Role of integrins in HIV/SIV transmission across cervico-vaginal mucosa

整合素在 HIV/SIV 宫颈阴道粘膜传播中的作用

• 批准号: 8610236
• 负责人: Elena Martinelli
• 金额: $ 77.84万
• 依托单位: POPULATION COUNCIL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-15 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8610236
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Affinity; Binding; Blood; CD4 Positive T Lymphocytes; Cell physiology; Cells; Cellular biology; Cessation of life; Characteristics; Chronic; Coculture Techniques; Coitus; Data; Dendritic Cells; Dose; Event; Exhibits; Exposure to; Frequencies; Genital system; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; Human Herpesvirus 2; In Vitro; Incidence; Infection; Inflammation; Integrins; Intervention; Lead; Learning; Lymphocyte; Macaca; Mediating; Modeling; Monkeys; Mucous Membrane; Pattern; Pharmaceutical Preparations; Phenotype; Predisposition; Role; Route; SIV; Site; Staging; Surface; T-Lymphocyte; Testing; Tissues; Vaccines; Vagina; Viral; Virus; Work; cell motility; insight; lymph nodes; microbicide; migration; mutant; novel; novel strategies; prevent; receptor; rectal; simian human immunodeficiency virus; tool; transmission process; vaginal transmission

DESCRIPTION (provided by applicant): HIV is most commonly acquired by mucosal route during sexual intercourse. Therefore, blocking this means of transmission will rapidly decrease HIV incidence worldwide. In the first days following mucosal exposure HIV must overcome numerous barriers offering a window of opportunity to act before HIV establishes infection. Unfortunately, the critical events that take place after viral exposure are poorly understood. We propose that HSV-2 influences these early events by modulating the mucosal microenvironment and, to explore how, we will use our recently established macaque model of HSV-2 infection in combination with a model of SHIV vaginal transmission. This combination constitutes a new powerful tool to study the earliest stages of SHIV infection in a controlled manner, explore the effect of HSV-2 and identify the events that influence transmission. Interestingly, we found that rectal HSV-2 infection increases the percentage of ¿4¿7highCD4+ T cells in the site of infection (rectal tissue), blood, and draining lymph nodes. And in earlier wors we described a specific interaction between the HIV/SIV envelope and ¿4¿7. Mucosal CD4+ T cells expressing high levels of this receptor (¿4¿7high) constitute a preferential target for HIV infection. Recent data has further indicated that early-transmitted viruses exhibit increased reactivity for ¿4¿7 (compared to chronic isolates and to their reactivity for CD4), suggesting that this molecule is especially important during the initial stages of infection. Additionally, we foun that dendritic cells (DCs) infected with HSV-2 in-vitro expand the ¿4¿7high subset of CD4+ T cells in co-culture and increase HIV infection in these mixtures. Thus, we hypothesize that HSV-2 influences DC function within the cervico-vaginal tissue and that this, in turn, increases the presence of ¿4¿7highCD4+ T cells in the mucosa. We intend to use HSV-2 as a tool to dissect the role of ¿4¿7highCD4+ T cells during early events of HIV transmission across the cervico-vaginal mucosa. We will study how HSV-2 modulates T cell and DC biology within the cervico-vaginal tissues (cell migration, activation, phenotype) to determine how this influences susceptibility to repeated low-dose SHIVSF162P3 vaginal challenge. Moreover, using a drug that specifically inhibits HIV-envelope binding to ¿4¿7 versus a mutant virus that has increased affinity for ¿4¿7 we will further demonstrate the importance of the ¿4¿7-HIV interaction in the onset of SHIV infection. These studies will provide critical insight into the role of ¿4¿7 in the earliest moments of HIV infection across the cervico-vaginal mucosa and how this is influenced by HSV-2 infection, opening up novel approaches to tackle HIV spread.

描述（由申请人提供）：HIV最常在性交时通过粘膜途径感染。因此，阻断这种传播途径将迅速降低全世界的艾滋病毒发病率。在粘膜暴露后的最初几天，艾滋病毒必须克服许多障碍，为在艾滋病毒建立感染之前采取行动提供机会。不幸的是，人们对病毒暴露后发生的关键事件知之甚少。