Human cytomegalovirus (HCMV) infection represents the most common viral infection transmitted in-utero and is a significant cause of neurodevelopmental disorders in children. The rate of congenital HCMV infection ranges from 0.2-1.0% of live births in the US and exceeds 1% in many parts of the world. Although maternal infection during pregnancy (primary maternal infection) represents a significant risk for virus transmission to the fetus and disease, infection and transmission to the fetus in women with existing immunity to this virus (non-primary maternal infection) is frequent. Disease in babies infected following non-primary maternal infection is well documented. Worldwide, including most US populations, the disease burden in infected infants born to women with non-primary infections exceeds that of offspring of women with primary maternal infection. In this proposal we will explore two mechanisms of non-primary maternal infections, reinfection with new strain of viruses and recurrence/reactivation of a persistent infection. Our goals are to define virological characteristics of non-primary infections and parameters of HCMV specific immunity in a highly seroimmune population in which non-primary maternal infections account for the vast majority of infected babies. We will also determine the incidence of the most common long term sequelae of congenital HCMV infection, hearing loss, in infected babies. We anticipate these studies will help identify host responses associated with intrauterine transmission and damaging fetal infections in this population of women with non-primary infection and could aid in the rationale development of effective prophylactic and possibly therapeutic vaccines to limit the morbidity from this congenital infection.

Public Health Relevance

This project will investigate the characteristics of human cytomegalovirus infection in a population of women in which over 98% have immunity to this virus. Even in the presence of immunity, these women still transmit virus to their developing offspring and about 10% of infected babies develop hearing loss, the most common sequelae of this congenital infection. Current vaccine strategies will not prevent this type of congenital infection and in almost every part of the world, including the US, infected infants born to immune mothers represent the largest contribution to the overall disease burden of this infection. Our goals are to elucidate the mechanisms responsible for transmission of virus in these immune women in order to more rationally design strategies that could prevent infection of the developing fetus with this virus.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD061959-10
Application #
8705911
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Reddy, Uma M
Project Start
2011-09-15
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Renzette, Nicholas; Kowalik, Timothy F; Jensen, Jeffrey D (2016) On the relative roles of background selection and genetic hitchhiking in shaping human cytomegalovirus genetic diversity. Mol Ecol 25:403-13
Renzette, Nicholas; Pokalyuk, Cornelia; Gibson, Laura et al. (2015) Limits and patterns of cytomegalovirus genomic diversity in humans. Proc Natl Acad Sci U S A 112:E4120-8
Chiuppesi, Flavia; Wussow, Felix; Johnson, Erica et al. (2015) Vaccine-Derived Neutralizing Antibodies to the Human Cytomegalovirus gH/gL Pentamer Potently Block Primary Cytotrophoblast Infection. J Virol 89:11884-98
Ross, Shannon A; Ahmed, Amina; Palmer, April L et al. (2014) Detection of congenital cytomegalovirus infection by real-time polymerase chain reaction analysis of saliva or urine specimens. J Infect Dis 210:1415-8
Hook, Lauren M; Grey, Finn; Grabski, Robert et al. (2014) Cytomegalovirus miRNAs target secretory pathway genes to facilitate formation of the virion assembly compartment and reduce cytokine secretion. Cell Host Microbe 15:363-73
Dreher, A Mackenzie; Arora, Nitin; Fowler, Karen B et al. (2014) Spectrum of disease and outcome in children with symptomatic congenital cytomegalovirus infection. J Pediatr 164:855-9
Renzette, Nicholas; Gibson, Laura; Jensen, Jeffrey D et al. (2014) Human cytomegalovirus intrahost evolution-a new avenue for understanding and controlling herpesvirus infections. Curr Opin Virol 8:109-15
Smith, Phillip D; Shimamura, Masako; Musgrove, Lois C et al. (2014) Cytomegalovirus enhances macrophage TLR expression and MyD88-mediated signal transduction to potentiate inducible inflammatory responses. J Immunol 193:5604-12
Hook, Lauren; Hancock, Meaghan; Landais, Igor et al. (2014) Cytomegalovirus microRNAs. Curr Opin Virol 7:40-6
Xiaofei, E; Kowalik, Timothy F (2014) The DNA damage response induced by infection with human cytomegalovirus and other viruses. Viruses 6:2155-85

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