The Zika Virus-Expert Review

The Zika virus (ZIKV) is a mosquito-borne virus originally discovered in the Zika Forest area in Uganda in 1947. It was not considered a relevant pathogen for humans until the outbreaks of fever illness that occurred in the Pacific area in 2007, and later in 2013-14. However, it was its arrival and dramatic spread in Brazil and other Latin American and Caribbean countries that alarmed public health authorities and the scientific community. Increasing evidence pointed to a link between the Zika virus and foetal microcephaly and Guillain-Barré syndrome, a rare condition in which the immune system attacks the nerves. This prompted the World Health Organisation (WHO) to declare ZIKV a Public Health Emergency of International Concern on 1 February 2016. In response to this emergency, research on ZIKV was intensified, and within a few months, large amounts of data and outstanding results have been produced.

Zika virus belongs to the genus Flavivirus, which includes other vector-borne viruses, like dengue virus and West Nile virus. Phylogenetic analysis has shown a close genetic similarity of ZIKV with dengue virus and has identified viral strains of the Asian lineage as responsible for the current epidemics. The virus is predominantly transmitted between humans through the bite of an infected mosquito, most of the species Aedes aegypti, but other modes of transmission have been identified, including transplacental transmission between expectant mothers and their babies. Prolonged shedding of infectious virus in semen and in vaginal fluids and efficient viral replication in vaginal mucosa explain the ability of ZIKV to be transmitted sexually, a unique feature among flaviviruses. Recent experimental infection in mice also showed that the virus persistently infects peritubular cells and spermatogonia, induces inflammation in the testis and epididymis that leads to male infertility. Moreover, the virus was detected by immunohistochemistry in spermatozoa from a patient with acute infection.

Guillain-Barré syndrome was identified to be a very rare neurological complication, reported in about 1-3 out of 10,000 infections. The incidence of foetal demise, microcephaly, or other congenital anomalies is still unknown, and has been estimated to range from 1% to 20%, higher during the first trimester of pregnancy.

The structure of key ZIKV proteins has been characterized and could be exploited for the design of vaccines, therapeutic antibodies, and antiviral drugs. In vitro models and in vivo mouse and non-human primate models of ZIKV infection have been set up and used to investigate virus transmission, tropism, neural damage and teratogenicity, and to test the immunogenicity and efficacy of vaccines. These studies allowed us to clarify important mechanisms of ZIKV neuro-pathogenesis, such as the identification of neural progenitor cells and placental macrophages as targets for ZIKV infection in the human brain and in the placenta, and the demonstration that ZIKV efficiently counteracts the innate antiviral response in humans.

Similarly to other mosquito-borne viral infections, like West Nile fever and dengue fever, ZIKV disease is characterized by a mild fever, rash, and arthralgia, making it almost undistinguishable. Because of this, during the acute phase of infection, diagnosis must rely on molecular testing from blood, urine, or saliva, while serology testing may be inconclusive due to the cross-reactivity of antibodies with other flaviviruses. This represents a serious problem for the diagnosis of infection in people who reside in ZIKV endemic areas, where other flaviviruses, like dengue virus and yellow fever virus, generally co-circulate.

The strong genetic and structural similarities of ZIKV to other flaviviruses poses a challenge not only to the differential diagnosis but also to vaccine development, because antibodies induced by a previous flavivirus infection or vaccination may worsen a subsequent infection with a heterologous flavivirus through a mechanism of antibody-mediated enhancement.

Nonetheless, some vaccines against ZIKV have been developed and are in the process of clinical trial evaluation. In addition, drug repositioning screenings have identified some molecules that inhibit ZIKV infection and replication, while genome-wide screenings have identified certain human genes that are essential for ZIKV to replicate in the body, which could hold answers for finding effective antiviral therapies.

Several questions still remain open, such as how the virus infects and interacts with mosquito and human cells; which are the key genetic and molecular determinants of pathogenesis; how long the virus persists in human blood and tissues and its transmissibility; and how the innate and adaptive immune responses can counteract the virus and protect from reinfection. The responses to these questions are crucial, in this New Year and the future, to developing new antiviral medicines and improved protocols for ZIKV control.

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