Controversies in the natural history of congenital human cytomegalovirus infection: the paradox of infection and disease in offspring of women with immunity prior to pregnancy

Britt, William J.

doi:10.1007/s00430-015-0399-9

Cited by 83 publications

(54 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The source of the multiple strains of patients in this study is unknown. Nonprimary maternal infections are increasingly recognized as important contributors to HCMV in utero transmission (71), accounting for up to 75% of HCMV congenital infections in the United States (72). Future investigation studying the natural history of HCMV infections, including viral population demographics of single and mixed strain infections, would allow for a much better quantification of the timing and dynamics of in utero mixed infections.…”

Section: Discussionmentioning

confidence: 99%

Limits and patterns of cytomegalovirus genomic diversity in humans

Renzette

Pokalyuk

Gibson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

113

129

View full text Add to dashboard Cite

Human cytomegalovirus (HCMV) exhibits surprisingly high genomic diversity during natural infection although little is known about the limits or patterns of HCMV diversity among humans. To address this deficiency, we analyzed genomic diversity among congenitally infected infants. We show that there is an upper limit to HCMV genomic diversity in these patient samples, with ∼25% of the genome being devoid of polymorphisms. These low diversity regions were distributed across 26 loci that were preferentially located in DNA-processing genes. Furthermore, by developing, to our knowledge, the first genome-wide mutation and recombination rate maps for HCMV, we show that genomic diversity is positively correlated with these two rates. In contrast, median levels of viral genomic diversity did not vary between putatively single or mixed strain infections. We also provide evidence that HCMV populations isolated from vascular compartments of hosts from different continents are genetically similar and that polymorphisms in glycoproteins and regulatory proteins are enriched in these viral populations. This analysis provides the most highly detailed map of HCMV genomic diversity in human hosts to date and informs our understanding of the distribution of HCMV genomic diversity within human hosts.human cytomegalovirus | HCMV | congenital CMV | virology | evolution

show abstract

Section: Discussionmentioning

confidence: 99%

Limits and patterns of cytomegalovirus genomic diversity in humans

Renzette

Pokalyuk

Gibson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

113

129

View full text Add to dashboard Cite

show abstract

“…The mechanism by which HCMV is involved in the occurrence of RE is not well understood. HCMV and other viruses detected in RE brain tissues are highly prevalent in the general population (Britt, 2015;Looker et al, 2015). Since the average age of seizure onset in patients with RE was 5.8 years, we speculated that congenital and/or neonatal HCMV infections occurred in patients with RE.…”

Section: Discussionmentioning

confidence: 99%

“…HCMV pp65 is the most abundant virion matrix protein and is often used as an indicator of HCMV infection. HCMV was found to have a 70%-90% prevalence in the general population and persists for the lifetime of the host after primary infection (Britt, 2015). Approximately 30% of pregnant women experiencing primary HCMV infection will transmit the virus to their developing fetuses during some stage of pregnancy, resulting in a congenital HCMV infection rate of 1%-7% at birth (Manicklal et al, 2013;Britt, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…HCMV was found to have a 70%-90% prevalence in the general population and persists for the lifetime of the host after primary infection (Britt, 2015). Approximately 30% of pregnant women experiencing primary HCMV infection will transmit the virus to their developing fetuses during some stage of pregnancy, resulting in a congenital HCMV infection rate of 1%-7% at birth (Manicklal et al, 2013;Britt, 2015). Congenital HCMV infection may either be asymptomatic or cause hearing impairment, mental retardation, cerebral palsy, and neuron developmental disabilities (Manicklal et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Expression of human cytomegalovirus components in the brain tissues of patients with Rasmussen’s encephalitis

et al. 2017

View full text Add to dashboard Cite

Rasmussen's encephalitis (RE) is a rare and severe progressive epileptic syndrome with unknown etiology. Infection by viruses, including human cytomegalovirus (HCMV), has been speculated to be a potential trigger for RE. However, no viral antigens have been detected in the brains of patients with RE; thus, a possible clinical linkage between viral infections and RE has not been firmly established. In this study, we evaluated the expression of HCMV pp65 antigen in brain sections from 26 patients with RE and 20 non-RE patients by immunohistochemistry and in situ hybridization, and assessed the associations between HCMV infection and clinical parameters. Elevated expression of HCMV pp65 protein and DNA was observed in 88.5% (23/26) and 69.2% (18/26) of RE cases, respectively. In the non-RE group, HCMV pp65 antigen was detected only in two cases (10%), both of which were negative for DNA staining. Additionally, the intensity of HCMV pp65 staining was correlated with a shorter duration of the prodromal stage, younger age of seizure onset, and more severe unilateral cortical atrophy. Elevated expression of HCMV pp65 was observed in RE brain tissue and was correlated with the clinical features of RE disease. In summary, our results suggested that HCMV infection may be involved in the occurrence and progression of RE disease. Thus, further studies are needed to determine whether early treatment with anti-HCMV antibodies could modulate the course of RE.

show abstract

“…Congenital HCMV infection is a leading cause of fetal abnormalities, which most commonly results in microcephaly, intellectual impairment, sensorineural hearing loss, and, in rare cases, even death and multiorgan failure (2,6). Permanent birth defects are associated more frequently with congenital HCMV infection than with other well-known childhood diseases, including trisomy 21, spina bifida, or fetal alcohol syndrome (2,5,(7)(8)(9). Given the medical, societal, and economical benefits for the human population that would result from an effective HCMV vaccine, the Institute of Medicine assessed HCMV vaccine development as a major public health priority.…”

mentioning

confidence: 99%

Identification of a Continuous Neutralizing Epitope within UL128 of Human Cytomegalovirus

Chiuppesi

Kaltcheva

Zhao

et al. 2017

J Virol

View full text Add to dashboard Cite

As human cytomegalovirus (HCMV) is the most common infectious cause of fetal anomalies during pregnancy, development of a vaccine that prevents HCMV infection is considered a global health priority. Although HCMV immune correlates of protection are only poorly defined, neutralizing antibodies (NAb) targeting the envelope pentamer complex (PC) composed of the subunits gH, gL, UL128, UL130, and UL131A are thought to contribute to the prevention of HCMV infection. Here, we describe a continuous target sequence within UL128 that is recognized by a previously isolated potent PC-specific NAb termed 13B5. By using peptide-based scanning procedures, we identified a 13-amino-acid-long target sequence at the UL128 C terminus that binds the 13B5 antibody with an affinity similar to that of the purified PC. In addition, the 13B5 binding site is universally conserved in HCMV, contains a previously described UL128/gL interaction site, and interferes with the 13B5 neutralizing function, indicating that the 13B5 epitope sequence is located within the PC at a site of critical importance for HCMV neutralization. Vaccination of mice with peptides containing the 13B5 target sequence resulted in the robust stimulation of binding antibodies and, in a subset of immunized animals, in the induction of detectable NAb, supporting that the identified 13B5 target sequence constitutes a PC-specific neutralizing epitope. These findings provide evidence for the discovery of a continuous neutralizing epitope within the UL128 subunit of the PC that could be an important target of humoral immune responses that are involved in protection against congenital HCMV infection.IMPORTANCE Neutralizing antibodies (NAb) targeting the human cytomegalovirus (HCMV) envelope pentamer complex (PC) are thought to be important for preventing HCMV transmission from the mother to the fetus, thereby mitigating severe developmental disabilities in newborns. However, the epitope sequences within the PC that are recognized by these potentially protective antibody responses are only poorly defined. Here, we provide evidence for the existence of a highly conserved, continuous, PC-specific epitope sequence that appears to be located within the PC at a subunit interaction site of critical importance for HCMV neutralization. These discoveries provide insights into a continuous PC-specific neutralizing epitope, which could be an important target for a vaccine formulation to interfere with congenital HCMV infection.

show abstract

Controversies in the natural history of congenital human cytomegalovirus infection: the paradox of infection and disease in offspring of women with immunity prior to pregnancy

Cited by 83 publications

References 64 publications

Limits and patterns of cytomegalovirus genomic diversity in humans

Limits and patterns of cytomegalovirus genomic diversity in humans

Expression of human cytomegalovirus components in the brain tissues of patients with Rasmussen’s encephalitis

Identification of a Continuous Neutralizing Epitope within UL128 of Human Cytomegalovirus

Contact Info

Product

Resources

About