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9/26/2014  |   2:15 PM - 2:45 PM   |  Topical Session 3   |  Ballroom B

Diagnosis of underlying congenital HCMV infection in cases of idiopathic intrauterine growth restriction and rescue of placental development by monoclonal antibodies and hyperimmune globulin

Mechanisms of transplacental transmission of human cytomegalovirus (HCMV), the leading viral cause of congenital infection and birth defects in the U.S. are largely unknown. Transmission is high (30-40%) when primary maternal infection occurs in the first trimester, and symptomatic babies have permanent birth defects. Recurrent infection is infrequently transmitted (2%) and generally asymptomatic. We reported a pilot study of pregnancies complicated by idiopathic intrauterine growth restriction (IUGR) and underlying congenital HCMV infection (J Infect Dis, 2014). Serology of maternal and cord blood and analysis of placental biopsy specimens for pathology and expression of viral proteins were performed. Among 7 IUGR cases, we identified 2 primary and 3 recurrent infections. Virus replicated in the decidua, cytotrophoblasts and blood vessels of floating villi. Fibrinoids, avascular villi, edema and inflammation were significantly increased. Detection of HCMV proteins in epithelial cells of the amnion indicated transmission in cases of IUGR with primary infection and recurrent infections. Having found HCMV proteins in trophoblast progenitor cells (TBPCs) in the chorion and amniotic epithelial cells (AECs) in the amnion in cases of symptomatic congenital infection, we conducted studies of these cells in vitro. We found that TBPCs are permissive and mAbs to gB blocked infection more potently than hyperimmune globulin (HIG) whereas antibodies to the viral pentamer complex did not. In dramatic contrast, only pathogenic HCMV strains infected AECs and mAbs to the pentamer had the most potent neutralizing activity. These results suggested that congenital HCMV infection and transmission can be diagnosed by detecting viral proteins in placental specimens, in particular the amniotic epithelium. In vitro studies suggest that a cocktail of anti-gB and anti-pentamer mAbs could effectively rescue the developing placenta from infection, reduce transmission and prevent congenital disease. Together these findings have important implications for vaccine development. Supported by NIAID RO1AI046657, R56AI21739 (L.P.), R44AI102396 (L.K.)

Lenore Pereira (Primary 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.

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

ASHA DISCLOSURE:

Financial - No relevant financial relationship exist.

Nonfinancial - No relevant nonfinancial relationship exist.

Martin Zydek (Co-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.

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

ASHA DISCLOSURE:

Financial - No relevant financial relationship exist.

Nonfinancial - No relevant nonfinancial relationship exist.

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

ASHA DISCLOSURE:

Financial - No relevant financial relationship exist.

Nonfinancial - No relevant nonfinancial relationship exist.

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.   Receives Salary,Consulting fee,Ownership interest for Employment,Management position,Board membership,Ownership from Trellis Bioscience.  

Nonfinancial - No relevant nonfinancial relationship exist.

Presentation:
164LenorePereira.pdf

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