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: 9084260
• 负责人: Ruth Margrit Ruprecht
• 金额: $ 73.81万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9084260
• 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; Fc Receptor; Fright; HIV; HIV Infections; HIV Seropositivity; Health; 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; fluorescence imaging; in vivo; infant morbidity/mortality; interest; lymph nodes; macrophage; neutralizing antibody; neutralizing monoclonal antibodies; neutrophil; novel; particle; pathogen; red fluorescent protein; research study; response; seropositive; simian human immunodeficiency virus; transmission process; viral RNA; viral transmission

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（由申请人提供）：我们试图在口头传播婴儿恒河猴（RMS）后将病毒进入和早期粘膜扩散到母乳传播模型中的R5 SHIV。在发展中国家，这种母亲到孩子传播（MTCT）的途径仍然存在问题。牛奶传播MTCT的风险与其他参数相关。然而，尚不清楚传播病毒体是否被母体抗体覆盖（ABS），如果是的，则调整化是否会影响病毒体感染性以及第一个有效感染的靶Cels的类型和/或数量。由于许多护理艾滋病毒+女性是血清阳性的，因此病毒体可能被调整。最近提出了AB介导的HIV收购增强的可能性。威利等。 [2011]表明，最近患有艾滋病毒感染的人的血清尚未开发为自体病毒的NAB，在补体存在下使HIV感染变得更加强大 - 高达350倍。该作用是由IgG和IgM介导的。 利用新生儿RMS中的SHIV挑战，我们已经产生了概念概念，即通过被广泛中和单克隆抗体（BNMAB）的被动免疫可以完全预防口腔病毒的传播。现在，我们试图检验以下假设，即用非中和ABS（非NABS）调子的病毒体将与在RM婴儿中施用Tonsilar病毒后的含FCR或补体受体（CR） - 含有FCR的受体（CR） - 含量。反过来，这将与扁桃体和邻近口服粘膜组织和淋巴结中的病毒+细胞数量较大有关。我们还假设，使用非NAB的婴儿RMS被动免疫会增加口服SHIV暴露后对病毒血症的敏感性。具体目的是：1。检查在艾滋病毒进化枝C阳性妇女的母乳和R5进化枝C SHIV（称为SHIV-C）感染的RMS的牛奶中发现的病毒体的物理状态。我们将使用Virion-rymune复合物捕获测定法测试病毒体是否被覆盖，以及这种病毒体是否与FCR和CR的细胞结合。 2。通过扁桃体暴露婴儿RMS在标准培​​养基中制备或用非NABS调查的荧光标记的病毒后，识别并枚举第一个病毒靶细胞。这些研究将使用单周期病毒体进行用绿色或红色荧光蛋白标记的单周期病毒元素+/-用RM非NABS进行调整。 3.测试从R5 SHIV-C挑战的RMS分离出具有早期感染的RM中和非中和IgG的RM婴儿是否会增加婴儿对口服R5 SHIV-C挑战的敏感性。我们将使用端点滴定来确定口服挑战的天真婴儿中最小的感染性病毒剂量与婴儿在病毒挑战之前用非中和非中性IgG被动免疫的婴儿。 该提案非常重要，因为它专注于口服传播和调子病毒的传播，这是鉴于大多数感染的哺乳期妇女是血清阳性的，最有可能参与牛奶传播HIV的形式。