SIV-specific Immunity in breast milk during infection and after vaccination

感染期间和疫苗接种后母乳中的 SIV 特异性免疫力

• 批准号: 7756330
• 负责人: Sallie R. Permar
• 金额: $ 13.23万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-08 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7756330
• 关键词: AIDS/HIV problem; Accounting; Acute; Adenovirus Vector; Adenoviruses; Biological Preservation; Blood; Breast Feeding; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Child; Chronic; Containment; DNA; Dose; Evolution; Exposure to; Gagging; Genes; HIV; HIV Infections; Human Milk; Humoral Immunities; Immune response; Immunity; Immunologics; Infant; Infection; Intervention; Kinetics; Lead; Macaca mulatta; Mammary gland; Modeling; Mothers; Pathogenesis; Recombinants; Route; SIV; Safety; Shapes; T-Lymphocyte; Treatment Protocols; Vaccinated; Vaccination; Vaccines; Viral load measurement; Virus; Virus Diseases; Virus Replication; base; design; feeding; improved; mucosal vaccination; nonhuman primate; plasmid DNA; postnatal; public health relevance; response; transmission process; vaccination schedule; vaccination strategy; virus envelope

DESCRIPTION (provided by applicant): HIV transmission via breast milk remains a significant mode of infant HIV transmission in the developing world. Interestingly, the majority of infants remain protected from breast milk transmission despite repeated low-dose exposures to the virus, with postnatal transmission occurring in only 10% of HIV-exposed, breastfed infants. This low rate of transmission raises the possibility that HIV-specific immunity in breast milk may protect infants from HIV transmission. We hypothesize that the evolution of compartmentalized virus quasispecies in breast milk is driven by virus-specific, local breast milk immunity. Using the rhesus monkey/SIV model of HIV pathogenesis, we will characterize cellular and humoral virus-specific immune responses and virus co-evolution in breast milk during acute and chronic SIV-infection. We will then investigate whether vaccination with a potent T cell-based vaccine regimen can elicit virus-specific immunity in breast milk. Uninfected, lactating Mamu-A*01+ rhesus monkeys will be vaccinated with plasmid DNA expressing the SIV genes gag, pol, and env, and boosted with a recombinant adenovirus vector expressing SIV gag, pol, and env. Vaccine-elicited SIV-specific cellular and humoral immune responses in breast milk will be examined throughout the vaccination schedule. Mucosal and systemic routes of vaccination will be compared for their ability to induce SIV-specific immune responses in breast milk. Finally, Mamu-A*01-H chronically SIV-infected, lactating rhesus monkeys will be vaccinated with the DNA prime/adenovirus boost regimen by the route that best elicited SIV-specific immune responses in the breast milk of uninfected rhesus monkeys. SIV-specific immune responses and virus replication kinetics in breast milk and blood will be examined in the chronically SIV-infected, lactating rhesus monkeys to determine if vaccine-elicited immune responses can control virus replication in breast milk. These studies will define the impact of virus-specific immunity in breast milk on local virus replication, and will provide a framework for the design of a maternal vaccine as a potential intervention to decrease breast milk transmission of HIV. PUBLIC HEALTH RELEVANCE: As breast milk transmission accounts for nearly one half of the 800,000 infant HIV infections occurring annually, interventions to impede transmission of HIV via breastfeeding are critical. Using the nonhuman primate model of HIV/AIDS, we will determine whether vaccination of lactating mothers can induce virus- specific immune responses in breast milk and reduce breast milk virus load.

描述（由申请人提供）：通过母乳传播的HIV传播仍然是发展中国家婴儿HIV传播的重要模式。有趣的是，尽管反复暴露于病毒，大多数婴儿仍免受母乳的影响，而产后传播发生在仅10％的HIV暴露于HIV的母乳喂养婴儿中。这种低传播率提高了母乳中HIV特异性免疫力可以保护婴儿免受艾滋病毒传播的可能性。我们假设母乳中分隔病毒准菜的演变是由病毒特异性的局部母乳免疫驱动的。使用HIV发病机理的恒河猴/SIV模型，我们将表征急性和慢性SIV感染期间母乳中的细胞和体液病毒特异性免疫反应和病毒共同进化。然后，我们将研究使用有效T细胞的疫苗方案进行疫苗接种是否可以在母乳中引起病毒特异性免疫。未感染的，哺乳的Mamu-A*01+恒河猴将用表达SIV基因GAG，POL和ENV的质粒DNA接种疫苗，并用表达SIV GAG，POL和ENV的重组腺病毒载体增强。在整个疫苗接种时间表中，将检查疫苗吸引的SIV特异性细胞和体液免疫反应。将比较粘膜和全身疫苗接种途径，以诱导母乳中SIV特异性免疫反应的能力。最后，MAMU-A*01-H慢性化感染，哺乳后的恒河猴将通过最能引起无感染恒河猴母乳中最能引起SIV特异性免疫反应的途径接种DNA Prime/腺病毒促进疗法。在长期感染的SIV，哺乳的恒河猴中，将检查母乳和血液中SIV特异性的免疫反应和病毒复制动力学，以确定疫苗吸收的免疫反应是否可以控制母乳中的病毒复制。这些研究将定义病毒特异性免疫对母乳的影响对局部病毒复制的影响，并将为设计母体疫苗的设计提供一个框架，以减少HIV母乳传播的潜在干预措施。公共卫生相关性：由于母乳传播占每年发生的80万名婴儿艾滋病毒感染中的一半，因此通过母乳喂养阻碍艾滋病毒传播的干预措施至关重要。使用艾滋病毒/艾滋病的非人类灵长类动物模型，我们将确定哺乳母亲的疫苗接种是否可以诱导母乳中的病毒特异性免疫反应并减少母乳病毒负荷。