지보수 등의 이슈를 도출하였다. 결론 사용자 쇼핑경험 향상을 위해 스마트카트 디자인은 고객의 매장 내 다양한 체험들을 통합적이고 자연스럽게 지원해야 한다. 또한, 디자인 개발 단계에서 본 논문의 실무자 인터뷰에서 분석된 이슈들이 고려되어야 할 것이다.
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ABSTRACT Although antiviral agents which block human immunodeficiency virus (HIV) replication can result in long-term suppression of viral loads to undetectable levels in plasma, long-term therapy fails to eradicate virus, which generally rebounds after a single treatment interruption. Multiple structured treatment interruptions (STIs) have been suggested as a possible strategy that may boost HIV-specific immune responses and control viral replication. We analyze viral dynamics during four consecutive STI cycles in 12 chronically infected patients with a history (>2 years) of viral suppression under highly active antiretroviral therapy. We fitted a simple model of viral rebound to the viral load data from each patient by using a novel statistical approach that allows us to overcome problems of estimating viral dynamics parameters when there are many viral load measurements below the limit of detection. There is an approximate halving of the average viral growth rate between the first and fourth STI cycles, yet the average time between treatment interruption and detection of viral loads in the plasma is approximately the same in the first and fourth interruptions. We hypothesize that reseeding of viral reservoirs during treatment interruptions can account for this discrepancy, although factors such as stochastic effects and the strength of HIV-specific immune responses may also affect the time to viral rebound. We also demonstrate spontaneous drops in viral load in later STIs, which reflect fluctuations in the rates of viral production and/or clearance that may be caused by a complex interaction between virus and target cells and/or immune responses.
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摘要: 准确的滑坡易发性建模对预警预报和风险管控具有重要意义.针对机器学习技术建模中非滑坡样本随机选取和单个分类器存在的精度不高问题,提出了一种耦合多模型的区域滑坡易发性建模框架.以三峡库区秭归-巴东段为例,选取高程、坡度等12个因子构建评价指标体系,应用信息量法定量分析各指标对滑坡空间发育的影响程度.随机选取70%的滑坡作为训练样本,剩余的30%作为验证样本;应用逻辑回归模型(LR)制作研究区的初始易发性分区图,确定非滑坡随机采样的约束范围.随后,分别采用LR模型约束和无约束条件下随机选取的非滑坡样本,应用单个分类回归树(LR-CART和No-CART)及分类回归树-Bagging组合模型(LR-CART-Bagging和No-CART-Bagging)开展滑坡易发性建模,并应用多个指标进行精度评估.结果发现:高程和水系等是滑坡发育的主控因素;LR-CART-Bagging模型精度为0.973,高于LR-CART模型的0.889;相比于No-CART和No-CART-Bagging模型,LR-CART和LR-CART-Bagging模型精度分别提升了0.057和0.047.LR模型可以有效约束非滑坡样本的选取范围,提升样本的选取质量;CART-Bagging模型综合了机器学习和集成学习的优势,预测性能更强,提出的LR-CART-Bagging模型是一种准确可靠的滑坡易发性建模方法. 关键词: 机器学习 / 滑坡 / 易发性制图 / 非滑坡样本选取 / 集成学习 / 三峡库区 / 工程地质
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전통시장의 중요성에 대한 사회적 관심과 정부차원의 여러 지원을 통해 전통시장의 활성화를 위해 환경개선, 접근성 개선, 서비스 개선은 물론 문화체험형 연계 서비스 등 다양한 방향으로 전통시장을 위한 신규 서비스가 제안 및 적용되고 있다. 본 연구에서는 장보기에 가장 핵심 서비스이면서도 상대적으로 전통시장에서의 대표적인 불편 요소 중 하나인 Shopping Cart Service 의 개선 방향을 제안하고자 한다. 최근 전통시장 현대화 사업의 하나로 몇몇 전통시장에서는 Shopping Cart 를 도입해서 제공되고 있으나 분실 및 파손 문제로 사용이 제한되고 있고, 시장 환경을 고려하지 않은 크기, 관리 부재 등으로 공간만 차지한 채 방치되고 있는 것을 쉽게 발견할 수 있다. 필요할 때 쉽게 사용하고 반납할 수 있는 공유 경제의 개념을 Shopping Cart 에 반영하여 고객에게는 편의를 제공하고, 궁극적으로는 전통시장 활성화에 이바지할 수 있는 공유형 Shopping Cart Service Model 을 제안하고자 한다.
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In a typical HIV-1-infected patient, plasma viral load (pVL) increases steeply in the first week after acute infection, then decreases as the immune system becomes activated, resulting in antibody seroconversion 3–13 days after infection and a full western blot pattern approximately 3 months later [1–3]. The so-called viral set point or steady-state viral load is reached after approximately 40–276 days from the acute infection moment [1]. Especially in the first few weeks of infection, differences are obvious in patients, especially with regard to time to peak load and time to viral load drop from peak to nadir [1], but also in the absolute viral RNA count. The viral set point is thought to represent a trade-off between viral replication capacity and repression of the virus by the host immune system. HIV-1 RNA levels vary considerably between individuals and also throughout the infection course in a particular individual. The viral load at set point is an important parameter, as it is strongly predictive of clinical progression [4,5]. Both the innate replicating capacity (fitness) of the virus strain and the strength of the host immune system would intuitively be the most obvious contributors, but it has been suggested that age, sex, shared human leukocyte antigen (HLA) alleles and duration of infection also contribute to the phenomenon [6]. The involvement of virus characteristics could easily be measured by analyzing the HIV replication capacity in donor–recipient pairs, wherein the viral load should be similar if viral replication fitness is the main determinant of pVL. A cohort of transmission pairs, necessary to study comparative HIV-1 viral load dynamics, is not easy to establish. Viral relationships indicative of transmission should first be determined by phylogenetic analysis. Then, an acute phase plasma sample (to minimize the effect of immune pressure) of the recipient and a matching sample from the donor should be available. Hecht et al. [7] have analyzed early plasma samples from 24 such transmission pairs, all comprising men having sex with men (MSM), and reported a significant correlation between the HIV-1 RNA levels within the transmission pairs. However, they cautioned that these results should be reproduced in other cohorts to validate the finding. We here report a similar analysis in early samples from 56 sequence-verified HIV-1 transmission pairs, 60% MSM and 40% heterosexual, from The Netherlands. Recipients were sampled during primary infection, 20 recipients were in Fiebig et al. [8] stages III–IV (viral RNA+/− or indeterminate western blot) and 36 recipients were in Fiebig et al. [8] stages V (viral RNA+/western blot p31−) and VI (viral RNA+/western blot fully developed). HIV-1 blood pVL measurements were done using the Versant HIV-1 RNA 3.0 assay (Bayer Diagnostics Division, Tarrytown, New York, USA), NucliSens HIV-1 RNA (bioMérieux, Boxtel, The Netherlands) or m2000rt (Abbott Molecular Inc., Des Plaines, Illinois, USA). Viral loads of all couples were measured using the same assay. Samples from donors matched the time point when recipient samples were taken. Linear regression analysis was done with GraphPad Prism, version 5.01 (GraphPad Software, San Diego, California, USA) and correlation coefficients were calculated. In contrast to Hecht et al. [7], we do not find a strong correlation between plasma viral RNA levels within the pairs (Fig. 1). The Pearson coefficient of correlation (r) in our cohort was 0.25 for all 56 transmission pairs, 0.29 (range −0.17 to 0.65) for pairs when the recipients were in Fiebig et al. [8] stages III–IV and 0.06 (range −0.27 to 0.39) for pairs when the recipients were in Fiebig et al. [8] stages V–VI, suggesting that the correlation is completely lost when the infection progresses. The correlation coefficient (r) between viral RNA levels in donors and recipients was 0.55 in the 24 pairs studied by Hecht et al. [7], which were in similar early stages of HIV infection. A correlation coefficient (r) above 0.8 is usually denoted as strong and below 0.5 as weak, whereas r is equal to 1 represents a perfect correlation. So, in our transmission pairs, we detect only a weak correlation between viral RNA levels in acutely infected recipients and donors. Similar results were obtained for a transmission cohort [6] in Zambia where the viral RNA levels between 115 donor and seroconverting recipient pairs had a correlation coefficient (r) of 0.21 (P = 0.03). In this study, factors such as sex, age, HLA markers and duration of infection were also shown to contribute.Fig. 1: Relationship of HIV-1 RNA levels in 56 transmission pairs. Viral RNA levels in blood plasma from source individuals were correlated with viral RNA levels in recipients in the acute or early stages of infection. Correlations are shown for all 56 transmission pairs or for sources and recipients when the latter are separated according to the primary infection stage criteria of Fiebig et al. [8].The low correlation between pVL in donors and recipients suggests that viral traits do contribute to pVL early in infection, but that other factors are equally or more important.
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In this study, we developed POP Cart that uses a shopping cart and an agent to recommend products. The agent on POP Cart is designed to call the customer by name, chatting and making recommendations to the customer casually like a friend. POP Cart has two advantages: first, the agent can form a positive relationship with the customer is in the store, which could be beneficial for a high recommendation success rate, as found in previous studies. Second, the agent can make multiple recommendations for different products according to the position of the customer while they are shopping in a large store. To evaluate the effectiveness of the recommendations made by the POP Cart agent, we conducted a field experiment in a real supermarket in Japan, where 49 participants shopped under three cart conditions. The results revealed that having an agent on a shopping cart is an effective way to recommend and sell products.
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