Mechanisms for HIV-1 Persistence in Human Mammary Tissue and Breast Milk Cells

HIV-1 在人类乳腺组织和母乳细胞中持续存在的机制

• 批准号: 7782729
• 负责人: Stephanie M Dorosko
• 金额: $ 8.56万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7782729
• 关键词: Address; Alveolar; Anti-Retroviral Agents; Apical; Breast; Breast Feeding; CD4 Positive T Lymphocytes; Cell Communication; Cells; Child; Clinical; Coculture Techniques; Data; Developing Countries; Development Plans; Ductal; Environmental Risk Factor; Epithelial; Epithelial Cells; Face; Female; HIV; HIV Seropositivity; HIV-1; Hand; Highly Active Antiretroviral Therapy; Hormonal; Human; Human Milk; IL8 gene; Immune; In Vitro; Infection; Interleukin-6; Laboratories; Lactation; Leukocytes; Life; Lymphocyte; Mammary Gland Parenchyma; Mammary gland; Mediating; Mentorship; Morbidity - disease rate; Mothers; Play; Pregnancy; Prevention; Regimen; Relative (related person); Risk; Role; Satellite Viruses; Site; Source; T-Cell Proliferation; Testing; Tissues; Training; Translating; Viral; Virus; Virus Activation; Virus Diseases; Water; White Blood Cell Count procedure; Woman; antiretroviral therapy; career development; cell type; chemokine; cost; cytokine; design; feeding; gastrointestinal; in vivo; insight; intrapartum; leukocyte proliferation; macrophage; migration; mortality; pregnant; reproductive; skills; trafficking; transcytosis; transmission process

DESCRIPTION (provided by applicant): Transmission of HIV during breastfeeding remains the most significant challenge for the prevention of mother-to-child HIV transmission (MTCT) worldwide. Although short-course antiretroviral regimens can reduce transmission to as low as 2-4% during the antenatal and intrapartum periods, these gains may be lost during breastfeeding, which poses a > 9% absolute risk of transmission by 18 months. HIV-infected mothers living in developing countries often do not have the choice to formula-feed due to cost, limited access to clean water, and strong cultural traditions. In addition, formula-feeding leads to excess morbidity and mortality throughout much of the developing world. Maternal highly active antiretroviral therapy (HAART) reduces the cell-free source of virus in breast milk, but does not lower cell-associated virus. Both may be responsible for breastfeeding transmission, and their relative contributions are critical to our understanding of whether maternal HAART can reduce breastfeeding MTCT. The cell types that serve as reservoirs for HIV in breast tissue and the mammary gland's role in perpetuating the virus are largely unknown. Our preliminary data suggest that mammary secretory alveolar luminal cells play a role in transferring the virus to susceptible CD4+ cells which enter breast milk. To develop these findings further, and to delineate mechanisms by which mammary epithelial cells may contribute to a cell-associated HIV-1 viral reservoir in the breast compartment, we will test the hypotheses that (1) mammary epithelial cells (MEC) are susceptible to infection with HIV-1 and/or can initiate a productive infection in susceptible CD4+ lymphocytes and macrophages; (2) HIV-infected CD4+ T lymphocytes and macrophages facilitate infection by cell-associated trancytosis of virus across MEC and, (3) innate immune factors secreted by MEC induce recruitment, proliferation, and HIV replication in CD4+ target cells. Understanding the source(s) of cell-associated virus in breast milk may contribute to clinical decisions regarding the initiation and duration of HAART for HIV-infected pregnant and lactating women in developing countries. The applicant has designed a career development plan that includes didactic, administrative, and hands-on laboratory training, with the intent to translate these skills and experimental findings into a competitive R-level proposal. This K08 project will take place within the context of expert mentorship and strong institutional support.

描述（由申请人提供）：母乳喂养期间的艾滋病毒传播仍然是预防全球预防母子艾滋病毒传播（MTCT）的最重大挑战。尽管短期抗逆转录病毒治疗方案可以在产前和产前时期将传播降低到低至2-4％，但在母乳喂养期间可能会损失这些收益，这在18个月内占9％的绝对传播风险> 9％。居住在发展中国家的艾滋病毒感染的母亲通常由于成本，有限的清洁水和强大的文化传统而无法选择配方奶粉。此外，配方奶粉会导致整个发展中国家的发病率和死亡率过高。母体高度活性的抗逆转录病毒疗法（HAART）降低了母乳中无细胞病毒的来源，但不会降低与细胞相关的病毒。两者都可能负责母乳喂养的传播，它们的相对贡献对于我们对母亲Haart是否可以减少母乳喂养MTCT的理解至关重要。用作乳腺组织中HIV的储存剂的细胞类型以及乳腺在永久性病毒中的作用是未知的。我们的初步数据表明，乳腺分泌肺泡腔细胞在将病毒转移到进入母乳的易感CD4+细胞中发挥作用。为了进一步发展这些发现，并描绘出乳腺上皮细胞可能有助于乳房中与细胞相关的HIV-1病毒储藏的机制，我们将测试（1）（1）乳腺上皮细胞（MEC）易于感染HIV-1和/或/或/或/或/或可能会产生cd cd cd cd的假设。 （2）感染HIV的CD4+ T淋巴细胞和巨噬细胞促进了MEC病毒与细胞相关的三脑tosisosis的感染，（3）MEC分泌的先天免疫因子在CD4+靶细胞中诱导募集，增殖，增殖和HIV复制。了解母乳中与细胞相关病毒的来源可能有助于有关HAART在发展中国家HAART的启动和持续时间的临床决定。申请人设计了一项职业发展计划，其中包括教学，行政和动手实验室培训，目的是将这些技能和实验发现转化为竞争性的R级建议。这个K08项目将在专家指导和强大的机构支持的背景下进行。