Birth Prevalence and Natural History of Congenital Cytomegalovirus Infection in a Highly Seroimmune Population

Mussi-Pinhata, Marisa Márcia; Yamamoto, Aparecida Yulie; Brito, Rosangela Moura; Isaac, Myriam de Lima; Oliveira, Patrícia Frizo de Carvalho e; Boppana, Suresh B.; Britt, William J.

doi:10.1086/600882

Cited by 247 publications

(204 citation statements)

References 48 publications

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“…The incidence of congenital HCMV infection does, however, correlate with HCMV seroprevelance. 82,[88][89][90] Consequently, non-primary infections caused by either re-infection of, or reactivation in, HCMV seropositive mothers are also likely to be a cause of congenital infection, despite preformed HCMV-specific maternal antibodies. Although the relative contribution of virus reactivation or reinfection to congenital infections is not clear, 91 prevention of infection in either scenario would be beneficial.…”

Section: Is Immune Targeting Of Latently Infected Cells Possible and mentioning

confidence: 99%

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

et al. 2014

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While the host immune response following primary human cytomegalovirus (HCMV) infection is generally effective at stopping virus replication and dissemination, virus is never cleared by the host and like all herpesviruses, persists for life. At least in part, this persistence is known to be facilitated by the ability of HCMV to establish latency in myeloid cells in which infection is essentially silent with, importantly, a total lack of new virus production. However, although the viral transcription programme during latency is much suppressed, a number of viral genes are expressed during latent infection at the protein level and many of these have been shown to have profound effects on the latent cell and its environment. Intriguingly, many of these latency-associated genes are also expressed during lytic infection. Therefore, why the same potent host immune responses generated during lytic infection to these viral gene products are not recognized during latency, thereby allowing clearance of latently infected cells, is far from clear. Reactivation from latency is also a major cause of HCMV-mediated disease, particularly in the immune compromised and immune naive, and is also likely to be a major source of virus in chronic subclinical HCMV infection which has been suggested to be associated with long-term diseases such as atherosclerosis and some neoplasias. Consequently, understanding latency and why latently infected cells appear to be immunoprivileged is crucial for an understanding of the pathogenesis of HCMV and may help to design strategies to eliminate latent virus reservoirs, at least in certain clinical settings.

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Section: Is Immune Targeting Of Latently Infected Cells Possible and mentioning

confidence: 99%

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

et al. 2014

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“…8 Primary maternal infection in the first and second trimester carries a 30% to 38% rate of transmission and the greatest risk of disease, 9,10 whereas babies infected in the third trimester (72%) are usually asymptomatic, 9 but progressive hearing loss can occur. 11,12 Diagnosis of virus transmission entails detection of HCMV DNA; however, high viral load in amniotic fluid does not correlate with poor outcome. 13e17 In contrast to the vascular chorionic membrane, 18 the amniotic membrane is an avascular structure lined with epithelial cells bathed in amniotic fluid that surrounds the fetus.…”

mentioning

confidence: 99%

Persistent Cytomegalovirus Infection in Amniotic Membranes of the Human Placenta

Tabata

Petitt

Fang-Hoover

et al. 2016

The American Journal of Pathology

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Human cytomegalovirus (HCMV) is the leading viral cause of birth defects, including microcephaly, neurological deficits, hearing impairment, and vision loss. We previously reported that epithelial cells in amniotic membranes of placentas from newborns with intrauterine growth restriction and underlying congenital HCMV infection contain viral proteins in cytoplasmic vesicles. Herein, we immunostained amniotic membranes from 51 placentas from symptomatic and asymptomatic congenital infection with HCMV DNA in amniotic fluid and/or newborn saliva, intrauterine growth restriction, preterm deliveries, and controls. We consistently observed HCMV proteins in amniotic epithelial cells (AmEpCs) from infected placentas, sometimes with aberrant morphology. Primary AmEpCs isolated from mid-gestation placentas infected with pathogenic VR1814 proliferated and released infectious progeny for weeks, producing higher virus titers than late-gestation cells that varied by donor. In contrast to intact virion assembly compartments in differentiated retinal pigment epithelial cells, infected AmEpCs made dispersed multivesicular bodies. Primary AmEpCs and explants of amniochorionic membranes from midgestation placentas formed foci of infection, and interferon-b production was prolonged. Infected AmEpCs up-regulated anti-apoptotic proteins survivin and Bcl-x L by mechanisms dependent and independent of the activated STAT3. Amniotic membranes naturally expressed both survivin and Bcl-x L , indicating that fetal membranes could foster persistent viral infection. Our results suggest strengthening innate immune responses and reducing viral functions could suppress HCMV infection in the fetal compartment. (Am J Pathol 2016 http://dx

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“…30,49,50 Clearly, hand washing would not be expected to prevent congenital diseases that follow a pattern of reactivation or long-term infections with multiple virus strains that reactivate independently during pregnancy. Antiviral chemotherapy with ganciclovir in newborns provides a benefit in severe cytomegalic inclusion disease; however, it does not reverse damage or impact progressive diseases, such as hearing loss.…”

Section: Infection and Disease Preventionmentioning

confidence: 99%

The immunological underpinnings of vaccinations to prevent cytomegalovirus disease

McCormick

Mocarski

2014

Cell Mol Immunol

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A universal cytomegalovirus (CMV) vaccination promises to reduce the burden of the developmental damage that afflicts up to 0.5% of live births worldwide. An effective vaccination that prevents transplacental transmission would reduce CMV congenital disease and CMV-associated still births and leave populations less susceptible to opportunistic CMV disease. Thus, a vaccination against this virus has long been recognized for the potential of enormous health-care savings because congenital damage is life-long and existing anti-viral options are limited. Vaccine researchers, industry leaders, and regulatory representatives have discussed the challenges posed by clinical efficacy trials that would lead to a universal CMV vaccine, reviewing the links between infection and disease, and identifying settings where disrupting viral transmission might provide a surrogate endpoint for disease prevention. Reducing the complexity of such trials would facilitate vaccine development. Children and adolescents are the targets for universal vaccination, with the expectation of protecting the offspring of immunized women. Given that a majority of females worldwide experience CMV infection during childhood, a universal vaccine must boost natural immunity and reduce transmission due to reactivation and re-infection as well as primary infection during pregnancy. Although current vaccine strategies recognize the value of humoral and cellular immunity, the precise mechanisms that act at the placental interface remain elusive. Immunity resulting from natural infection appears to limit rather than prevent reactivation of latent viruses and susceptibility to re-infection, leaving a challenge for universal vaccination to improve upon natural immunity levels. Despite these hurdles, early phase clinical trials have achieved primary end points in CMV seronegative subjects. Efficacy studies must be expanded to mixed populations of CMV-naive and naturally infected subjects to understand the overall efficacy and potential. Together with CMV vaccine candidates currently in clinical development, additional promising preclinical strategies continue to come forward; however, these face limitations due to the insufficient understanding of host defense mechanisms that prevent transmission, as well as the age-old challenges of reaching the appropriate threshold of immunogenicity, efficacy, durability and potency. This review focuses on the current understanding of natural and CMV vaccine-induced protective immunity.

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Birth Prevalence and Natural History of Congenital Cytomegalovirus Infection in a Highly Seroimmune Population

Cited by 247 publications

References 48 publications

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

Persistent Cytomegalovirus Infection in Amniotic Membranes of the Human Placenta

The immunological underpinnings of vaccinations to prevent cytomegalovirus disease

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