SIV MACAQUE MODEL FOR BREAST MILK TRANSMISSION OF HIV

用于 HIV 母乳传播的 SIV 猕猴模型

• 批准号: 6164426
• 负责人: ANGELA M AMEDEE
• 金额: $ 28.42万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2001-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6164426
• 关键词: HIV infections; Macaca mulatta; adenine; antiinfective agents; blood chemistry; breast feeding; cellular immunity; communicable disease transmission; disease /disorder model; drug screening /evaluation; enzyme linked immunosorbent assay; genotype; helper T lymphocyte; humoral immunity; immunoglobulins; infant animal; microorganism disease chemotherapy; nonhuman therapy evaluation; nucleic acid sequence; polymerase chain reaction; saliva; simian immunodeficiency virus; virus genetics; virus infection mechanism

Breast-feeding accounts for a substantial proportion of mother-to-child HIV transmission in areas of the world where safe alternatives for infant feeding are not available. Understanding the mechanisms involved in oral transmission of HIV via breast milk and determining the correlates of transmission can lead us to develop specific therapeutic agents that will significantly lower or eliminate the risk of HIV transmission by this route. To decipher the virological and immunological variables involved in HIV transmission via breast milk, we will utilize the SIV-infected rhesus macaque model for mother-to- infant transmission and a well characterized virus inoculum, SIV/ DeltaB670. In this study we will: 1.) Determine the relationship between virus levels in breast milk and oral infection of the infant by inoculating lactating macaque females with SIV after parturition. We will quantitate virus loads in breast milk by QC-PCR at biweekly intervals to determine the correlation between virus levels and infant infection. Viral genotypes expressed in milk will be identified by dideoxy sequencing of the envelope gene and compared to those expressed in maternal plasma and infected infants to determine if only selected variants are transmitted to infants. 2.) Determine if immune responses in a chronically-infected macaque mother provide protection against oral transmission of virus in some infants. We will evaluate the levels of SIV-specific immunoglobulin in breast milk of chronically-infected macaque mothers and measure the levels of maternally-acquired SIV- specific IgG in infant plasma and saliva. We will also evaluate the presence of SIV-specific cellular immune responses in the infant that may have developed through in utero or low-dose breast milk exposure to SIV. 3.) Determine if the immune responses present in an infant born to a chronically-infected mother can protect them from oral challenge with SIV. The levels of SIV-specific maternally-acquired IgG in plasma and saliva will be quantitated and CTL responses will be measured in the infants prior to challenge. 4.) Evaluate the effectiveness of a therapeutic agent, (R)-9-(2-phosphonylmethoxypropyl) adenine (PMPA) on preventing transmission of virus to breast-fed infants. We will measure virus loads in breast milk and plasma of treated macaques and compare these levels to those found in the untreated controls. These studies will also determine how PMPA treatment affects the humoral and cellular immune responses in the lactating female and the infant that help to prevent transmission.

母乳喂养占世界上没有可用于婴儿喂养替代品的世界的母亲艾滋病毒传播的很大比例。 了解通过母乳进行口服HIV涉及的机制并确定传播的相关性可能会导致我们开发特定的治疗剂，从而大大降低或消除通过这种途径传播HIV的风险。 为了解解通过母乳传播参与HIV传播的病毒学和免疫变量，我们将利用SIV感染的恒河猴模型进行母亲到婴儿传播和良好特征的病毒接种物，SIV/ Deltab670。 在这项研究中，我们将：1。）确定母乳中病毒水平与婴儿在分娩后用SIV接种乳珠雌性通过接种哺乳期感染的关系。 我们将以QC-PCR每两周间隔量化母乳中的病毒负荷，以确定病毒水平与婴儿感染之间的相关性。 在牛奶中表达的病毒基因型将通过包膜基因的二氧氧基测序鉴定，并将其与在母体血浆和感染婴儿中表达的基因进行比较，以确定是否仅将选定的变体传播到婴儿。 2.）确定长期感染的猕猴的免疫反应是否可以保护某些婴儿的口服病毒。我们将评估长期感染的猕猴的母乳中SIV特异性免疫球蛋白的水平，并测量婴儿血浆和唾液中母体获得的SIV特异性IgG水平。 我们还将评估婴儿在子宫或低剂量母乳暴露于SIV的婴儿中可能存在SIV特异性细胞免疫反应。 3.）确定长期感染的母亲出生的婴儿中存在的免疫反应是否可以保护他们免受SIV的口腔挑战。 血浆和唾液中SIV特异性的孕期IgG水平将在挑战之前在婴儿中进行定量，并在婴儿中测量CTL反应。 4.）评估治疗剂（R）-9-（2-磷酸甲氧基丙基）腺嘌呤（PMPA）对防止病毒传播到母乳喂养的婴儿的有效性。 我们将测量母乳中的病毒载荷和处理过的猕猴的血浆，并将这些水平与未经处理的对照中发现的水平进行比较。这些研究还将决定PMPA治疗如何影响哺乳雌性和婴儿的体液和细胞免疫反应，从而有助于防止传播。