Semen protects genital cells from Zika virus infection

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The paper in Nature Communications is here:

In 2015, Brazil was struck by a sudden and unexpected outbreak of Zika virus (ZIKV) that infected more than one million people and further spread throughout the Americas. The virus was previously known to occasionally infect humans causing none or only mild symptoms. During the recent outbreaks, however, virus infection was associated with severe neurological diseases like myelitis and encephalitis or the rapid-onset muscle weakness Guillain-Barrée syndrome. Infections during pregnancy revealed to be most devastating, increasing the risk of developmental defects in the newborns resulting in microcephaly or even miscarriages. This prompted the World Health Organization to constitute a Public Health Emergency of International Concern to increase surveillance of this fast spreading virus. Its rapid spread within large populations was fueled by the presence of Aedes mosquitos that efficiently transmit the virus. Untypically, there were cases (predominantly recorded in countries outside the Americas) in which ZIKV was also transmitted from human to human via sexual intercourse. This mode of spread would allow the virus to expand into areas where the mosquitos are not present, and could potentially pose the risk of direct transmission to the fetus of an expecting mother.

In our Institute, we are interested in the sexual transmission of viruses. Our work with the human immunodeficiency virus (HIV), the virus that predominantly spreads via sexual intercourse, has shown that the male body fluid semen enhances HIV infection rates. This enhancing activity can be attributed to amyloid fibrils in semen and might increase the efficiency of sexual HIV transmission. In symptomatic and asymptomatic ZIKV-infected male individuals, virus loads in semen can be exceedingly high and viral RNA has been detected in semen for more than 6 months after infection. Therefore, we asked the question whether semen might as well influence ZIKV infection and thus sexual transmission.

To our surprise, we found that semen and seminal plasma (semen devoid of spermatocytes) protected cells from infection by ZIKV (Figure 1). When assessing the effect of semen on HIV and ZIKV in parallel, HIV infection rates increase dramatically whereas ZIKV infection is hardly detectable. Interestingly, we observed similar inhibition of Dengue and West Nile viruses which belong to the same family (flaviviruses) as ZIKV. Further analyses revealed that semen prevents the attachment of ZIKV to target cells. The factor responsible for this anti-ZIKV effect is not of protein origin but is retained in an extracellular vesicle preparation from semen. Extracellular vesicles are commonly found in body fluids and are present in semen at high concentrations where they are involved in a plethora of functions.

We further analyzed whether ZIKV is able to infect cells that are exposed during sexual intercourse. All tested cells from the female and male reproductive tract and tissues from the vagina or endometrium were infected by ZIKV and produced viral offspring. Thus, these cells could serve as target cells allowing human to human ZIKV transmission. However, when these experiments were done in the presence of semen, the measured infection rates were drastically decreased and the amount of produced progeny virus in the tissues was significantly reduced.

Overall, our work suggests that the female and male genital tract is susceptible to ZIKV infection during sexual intercourse. High virus levels in semen might represent a risk of transmission, however, this bioactive body fluid contains an entity in the extracellular vesicle fraction that potently inhibits flavivirus infection. This could explain the very limited spread of ZIKV via the sexual route (and the absence of sexual transmission of other mosquito-transmitted flaviviruses). Such an inefficient transmission renders ZIKV unlikely to spread in a self-sustained way as a sexually transmitted pathogen into countries without mosquitos as a vector. Importantly, this study emphasizes the relevance of analyzing sexual transmission in the context of naturally present biological fluids, and highlights the different roles semen can play in the enhancement of HIV and inhibition of ZIKV during the sexual transmission. We are currently investigating the nature of the responsible factor to learn more about the ZIKV attachment, entry, inhibition, and potential antiviral applications.

Janis A Müller

Post-Doc, Institute of Molecular Virology