Effect of Lactobacillus on genital HIV-1 RNA and DNA shedding in women

描述(申请人提供)：生殖器艾滋病毒-1病毒载量是性传播和围产期艾滋病毒传播的主要预测因素，迫切需要在促进阴道健康的同时减少艾滋病毒-1脱落的战略。我们推测，产生过氧化氢的乳杆菌是正常阴道菌群的关键成分，通过直接抑制病毒和相对抑制与细菌性阴道病(BV)相关的潜在致病阴道细菌，减少了HIV-1感染女性的生殖器HIV-1 RNA和DNA的脱落。我们建议使用来自美国和肯尼亚的HIV-1感染妇女的平行队列的宫颈阴道灌洗液(CVL)和宫颈细胞刷样本来评估这一假设。具体地说，我们将：1.检测随着时间的推移，卷曲乳杆菌、简氏乳杆菌和乳杆菌对CVL中HIV-1RNA载量的影响，以及这些微生物对促炎细胞因子和其他BV相关菌群的影响。我们预计，获得和/或较高浓度的卷曲乳杆菌和简氏乳杆菌(但不是简氏乳杆菌)将导致CVL HIV-1 RNA显著下降，这是考虑到其他因素，如血浆病毒载量和抗逆转录病毒治疗，这种保护作用可能是通过下调促炎细胞因子和/或抑制BV相关细菌而介导的。2.评估阴道乳杆菌、其他BV相关生物和促炎细胞因子对宫颈内HIV-1DNA定量和宫颈内HIV-1RNA的纵向影响。我们推测，L和L的保护作用将延伸到宫颈内，包括减少HIV-1感染细胞的增殖和病毒复制。综上所述，这些目标将增加我们对产生过氧化氢的乳杆菌调节女性生殖道中HIV-1的机制的理解，并可能为进一步评估益生菌作为潜在的HIV-1二级预防策略提供理论基础。公共卫生相关性：阴道和宫颈中艾滋病毒的数量是性伴侣之间和母婴之间艾滋病毒传播的主要预测因素。这项研究将研究乳杆菌--一种对阴道健康至关重要的细菌--如何降低女性生殖道中的艾滋病毒数量。

DESCRIPTION (provided by applicant): Genital HIV-1 viral load is a major predictor of sexual and perinatal HIV transmission, and strategies to decrease HIV-1 shedding while promoting vaginal health are urgently needed. We hypothesize that hydrogen peroxide-producing Lactobacillus (L. crispatus and L. jensenii), key components of the normal vaginal flora, decrease genital HIV-1 RNA and DNA shedding among HIV-1-infected women by direct viral inhibition and also by relative suppression of potentially pathogenic vaginal bacteria associated with bacterial vaginosis (BV). We propose to evaluate this hypothesis using archived cervicovaginal lavage (CVL) and cervical cytobrush samples from parallel cohorts of HIV-1-infected women in the United States and Kenya. Specifically, we will: 1. Examine the effect over time of L. crispatus, L. jensenii and L. iners presence and concentrations on HIV-1 RNA load in CVL, as well as the effect of these organisms on pro-inflammatory cytokines and other BV-associated flora. We anticipate that acquisition and/or higher concentrations of L. crispatus and L. jensenii (but not L. iners) will result in a significant decrease in CVL HIV-1 RNA, accounting for other factors such as plasma viral load and antiretroviral therapy, and that this protective effect may be mediated by down-regulation of pro-inflammatory cytokines and/or suppression of BV-associated bacteria. 2. Assess the longitudinal effect of vaginal Lactobacillus species, other BV-associated organisms, and pro-inflammatory cytokines on endocervical HIV-1 DNA quantitation, as well as endocervical HIV-1 RNA. We hypothesize that the protective effect of L crispatus and L jensenii will extend to the endocervix and will include a decrease in proliferation of HIV-1-infected cells as well as viral replication. Taken together, these aims will add to our understanding of the mechanisms by which hydrogen peroxide- producing Lactobacillus modulates HIV-1 in the female genital tract, and may add rationale for further evaluation of probiotics as a potential secondary HIV-1 prevention strategy. PUBLIC HEALTH RELEVANCE: The amount of HIV in the vagina and cervix is a major predictor of HIV transmission between sex partners and from mother to child. This study will examine how Lactobacillus, an essential bacteria for vaginal health, works to decrease the amount of HIV in the female reproductive tract.