Unit of Infectious Diseases, Department of Medicine, Solna, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
PLoS One. 2012;7(2):e31996. doi: 10.1371/journal.pone.0031996. Epub 2012 Feb 28.
HIV exposed seronegative (HESN) women represent the population most in need of a prophylactic antiviral strategy. Mucosal cationic polypeptides can potentially be regulated for this purpose and we here aimed to determine their endogenous expression and HIV neutralizing activity in genital secretions of women at risk of HIV infection.
METHODOLOGY/PRINCIPAL FINDINGS: Cervicovaginal secretions (CVS) of Kenyan women in HIV-serodiscordant relationships (HESN, n = 164; HIV seropositive, n = 60) and low-risk controls (n = 72) were assessed for the cationic polypeptides HNP1-3, LL-37 and SLPI by ELISA and for HIV neutralizing activity by a PBMC-based assay using an HIV primary isolate. Median levels of HNP1-3 and LL-37 in CVS were similar across study groups. Neither HSV-2 serostatus, nor presence of bacterial vaginosis, correlated with levels of HNP1-3 or LL-37 in the HESN women. However, an association with their partner's viral load was observed. High viral load (>10,000 HIV RNA copies/ml plasma) correlated with higher levels of HNP1-3 and LL-37 (p = 0.04 and 0.03, respectively). SLPI was most abundant in the low-risk group and did not correlate with male partner's viral load in the HESN women. HIV neutralizing activity was found in CVS of all study groups. In experimental studies, selective depletion of cationic polypeptides from CVS rendered the remaining CVS fraction non-neutralizing, whereas the cationic polypeptide fraction retained the activity. Furthermore, recombinant HNP1-3 and LL-37 could induce neutralizing activity when added to CVS lacking intrinsic activity.
CONCLUSIONS/SIGNIFICANCE: These findings show that CVS from HESN, low-risk, and HIV seropositive women contain HIV neutralizing activity. Although several innate immune proteins, including HNP1-3 and LL-37, contribute to this activity these molecules can also have inflammatory properties. This balance is influenced by hormonal and environmental factors and in the present HIV serodiscordant couple cohort study we show that a partner's viral load is associated with levels of such molecules.
HIV 暴露阴性（HESN）妇女是最需要预防性抗病毒策略的人群。黏膜阳离子多肽可能为此目的而受到调节，我们旨在确定这些多肽在有 HIV 感染风险的女性生殖道分泌物中的内源性表达和 HIV 中和活性。
方法/主要发现：评估了肯尼亚 HIV 血清不一致关系（HESN，n=164；HIV 血清阳性，n=60）和低危对照组（n=72）女性的宫颈阴道分泌物（CVS）中的阳离子多肽 HNP1-3、LL-37 和 SLPI，通过 ELISA 进行测定，通过使用 HIV 原发性分离物的基于 PBMC 的测定法测定 HIV 中和活性。研究组之间 CVS 中 HNP1-3 和 LL-37 的中位水平相似。HSV-2 血清状态或细菌性阴道病的存在均与 HESN 女性的 HNP1-3 或 LL-37 水平无关。但是，观察到与伴侣病毒载量之间存在关联。高病毒载量（>10,000 HIV RNA 拷贝/ml 血浆）与 HNP1-3 和 LL-37 水平升高相关（p=0.04 和 0.03）。SLPI 在低危组中最为丰富，与 HESN 女性中男性伴侣的病毒载量无关。在所有研究组的 CVS 中均发现了 HIV 中和活性。在实验研究中，从 CVS 中选择性耗竭阳离子多肽会使剩余的 CVS 部分失去中和能力，而阳离子多肽部分则保留活性。此外，当添加到缺乏内在活性的 CVS 时，重组 HNP1-3 和 LL-37 可以诱导中和活性。
结论/意义：这些发现表明，HESN、低危和 HIV 血清阳性女性的 CVS 含有 HIV 中和活性。尽管包括 HNP1-3 和 LL-37 在内的几种先天免疫蛋白对此活性有贡献，但这些分子也具有炎症特性。这种平衡受激素和环境因素的影响，在本 HIV 血清不一致的夫妻队列研究中，我们表明伴侣的病毒载量与此类分子的水平相关。
