How maternal HCMV facilitates in utero transmission of HIV and impacts the developing fetal immune system during gestation

母体 HCMV 如何促进 HIV 子宫内传播并影响妊娠期间胎儿免疫系统的发育

• 批准号: 10005430
• 负责人: Rana Chakraborty
• 金额: $ 30.68万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005430
• 关键词: Adherence; Africa South of the Sahara; Antiviral Agents; Antiviral Response; Antiviral Therapy; Blood; Blood Circulation; CCR5 gene; Cells; Child; Clinical; Cytomegalovirus; Cytomegalovirus Infections; Data; Development; Exposure to; Fetus; HIV; HIV Infections; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunity; In Vitro; Infant; Infection; Inflammation; Inflammation Mediators; Innate Immune Response; Interferons; Knowledge; Lymphocyte; Maternal Exposure; Maternal-Fetal Exchange; Maternal-Fetal Transmission; Mediator of activation protein; Mononuclear; Mother-to-child HIV transmission; Mothers; Outcome; Pattern recognition receptor; Placenta; Predisposition; Pregnancy; Prevalence; Prevention; Production; Resources; STAT2 gene; Signal Transduction; T-Cell Activation; Third Pregnancy Trimester; Vertical Disease Transmission; Villous; Viral; Viremia; Virus; Woman; antiretroviral therapy; co-infection; epidemiology study; fetal; immune activation; improved; in utero; macrophage; pathogen; permissiveness; receptor; response; transmission process; trophoblast

ABSTRACT In 2016, an estimated 160,000 new HIV infections occurred in infants and children; most from mother-to-child transmission (MTCT). Even with optimal adherence, maternal antiretroviral therapy (ART) reduces, but does not eliminate vertical transmission of HIV. A potential barrier for elimination, particularly in resource-poor settings, are maternal co-infections during pregnancy. Among HIV-infected mothers, human cytomegalovirus (HCMV) is a significant co-pathogen and numerous epidemiological studies have strongly associated maternal HCMV viremia with MTCT of HIV. However, the mechanisms by which HCMV exposure promotes placental and fetal HIV infection are poorly understood. We seek to develop a mechanistic understanding for how maternal HCMV viremia facilitates in utero transmission of HIV and also impacts the developing fetal immune system during gestation. The placenta is characterized by a unique state of immune tolerance, which limits infections. This interface is also a target for many viruses, including HCMV. Studies have shown that HIV+ women are more likely to reactivate and become viremic with HCMV. Maternal HCMV infection is associated with inflammation and trophoblast damage, and placental cells can recognize and respond to pathogens in a highly regulated manner via pattern recognition receptors and production of type I IFNs. Resulting inflammation can disrupt the development and function of the placenta, and fetal immune system. Several studies including from our group, have identified trophoblasts and placental macrophages (Hofbauer cells [HCs]) as key mediators of HCMV infection, while HCs and fetal lymphocytes are targets for HIV. We have also demonstrated that stimulation of fetal lymphocytes with HCMV increased expression of CCR5, suggesting a mechanism to increase fetal susceptibility to HIV. In preliminary data, we show that HCMV infection of HCs upregulates CCR5 expression, induces cellular activation and secretion of inflammatory mediators, and inhibits STAT2 activity, which may contribute to observed increases in HIV susceptibility and replication. Therefore, we hypothesize that maternal HCMV viremia promotes placental cell HIV replication and in utero HIV transmission as a consequence of local inflammation, fetal immune activation and inhibition of intrinsic antiviral responses. Two Specific Aims are proposed to validate our hypothesis:1) To define the innate immune profile of trophoblasts and HCs in response to HCMV and HIV during pregnancy; and 2) To determine the impact of placental HIV/HCMV co-infection on HIV susceptibility and fetal immunity. Although significant progress has been made over 3 decades in prevention of MTCT of HIV, there is a paucity of mechanistic studies showing how maternal co-infection with HIV/HCMV facilitates in utero transmission of HIV and adversely impacts the developing fetal immune system. These studies may contribute towards the development of specific antiviral therapies to further reduce MTCT of HIV and improve clinical outcomes in HIV-exposed infants globally.

摘要