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）：我们寻求在母乳传播模型中研究将幼年恒河猴 (RM) 口服暴露于 R5 SHIV 后的病毒进入和早期粘膜传播。这种母婴传播（MTCT）途径在发展中国家仍然存在问题。乳源性母婴传播的风险与乳血清中的病毒载量以及其他参数有关。然而，尚不清楚传播的病毒粒子是否被母体抗体（Abs）覆盖，如果是，则调理作用是否会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。由于许多艾滋病病毒感染者的哺乳期妇女血清呈阳性，因此病毒粒子可能会被调理。最近提出了抗体介导的增强艾滋病毒感染的可能性。威利等人。 [2011] 表明，来自最近感染 HIV 的个体（尚未产生针对自体病毒的 nAb）的血清，在补体存在的情况下使体外 HIV 感染的毒性显着增强 - 高达 350 倍。该作用由 IgG 和 IgM 介导。 利用新生儿 RM 中的 SHIV 挑战，我们得出了概念证明，即通过广泛中和单克隆抗体 (bnmAb) 的被动免疫完全可以预防口腔病毒传播。我们现在试图检验这样的假设：在 RM 婴儿中应用扁桃体病毒后，用非中和性抗体（非 nAbs）调理的病毒粒子将与带有 FcR 或带有补体受体（CR）的细胞相关。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病毒+细胞有关。我们还假设婴儿 RM 的非 nAb 被动免疫会增加他们在口服 SHIV 暴露后对病毒血症的易感性。具体目标是： 1. 检查 HIV 分支 C 阳性女性母乳中和 R5 分支 C SHIV（称为 SHIV-C）感染 RM 的乳汁中发现的病毒粒子的物理状态。我们将使用病毒粒子免疫复合物捕获测定来测试病毒粒子是否被 Ab 包被，以及此类病毒粒子是否与带有 FcR 和 CR 的细胞离体结合。 2. 将婴儿 RM 通过扁桃体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 +/- 与 RM 非 nAb 调理作用标记的单周期病毒体进行。 3.测试使用从R5 SHIV-C攻击的早期感染RM（在产生nAb之前）分离出的非中和性IgG对RM婴儿进行被动免疫是否会增加婴儿对口服R5 SHIV-C攻击的敏感性。我们将使用终点滴定法来确定经口攻击的幼稚婴儿与病毒攻击前用非中和性 IgG 被动免疫的婴儿的最低感染病毒剂量。 该提案意义重大，因为它重点关注经口传播和调理病毒的传播，考虑到大多数受感染的哺乳期妇女血清呈阳性，调理病毒是最有可能参与乳源性艾滋病毒传播的形式。