Do Early Maternal Antibodies Facilitate Oral Transmission of HIV in Infants?

早期母体抗体是否会促进艾滋病毒在婴儿中的经口传播？

• 批准号: 8513307
• 负责人: Ruth Margrit Ruprecht
• 金额: $ 4.86万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-20 至 2013-08-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8513307
• 关键词: AIDS/HIV problem; Animals; Antibodies; Antigen-Antibody Complex; Autologous; B-Lymphocytes; Binding; Biological Assay; Birth; Breast Feeding; CD4 Positive T Lymphocytes; Cell Communication; Cells; Collaborations; Complement; Complement Receptor; Culture Media; Cultured Cells; Data; Dendritic Cells; Developing Countries; Development; Discipline of Nursing; Dose; Epidemiologic Studies; Event; Fright; HIV; HIV Infections; HIV Seropositivity; Human Milk; Imaging technology; Immunity; Immunoglobulin G; Immunoglobulin M; In Vitro; Individual; Infant; Infection; Label; Lentivirus Infections; Link; Lung diseases; Macaca mulatta; Maternal antibody; Mediating; Milk; Modeling; Mothers; Mucous Membrane; National Institute of Dental and Craniofacial Research; Natural Killer Cells; Neonatal; Nevirapine; Oral; Oral Manifestations; Oral mucous membrane structure; Passive Immunization; Phase; Plasma; Predisposition; Pregnancy; Primate Lentiviruses; Primates; Resources; Risk; Route; SIV; Serum; Staging; Stigmatization; Study models; Systemic infection; Testing; Titrations; Tonsil; Vertical Disease Transmission; Viral; Viral Load result; Viremia; Virion; Virulent; Virus; Virus Diseases; Water; Woman; in vivo; infant morbidity/mortality; interest; lymph nodes; macrophage; neutralizing antibody; neutralizing monoclonal antibodies; neutrophil; novel; particle; pathogen; public health relevance; receptor; red fluorescent protein; research study; response; simian human immunodeficiency virus; transmission process; viral RNA

DESCRIPTION (provided by applicant): We seek to study virus entry and early mucosal spread after orally exposing infant rhesus monkeys (RMs) to an R5 SHIV in a model of breast milk transmission. This route of mother-to-child transmission (MTCT) continues to be problematic in developing countries. The risks of milk-borne MTCT have been linked to viral loads in lactoserum, among other parameters. It is not known, however, whether transmitted virions are covered by maternal antibodies (Abs), and if so, whether opsonization influences virion infectivity as well as the types and/or numbers of the first productively infected target cels. Since many nursing HIV+ women are seropositive, virions are likely opsonized. The possibility of Ab-mediated enhancement of HIV acquisition was raised recently. Willey et al. [2011] showed that sera from individuals with recent HIV infection, who had not yet developed nAbs to autologous virus, rendered HIV infection in vitro significantly more virulent in the presence of complement - up to 350-fold. The effect was mediated by IgG and IgM. Using SHIV challenges in neonatal RMs, we have generated proof-of-concept that oral virus transmission is completely preventable by passive immunization with broadly neutralizing monoclonal antibodies (bnmAbs). We now seek to test the hypothesis that virions opsonized with non-neutralizing Abs (non-nAbs) will be associated with FcR-bearing or complement receptor (CR)-bearing cells after tonsilar virus application in RM infants. This in turn will be associated with a larger number of virus+ cells in the tonsils and adjacent oral mucosal tissues and lymph nodes. We also postulate that passive immunization with non-nAbs of infant RMs will increase their susceptibility to viremia after oral SHIV exposure. The Specific Aims are to: 1. Examine the physical status of virions found in breast milk of HIV clade C-positive women and in milk of R5 clade C SHIV (termed SHIV-C)-infected RMs. We will test whether virions are Ab coated using virion- immune complex capture assays and whether such virions bind to FcR-and CR-bearing cells ex vivo. 2. Identify and enumerate the first virus target cells after exposing infant RMs via the tonsils to fluorescently labeled virus prepared either in standard culture medium or opsonized with non-nAbs. These studies will be conducted with single-cycle virions labeled either with green or red fluorescent proteins +/- opsonization with RM non-nAbs. 3. Test whether passive immunization of RM infants with non-neutralizing IgG isolated from R5 SHIV-C- challenged RMs with early-stage infection (before developing nAbs) will increase the infants' susceptibility to oral R5 SHIV-C challenge. We will use endpoint titration to determine the minimal infectious virus dose in orally challenged naive infants versus infants passively immunized with non-neutralizing IgG prior to virus challenge. The proposal is significant due to its focus on oral transmission and spread of opsonized virus, the most likely form to be involved in milk-borne HIV transmission given that most infected, lactating women are seropositive.

描述（由申请方提供）：我们试图在母乳传播模型中研究恒河猴（RM）经口暴露于R5 SHIV后的病毒进入和早期粘膜传播。这种母婴传播途径在发展中国家仍然是一个问题。经乳汁传播的母婴传播的风险与血清中的病毒载量以及其他参数有关。然而，目前尚不清楚传播的病毒粒子是否被母体抗体（Abs）覆盖，如果是，调理作用是否影响病毒粒子的感染性以及第一个有效感染的靶细胞的类型和/或数量。由于许多哺乳期艾滋病毒阳性妇女血清反应阳性，病毒粒子可能调理。最近提出了Ab介导的增强HIV获得的可能性。Willey et al. [2011]显示，来自近期HIV感染个体的血清（尚未产生针对自体病毒的nAb）在补体存在下使体外HIV感染的毒力显著更强-高达350倍。这种作用是由IgG和IgM介导的。 在新生儿RM中使用SHIV挑战，我们已经产生了概念验证，即通过使用广泛中和单克隆抗体（bnmAbs）进行被动免疫完全可以预防口服病毒传播。我们现在试图检验这样的假设，即在RM婴儿中扁桃体病毒应用后，用非中和抗体（非nAb）调理的病毒粒子将与FcR或补体受体（CR）细胞相关。这反过来又与扁桃体和邻近口腔粘膜组织和淋巴结中大量的病毒+细胞有关。我们还假设，被动免疫与非nAb的婴儿RM将增加他们的易感性，口服SHIV暴露后的病毒血症。具体目标是：1.检查在HIV C分支阳性妇女的母乳和R5 C分支SHIV（称为SHIV-C）感染RM的乳汁中发现的病毒粒子的物理状态。我们将使用病毒体-免疫复合物捕获测定来测试病毒体是否被Ab包被，以及此类病毒体是否离体结合至携带FcR和CR的细胞。 2.通过扁桃体将婴儿RM暴露于在标准培养基中制备或用非nAb调理的荧光标记病毒后，鉴定并计数第一个病毒靶细胞。这些研究将使用用绿色或红色荧光蛋白标记的单循环病毒体+/-用RM非nAb调理进行。 3.测试RM婴儿被动免疫接种从R5 SHIV-C激发的RM中分离的非中和IgG是否会增加婴儿对口服R5 SHIV-C激发的易感性。我们将使用终点滴定法来确定经口激发的初次感染婴儿与病毒激发前用非中和IgG被动免疫的婴儿的最小感染病毒剂量。 该提案意义重大，因为它侧重于调理病毒的口服传播和传播，鉴于大多数受感染的哺乳期妇女血清反应呈阳性，调理病毒是最有可能参与经乳汁传播艾滋病毒的形式。