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(由申请人提供)：我们试图研究在母乳传播的模型中，婴儿恒河猴(RMS)口服R5SHV后病毒进入和早期粘膜传播。这种母婴传播途径(母婴传播)在发展中国家仍然存在问题。母乳传播母婴传播的风险与乳清中的病毒载量等参数有关。然而，目前尚不清楚传播的病毒粒子是否被母源抗体(Abs)覆盖，如果是，调理作用是否会影响病毒粒子的传染性以及第一批有效感染的靶细胞的类型和/或数量。由于许多哺乳的HIV+妇女是血清阳性的，病毒粒子可能被调理。抗体介导的增强HIV获得性的可能性最近被提出。Willey等人。[2011]结果表明，新近感染艾滋病毒但尚未对自体病毒产生抗体的人的血清，在补体存在的情况下，使体外感染艾滋病毒的毒力大大增加-350倍这种作用是通过免疫球蛋白G和免疫球蛋白M介导的。在新生儿RMS中使用SIV挑战，我们已经产生了概念证明，即通过广泛中和单抗(BnmAbbs)被动免疫完全可以预防口腔病毒传播。我们现在试图验证这样的假设，即在RM婴儿应用扁桃体病毒后，与非中和抗体(Non-Nabs)调理的病毒粒子将与携带FCR或补体受体(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的病毒阳性细胞有关。我们还推测，被动免疫婴儿RMS的非NAB将增加他们在口服SHV后发生病毒血症的易感性。其具体目的是：1.检测HIV C亚型阳性妇女母乳中病毒粒子的物理状态和R5 C亚型Shiv(简称SHIV-C)感染RMS的乳中病毒粒子的物理状态。我们将使用病毒粒子免疫复合体捕获分析来测试病毒粒子是否被抗体包裹，以及这些病毒粒子是否在体外与FCR和CR承载细胞结合。2.经扁桃体将婴幼儿RMS暴露于用标准培养液制备的或用非NaBS调理的荧光标记病毒后，鉴定和计数第一病毒靶细胞。这些研究将使用标记有绿色或红色荧光蛋白+/-与RM非NAB调理的单循环病毒粒子进行。3.用R5Shiv-C攻击RMS的非中和免疫球蛋白被动免疫早期感染的RMS婴儿(发病前)是否会增加R5Shiv-C攻击的易感性。我们将使用终点滴定来确定口服攻击的幼稚婴儿与在病毒攻击前被动接种非中和免疫球蛋白的婴儿的最小感染病毒剂量。这项提案意义重大，因为它侧重于口腔传播和调理病毒的传播，鉴于大多数受感染的哺乳期妇女都是血清阳性，调理病毒最有可能参与通过牛奶传播的艾滋病毒。