Predictive Biomarkers of CVD Risk in Diverse HIV-1+ Cocaine Abusers

描述（由申请人提供）：佛罗里达州的艾滋病病例在美国排名第三，部分原因是可卡因滥用与危险性行为和HIV-1传播有关。尽管用cART治疗的HIV-1感染现在是一种慢性疾病，但与HIV相关的合并症，如心血管疾病（CVD）已经成为一种新的挑战，特别是在HIV感染的可卡因滥用者中。确定心血管疾病风险的传统方法，如Framingham风险评分，可能不能有效地识别年轻的HIV感染群体的风险，因为这些方法没有考虑到HIV和可卡因滥用中发生的炎症途径、心脏内皮功能、内分泌和免疫激活的异常。该应用假设HIV-1感染和可卡因滥用由于这些生物标志物的干扰而导致发生CVD的风险增加，并且传统的基于ADA /NCEP的护理标准（SOC）在降低该人群CVD风险方面可能效果较差。为了验证这一假设，这项为期5年的申请建议对总共600名男性和女性，非洲裔美国人，白种人和西班牙裔美国人进行横断面调查，分为4组：HIV-1+ -可卡因滥用者（n=200）；HIV-1-可卡因滥用者（n=100）；HIV-1+ -非可卡因滥用者（n=100）；HIV-1-非可卡因滥用者，对照组（n=200）。所有参与者将接受颈动脉内膜-中膜厚度（IMT）测量，那些被确定为心血管疾病高风险的参与者将接受SOC治疗，并在24个月后重新评估。目的1：对HIV-1+可卡因滥用者、HIV-1-可卡因滥用者、HIV-1+非可卡因滥用者、HIV-1-非可卡因滥用者（对照）进行颈动脉IMT测量。目的2：评估胰岛素抵抗、炎症和免疫生物标志物以及内皮祖细胞作为IMT定义的心血管疾病风险的预测因子：a：调查HIV-1+可卡因滥用者、HIV-1-可卡因滥用者、HIV-1+非可卡因滥用者、HIV-1-非可卡因滥用者（对照组）的胰岛素抵抗。b：研究HIV-1+可卡因滥用者、HIV-1-可卡因滥用者、HIV-1+非可卡因滥用者、HIV-1-非可卡因滥用者（对照）的炎症标志物（血浆CRP、IL-1、IL-6和TNF-?）c：探讨HIV-1+可卡因滥用者、HIV-1-可卡因滥用者、HIV-1+非可卡因滥用者、HIV-1-非可卡因滥用者的免疫激活替代标志物sCD14、sCD163和LPS。d：研究所有研究组的循环内皮祖细胞，EPCs, (CD34+ -VEGFR+)，循环未成熟内皮祖细胞（CD133+ -VEGFR+）和血浆VEGFR水平。目的3：比较研究组（HIV-1+ -可卡因滥用者、HIV-1-可卡因滥用者、HIV-1+ -非可卡因滥用者、HIV-1-非可卡因滥用者）在24个月时对ADA/NCEP SOC干预的反应，评估生物标志物（胰岛素、免疫激活、祖细胞）和IMT。

DESCRIPTION (provided by applicant): Florida ranks third in HIV cases in the US, in part due to the association of cocaine abuse with risky sexual behavior and transmission of HIV-1. Although HIV-1 infection treated with cART is now a chronic disease, HIV- related co-morbidities such as cardiovascular disease (CVD) have emerged as a new challenge, particularly among HIV infected - cocaine abusers. Conventional methods to determine CVD risk, e.g., Framingham Risk Scores, may not be as effective in identifying risk in this younger, HIV- infected group as these methods do not take into consideration abnormalities in the inflammatory pathways, cardiac endothelial functions, endocrines and immune activation that occur in HIV and cocaine abuse. This application hypothesizes that HIV-1 infection and cocaine abuse lead to a higher risk of developing CVD due to disturbances in these biomarkers and that the conventional ADA /NCEP based standard of care (SOC) may be less effective in reducing CVD risk in this population. To test this hypothesis, this 5-year application proposes to conduct a cross-sectional investigation of a total of 600 men and women, African Americans, Caucasians, and Hispanics, in 4 groups: HIV-1+ -cocaine abusers (n=200); HIV-1- -cocaine abusers (n=100); HIV-1+ - non- cocaine abusers (n=100); and, HIV-1- - non-cocaine abusers, control, (n=200). All participants will undergo measurement of carotid artery intima-media thickness (IMT), and those identified at high risk of CVD will be referred for SOC treatment and re-assessed after 24 months. AIM 1: To conduct carotid IMT measurement among HIV-1+ cocaine abusers, HIV-1- cocaine abusers, HIV-1+ non-cocaine abusers, HIV-1- non-cocaine abusers (control). AIM2: To evaluate insulin resistance, inflammatory and immunologic biomarkers, and endothelial progenitor cells as predictors of CVD risk, as defined by IMT: a: To investigate insulin resistance among HIV-1+ cocaine abusers, HIV-1- cocaine abusers, HIV-1+ non-cocaine abusers, HIV-1- non-cocaine abusers (control). b: To investigate inflammatory markers (plasma CRP, IL-1, IL-6, and TNF-?) among HIV-1+ cocaine abusers, HIV-1- cocaine abusers, HIV-1+ non-cocaine abusers, HIV-1- non-cocaine abusers (control). c: To investigate the surrogate markers of immune activation, sCD14, sCD163 and LPS, among HIV- 1+ cocaine abusers, HIV-1- cocaine abusers, HIV-1+ non-cocaine abusers, HIV-1- non-cocaine abusers. d: To investigate circulating endothelial progenitor cells, EPCs, (CD34+ -VEGFR+), circulating immature-endothelial progenitor cells (CD133+ - VEGFR+), and levels of plasma VEGFR in all study groups. AIM 3: To compare the response to ADA/NCEP SOC intervention at 24 months by study group (HIV-1+ - cocaine abusers, HIV-1- cocaine abusers, HIV-1+ non-cocaine abusers, HIV-1- non-cocaine abusers) evaluating biomarkers (insulin, immune activation, progenitor cells) and IMT.