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9/26/2014  |   4:30 PM - 6:00 PM   |  

Protection of placental stem cells against CMV infection by human monoclonal antibodies

Human cytomegalovirus (CMV) is the leading cause of congenital infection and affects 1%-3% of births in the United States. The risk of transplacental transmission upon primary maternal infection in the first trimester of pregnancy is high (40-50%) and symptomatic babies can have permanent birth defects, such as neurological deficiencies and deafness. The molecular mechanisms that govern congenital CMV infection and disease are largely unknown. With regard to the maternal-fetal interface, it is now believed that upon placental infection CMV dysregulates the development of chorionic villi, resulting in functional defects that reduce transport of substances from the mother to the fetus. Trophoblast stem cells (TBPCs) are essential for the normal development of chorionic villi, being the only source of cells that can differentiate to form the mature cell populations of syncytiotrophoblasts and cytotrophoblasts. Our recent research revealed that TBPCs can be infected with CMV and that the cells support the entire lytic infectious cycle of the virus, leading to the release of progeny virions. In addition, infection inhibits the differentiation of TBPCs. Important for future interventions, CMV infection of TBPCs can be prevented by highly potent neutralizing antibodies to glycoprotein B (gB) but not by antibodies, which target another viral surface protein complex known as the pentamer complex. Virus neutralization with anti-gB proved to be sufficient to preserve the ability of TBPCs to differentiate. Our data indicate that – in order to be broadly effective – a future preventative treatment based on monoclonal antibodies should not exclusively target the viral pentamer complex but also gB. Our research was supported by NIAID RO1AI046657, R56AI21739 (L.P.), R44AI102396 (L.K.); and DFG ZY110/1-1 (M.Z.).

Martin Zydek (Primary Presenter), martin.zydek@ucsf.edu;
Postdoctoral fellow interested in molecular virology of CMV infection.

ASHA DISCLOSURE:

Financial - No relevant financial relationship exist.

Nonfinancial - No relevant nonfinancial relationship exist.

Takako Tabata (Co-Presenter), takako.tabata@ucsf.edu;
Researcher at UCSF.

ASHA DISCLOSURE:

Financial -

Nonfinancial -

Matthew Petitt (Co-Presenter), matthew.petitt@ucsf.edu;
Researcher in cell biology of the human placenta and HCMV replication

ASHA DISCLOSURE:

Financial -

Nonfinancial -

June Fang-Hoover (Co-Presenter), june.fang-hoover@ucsf.edu;
Researcher in congenital HCMV infection in the human placenta

ASHA DISCLOSURE:

Financial -

Nonfinancial -

Lawrence M Kauvar (Co-Presenter), lkauvar@trellisbio.com;
Larry Kauvar, PhD is a serial entrepreneur scientist who founded Trellis Bioscience where he serves as Senior VP, Chief Scientific Officer. He was previously the founder and Chief Scientific Officer of Telik, a public development stage small molecule drug company focused on oncology, and is a co-founder of Promedior, a private development stage biologics company focused on fibrotic diseases. He holds 60 US patents for drug discovery methods and tools as well as specific compounds. He is one of the inventors of CellSpot™, Trellis' core technology for discovery of native human monoclonal antibodies. Dr. Kauvar received his undergraduate degree in mathematics from Harvard in 1973, his PhD from Yale in Molecular Biophysics and Biochemistry in 1978, and conducted postdoctoral research at Caltech and UC San Francisco before founding Telik.

ASHA DISCLOSURE:

Financial - Receives Salary,Ownership interest for Employment,Management position,Board membership,Ownership from Trellis Bioscience.  

Nonfinancial - No relevant nonfinancial relationship exist.

Lenore Pereira (Co-Presenter), lenore.pereira@ucsf.edu;
My laboratory focuses on the biology of HCMV infection in the developing human placenta and its function as a conduit for virus transmission. Supported by NIAID for 14 years, our focus includes: (1) natural protective immune responses that suppress intrauterine viral replication and transmission by analyzing placentas and maternal sera at delivery from HCMV-complicated pregnancies, (2) studies in a villous explant model for characterizing patterns of HCMV replication in early gestation placentas based on differentially expressed receptors, 3) serological diagnosis of infection and transmission from analysis of placentas at delivery, and (4) quantitative studies showing the potential for anti-HCMV neutralizing antibodies to reduce infection in explants of human placental villi and xenografts in Scid-hu mouse model. We are committed to increasing clinical awareness of congenital HCMV infection through translational studies of infected human placentas, emphasis on the value of prenatal serodiagnosis and necessity for screening all newborns for congenital infection.

ASHA DISCLOSURE:

Financial - Receives Ownership interest for Ownership from Trellis Biosciences.  

Nonfinancial - No relevant nonfinancial relationship exist.

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