Research points to potential window for treating CMV and preventing mother-to-child transmission

October 30, 2013

New insights into how human cytomegalovirus (CMV), the leading cause of birth defects associated with infection spreads from pregnant mother to fetus and from organ to organ in newborns provides translational researchers an exciting new avenue for investigation that may lead to the development of therapeutic interventions. Using next generation sequencing and population genetic modeling, scientists at the University of Massachusetts Medical School (UMMS) and the Ecole Polytechnique Fédérale de Lausanne (EPFL) have found that CMV evolves rapidly and dramatically in humans. These findings, published in PLoS Genetics, provide new genetic targets that could impede the evolution of CMV and prevent its spread.

"These findings have important implications for how we think about and develop new therapeutic treatments for CMV," said Timothy F. Kowalik, PhD, associate professor of microbiology and physiological systems and senior author of the study. "Although CMV is able to infect a wide variety of organs throughout the body, there are a substantial number of that occur before the virus can spread and replicate efficiently in different anatomic niches. If these genetic changes can be prevented, it may be possible to isolate and block the spread of CMV."

CMV is a ubiquitous virus that infects most of the human population and can move throughout the body from organ to organ. Infection is usually asymptomatic in healthy hosts, but may cause severe symptoms for patients with a compromised immune system, such as organ transplant recipients, HIV-infected persons, newborn infants or the fetus during gestation.

Congenital CMV , which is passed from a pregnant mother to fetus, is a significant cause of , and remains a high priority for vaccine development according to the nonprofit, Institute of Medicine. An estimated 30,000 infants per year in the U.S. are diagnosed with congenital CMV infection, and nearly 20 percent exhibit permanent neurologic effects such as hearing loss or developmental delay.

To better understand how CMV evolves in fetuses and newborns during symptomatic congenital infection, researchers at UMMS and the University of Minnesota Medical School collected samples from the plasma and urine of five congenitally infected infants during the first year after birth. Using next generation DNA sequencing, Kowalik and colleagues studied the diversity and changes in viral DNA sequences over time and between organs. Though the DNA sequences from viruses taken from the same type of sample (e.g. plasma) were similar to each other, the study's authors found dramatic differences between the sequences collected from viruses in the plasma and urine of the same infant. Surprisingly, the plasma and urine sequences from the same infant were as different as sequences from two unrelated infants.

These results suggest that CMV is able to evolve very quickly as the differences between the plasma and urine sequences likely occurred in the short period between the initial, in utero infection, and the first year after birth. However, the mechanism driving this phenomenon remained unclear.

To answer this question, researchers used mathematical modeling and statistical inference to uncover evidence that population bottlenecks and expansions may play a significant role in the virus' evolution after infection. Characterized by a substantial reduction in viral copies followed by a quick rebound, population bottlenecks and expansions can lead to dramatic changes in DNA sequences that result in two related populations quickly becoming dissimilar. In the case of CMV infection, this phenomenon appeared to coincide with the virus moving from the mother to the fetus and later migrating from the plasma to the kidneys.

The model also suggests that the timing of initial fetal infection in the patients was at 13 to 18 weeks gestational age, while viral spread from blood to the kidneys occurred about 11 weeks later. "This timing," said Kowalik, "may provide an important window for treating CMV when it is most vulnerable and before it can evolve and spread."

Additional study showed that natural selection, the process through which certain advantageous biological traits become more common, results in as much as 20 percent of the viral genes changing as it moved from one biological niche to another. "Not surprisingly, the genes impacted by this selection process affect several viral functions involved in dissemination, including viral replication in distinct cell types and evasion of the host immune response, and are required to allow the virus to move to and replicate efficiently in different organs," said lead author of the study, Nicholas Renzette, PhD, a postdoctoral fellow at UMMS.

This new understanding of how CMV adapts and evolves after infection provides researchers with potential targets for treating the disease, said Kowalik. "This work shows that CMV infection spreads during a relatively small window during gestation, suggesting an opportunity for preventative treatments," he said. "Furthermore, the delay between initial fetal infection and dissemination to the kidneys, may present a window for stopping spread of the throughout the body, thereby preventing symptoms of infection, such as hearing loss."

The next step for Renzette, Kowalik and colleagues is to determine which genetic changes associated with immune responses to infection may be amendable to potential treatments.

Explore further: Novel vaccine approach to human cytomegalovirus found effective

Related Stories

Novel vaccine approach to human cytomegalovirus found effective

September 18, 2013
An experimental vaccine against human cytomegalovirus (CMV) infection, which endangers the developing fetus, organ transplant recipients, patients with HIV and others who have a weakened immune system, proved safe and more ...

Test approved to help treat common infection in transplant patients

July 5, 2012
(HealthDay) -- The first DNA test to help doctors treat a common viral infection in people who have had a solid organ transplant has been approved by the U.S. Food and Drug Administration.

Novel drug prevents common viral disease in stem-cell transplant patients, study finds

September 25, 2013
A new drug can often prevent a common, sometimes severe viral disease in patients receiving a transplant of donated blood-making stem cells, a clinical trial led by researchers at Dana-Farber Cancer Institute and Brigham ...

Pregnacy virus warning

June 21, 2011
A virus that causes hearing loss and intellectual disabilities in infants is being underdiagnosed, according to UNSW researchers, who are calling for routine screening for all pregnant women and newborns.

Study identifies powerful infection strategy of widespread and potentially lethal virus

December 20, 2012
Scientists at the Gladstone Institutes have mapped the molecular mechanism by which a virus known as cytomegalovirus (CMV) so successfully infects its hosts. This discovery paves the way for new research avenues aimed at ...

CMV-linked eye infections ID'd in patients without HIV

March 18, 2013
(HealthDay)—Cytomegalovirus (CMV)-associated posterior uveitis or panuveitis can develop in patients without HIV infection, most of whom have evidence of compromised immune function, according to a study published online ...

Recommended for you

Genome editing reveals role of gene important for human embryo development

September 20, 2017
Researchers have used genome editing technology to reveal the role of a key gene in human embryos in the first few days of development. This is the first time that genome editing has been used to study gene function in human ...

A piece of the puzzle: Eight autism-related mutations in one gene

September 19, 2017
Scientists have identified a hotspot for autism-related mutations in a single gene.

Scientists identify key regulator of male fertility

September 19, 2017
When it comes to male reproductive fertility, timing is everything. Now scientists are finding new details on how disruption of this timing may contribute to male infertility or congenital illness.

New assay leads to step toward gene therapy for deaf patients

September 18, 2017
Scientists at Oregon State University have taken an important step toward gene therapy for deaf patients by developing a way to better study a large protein essential for hearing and finding a truncated version of it.

Biologists identify gene involved in kidney-related birth defects

September 18, 2017
A team led by University of Iowa researchers has identified a gene linked to rare, often fatal kidney-related birth defects.

Genomic recycling: Ancestral genes take on new roles

September 18, 2017
One often hears about the multitude of genes we have in common with chimps, birds or other living creatures, but such comparisons are sometimes misleading. The shared percentage usually refers only to genes that encode instructions ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.