Repurposed drug effective for Zika virus

In both cell cultures and mouse models, a drug used to treat Hepatitis C effectively protected and rescued neural cells infected by the Zika virus and blocked transmission of the virus to mouse fetuses. Researchers at University of California San Diego School of Medicine, with colleagues in Brazil and elsewhere, say their findings support further investigation of using the repurposed drug as a potential treatment for Zika-infected adults, including pregnant women.

 Zika infection during the first trimester confers the greatest risk of congenital microcephaly. Outbreaks of Zika virus in Brazil in 2015 and 2016 were marked by an increased incidence of newborns with congenital malformations, most notably undersized heads (microcephaly) and significant neurological abnormalities.

A great deal of research has focused on the pathology of Zika infections, including earlier work by the Muotri lab and collaborators that described how the virus is transmitted from mother to fetus by infecting cells that, ironically, will later develop into the brain's first and primary form of defense against invasive pathogens.

In its latest work, however, the Muotri lab sought clinical solutions. The team investigated an antiviral drug called sofosbuvir, approved and marketed under the brand name Sovaldi to treat and cure hepatitis C infections. The drug works by inhibiting replication of the hepatitis C virus; researchers noted that both hepatitis C and Zika belong to the same viral family and bore strong structural similarities that could make sofosbuvir effective against the latter. In addition, it had been reported that sofosbuvir was protective against Zika in different cell types.

In tests using human neural progenitor cells (NPCs)-self-renewing, multipotent cells that generate neurons and other brain cell types-the scientists found that exposure to sofosbuvir not only rescued dying NPCs infected with the Zika virus, but restored gene expression linked to their antiviral response. In subsequent tests using an immunodeficient mouse model infected by Zika, intravenous injections of sofosbuvir significantly reduced viral loads in blood serum compared to a placebo group.

Fetuses of Zika-infected pregnant mice did not show detectable Zika virus amplification in the sofosbuvir-treated group. This shows that the drug was well-tolerated by the Zika-infected pregnant mice and that it was able to arrest Zika replication in vivo and stop transmission from mother to fetus.
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How Zika virus infects developing brain

Zika virus is transmitted from mother to fetus by infected cells that later develop into the brain's first and primary form of defense against invasive pathogens. During embryogenesis- the early stages of prenatal development cells called microglia form in the yolk sac and then disperse throughout the central nervous system CNS of the developing fetus.

In the brain, these microglia will become resident macrophages whose job is to constantly clear away plaques, damaged cells and infectious agents. The Zika virus can infect these early microglia, moving into the brain where they transmit the virus to other brain cells, leading to devastating neurological damage.

The Zika virus is transmitted to people through the bite of infected Aedes species mosquitoes. However, a pregnant woman can also pass the virus to her fetus, the researchers used human induced pluripotent stem cells to create two relevant CNS cell types: microglia and neural progenitor cells (NPCs), which generate the millions of neurons and glial cells required during embryonic development.

Then they established a co-culture system that mimicked the interactions of the two cell types in vitro when exposed to the Zika virus. They discovered that the microglia cells engulfed Zika-infected NPCs, doing their job. But when these microglia carrying the virus were placed in contact with non-infected NPCs, they transmitted the virus to the latter.
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