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

描述（由申请人提供）：佛罗里达在美国艾滋病毒病例中排名第三，部分原因是可卡因滥用与危险性行为和HIV-1传播有关。虽然用cART治疗的HIV-1感染现在是一种慢性疾病，但HIV相关的合并症如心血管疾病（CVD）已成为一种新的挑战，特别是在HIV感染的可卡因滥用者中。确定CVD风险的常规方法，例如，在识别这种年轻的HIV感染人群中的风险时，FRA风险评分可能不那么有效，因为这些方法没有考虑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。本申请假设HIV-1感染和可卡因滥用导致这些生物标志物紊乱导致CVD发生风险升高，并且基于ADA /NCEP的常规标准治疗（SOC）在降低该人群CVD风险方面可能不太有效。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、高加索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）。所有受试者将接受颈动脉内膜中层厚度（IMT）的测量，那些被确定为CVD高风险的受试者将接受SOC治疗，并在24个月后重新评估。目标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。目标2：评价胰岛素抵抗、炎症和免疫学生物标志物以及内皮祖细胞作为CVD风险的预测因子（根据IMT定义）：a：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）中的胰岛素抵抗。B：研究炎症标志物（血浆CRP、IL-1、IL-6和TNF-？）在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）中。C：探讨HIV- 1+可卡因滥用者、HIV- 1+可卡因滥用者、HIV-1+非可卡因滥用者和HIV-1-非可卡因滥用者中免疫激活的替代标志物sCD 14、sCD 163和LPS。D：研究所有研究组中的循环内皮祖细胞、EPCs（CD 34 + -VEGFR+）、循环未成熟内皮祖细胞（CD 133 + - VEGFR+）和血浆VEGFR水平。目标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干预的应答，评价生物标志物（胰岛素、免疫活化、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.