Livo Esemu, BSc, MSc

Esemu Livo Forgu pic

Nominated From: University of Hawaii

Research Site: Cameroon

Research Area: Infectious Disease & Immunology

Primary Mentor: Diane Taylor

Research Project

 

The effects of HIV-1 on expression of microRNA in plasma and placenta

 

The number of newly infected HIV infants decreased from 570,000 in 1999 to 240,000 in 2013 as a result of the introduction of antiretroviral therapy (ART) among HIV-infected pregnant women, which drastically decreased the risk of mother–child transmission worldwide (1,2,3). Even when the neonate escapes HIV infection, the HIV infected maternal–fetus interface may present an altered environment for fetal growth and development (2,4). A major consequence of this alteration is increased morbidity and mortality seen in these infants during their postnatal life (2,5). Infants born to HIV-infected mothers in sub-Saharan Africa are vulnerable to more severe forms of common childhood infections, including malaria (3,6–8).

Maternal antibody transfer to the fetus is an important mechanism that provides protection to newborns during their first year of life (6,7,9,10). Immunoglobulin (Ig) IgG1 is the major antibody isotype to cross the human placenta (6,7,11) and is mediated by the neonatal Fc receptor (FcRn) expressed on syncytiotrophoblast cells via an endocytosis dependent pathway (6,8,9,11). Our previous study demonstrated maternal HIV-associated hypergammaglobulinemia (HGG) was associated with reduced transplacental transfer of antibodies specific to three malaria antigens (12). Although maternal HIV-associated HGG is incriminated for this reduction in antibody transfer, the model remains speculative.

MicroRNAs regulate a plethora of fundamental biological processes such as cell differentiation, signal recognition and pathogen responses (13) by fine-tuning the transcriptome (13,14). Pregnancy specific microRNAs have been described in both normal and abnormal pregnancies (15,16). Some microRNA have been shown to regulate B cell differentiation in pregnant women (17,15). Recent findings show that miR3181 regulates the expression of the FcRn gene (fcgrt) by interacting with its 3’ untranslated region (UTR) in liver cells (18). It is also known that miR-199a and miR-199b regulate endocytic transport (19). HIV-1 infection reduces the transplacental transfer of maternal antibodies but the mechanism remains unclear (8,9,11,12). Even when neonates escape HIV-infection, in utero exposure to HIV, ART and HIV immune activation may cause changes in the placental natural environment originally conducive for fetal growth and development (9,12). It is known that HIV-1 infectivity is influenced by cellular miRNAs (14) and some miRNAs (miR-150 and miR-146) show promising potential as markers for disease progression in patients adminstered ART (20). Some pregnancy-specific miRNA which belong to chromosome 19 microRNA cluster (C19MC) such as miR- 516-5p, miR-517, miR-518b, miR-520h, miR-525, miR-526, expressed in term placenta have been suggested to have diagnostic potentials for pathology like breast cancer (15,17). Members of this cluster are involved in biological and pathological processes but their role remains conflicting (16–19).

We hypothesize that specific miRNA following (a) exposure to HIV during pregnancy will reduce placental FcRn synthesis and (b) this reduction in FcRn levels will reduce anti-malaria antibody transplacental transfer to the newborn. To investigate this hypothesis, we have access to biological specimens collected at delivery from a retrospective study of 24 HIV-infected and 58 -uninfected pregnant women from a malaria endemic area. Biopsies from freshly expulsed placentas, maternal, placental and cord blood were banked. We proposed the following two aims to address the stated hypothesis.

 

Research Significance

This study will provide key information on how HIV infection during pregnancy modulates the transplacental transfer of antibody by modulating placental and plasma miRNAs. If successful, identification of potential biomarkers will be useful to ascertain decrease in transplacental transfer of maternal antibodies and its correlation to malaria antigens. These data will also serve as a basis for subsequent grant applications on a genome-wide approach in understanding the impact of HIV on the transplacental transfer of antibodies and to use microRNAs as biomarkers and therapeutic tools. This study is directly relevant to HIV-infected mothers in Cameroon, in the United States and all other countries where HIV infection is present.

 

Specific Aims

Aim 1: To measure plasma and placental miRNA expression levels in HIV-infected and -uninfected women.
Aim II: To measure the expression levels of FcRn receptor in placental tissues derived from HIV-infected and -uninfected pregnant women at delivery.

 

Publications

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Mentors

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