Behavioral, Epidemiologic and Clinical Sciences, FHI 360, Durham, NC.
Biostatistics, FHI 360, Durham, NC.
J Acquir Immune Defic Syndr. 2020 May 1;84(1):85-91. doi: 10.1097/QAI.0000000000002299.
We previously reported association of increased cervical RANTES and decreased secretory leukocyte protease inhibitor (SLPI) with higher risk of HIV acquisition in reproductive-age women. We now examine the interaction of concomitantly altered systemic and cervical immunity on such risk.
We measured immune biomarkers in 4390 cervical and 2390 paired serum specimens at quarterly visits in 218 HIV seroconverters and 784 seronegative women. We assessed proinflammatory (IL-1β, IL-6, IL-8, MIP-3α, and RANTES), anti-inflammatory (IL-1RA and SLPI), vascular activation (vascular endothelial growth factor and Intercellular Adhesion Molecule-1) and defensin (BD2) cervical biomarkers and systemic (peripheral blood) C reactive protein (CRP), IL-6, IL-7, and sCD14 as indicators of immune dysregulation. Biomarker levels were Box-Cox transformed and odds ratios for HIV acquisition calculated based on top quartile or higher/lower than median levels for all HIV-negative visits.
Subsequent HIV acquisition was associated with 5 of 14 individual biomarkers: low systemic CRP [odds ratio (OR) = 1.49, 1.21-1.83] and IL-6 (OR = 1.23, 1.00-1.51), high cervical BD-2 (OR = 1.33, 1.11-1.58) and RANTES (OR = 1.20, 1.01-1.43), and low cervical IL-1RA (OR = 0.65, 0.48-0.86). Low systemic CRP concomitant with altered cervical immunity, especially high BD2, conveyed highest HIV risk (1.63, 1.29-2.05). Additional markers of increased risk emerged when low systemic CRP coincided with: low systemic IL-6 and IL-7 (OR = 1.53, 1.18-1.97); high cervical IL-8 and MIP-3α (OR = 1.40, 1.07-1.83); high cervical IL-1β and IL-6 (OR = 1.43, 1.09-1.86); or low cervical SLPI (OR = 1.36, 1.08-1.71).
Changes in both peripheral and mucosal immunity may precede and predispose women to HIV infection. Suppressed systemic immunity (ie, low CRP) alone or in combination with imbalanced cervical innate immunity (high proinflammatory and low anti-inflammatory mediators) indicated increased vulnerability to infection. Understanding these combined effects on HIV susceptibility is essential to preventing new infections.
我们之前的研究报告指出，在育龄妇女中，宫颈 RANTES 水平升高和分泌型白细胞蛋白酶抑制剂（SLPI）水平降低与 HIV 感染风险增加有关。本研究旨在进一步探讨系统和宫颈免疫同时改变对这种风险的影响。
我们在 218 名 HIV 血清转换者和 784 名血清阴性女性的每季度随访中，测量了 4390 份宫颈和 2390 份配对血清标本中的免疫生物标志物。我们评估了促炎（IL-1β、IL-6、IL-8、MIP-3α 和 RANTES）、抗炎（IL-1RA 和 SLPI）、血管活化（血管内皮生长因子和细胞间黏附分子-1）和防御素（BD2）的宫颈生物标志物以及外周血（C 反应蛋白、IL-6、IL-7 和 sCD14）作为免疫失调的指标。根据所有 HIV 阴性访问的最高四分位数或高于/低于中位数的水平，对生物标志物水平进行 Box-Cox 转换，并计算 HIV 获得的比值比。
随后发生的 HIV 感染与 14 个单独标志物中的 5 个相关：全身 CRP 水平低（比值比[OR] = 1.49，1.21-1.83）和 IL-6（OR = 1.23，1.00-1.51），宫颈 BD-2 和 RANTES 水平高（OR = 1.33，1.11-1.58）和（OR = 1.20，1.01-1.43），宫颈 IL-1RA 水平低（OR = 0.65，0.48-0.86）。全身 CRP 水平低同时伴有宫颈免疫改变，尤其是 BD2 水平高，HIV 感染风险最高（OR = 1.63，1.29-2.05）。当全身 CRP 水平低同时伴有以下情况时，出现了更多的高危标志物：全身 IL-6 和 IL-7 水平低（OR = 1.53，1.18-1.97）；宫颈 IL-8 和 MIP-3α 水平高（OR = 1.40，1.07-1.83）；宫颈 IL-1β 和 IL-6 水平高（OR = 1.43，1.09-1.86）；或宫颈 SLPI 水平低（OR = 1.36，1.08-1.71）。
外周和黏膜免疫的改变可能先于并使女性易感染 HIV。单独的全身免疫抑制（即 CRP 水平低）或与宫颈固有免疫失衡（促炎介质水平高而抗炎介质水平低）相结合，表明感染的易感性增加。了解这些对 HIV 易感性的综合影响对于预防新的感染至关重要。
