Zika virus’ surprising tricks

Issue: October 2016

ByDonald Kaye, MD, MACP

ByThomas M Yuill, PhD

Donald Kaye

Thomas M. Yuill

Zika virus was discovered in 1947, when it was isolated from a febrile sentinel rhesus monkey in the Zika Forest of Uganda. Shortly thereafter, it was isolated from humans, nonhuman primates and mosquitoes (Aedes africanus) in Africa. In 1956, it was shown experimentally that A. aegypti mosquitoes could be infected and transmit the virus. Epidemics in Africa were documented in Uganda and Nigeria, as well as in Southeast Asia in Malaysia and Indonesia. From 1951 through 1981, serologic evidence of human Zika virus infection was reported from other African countries such as Tanzania, Egypt, Central African Republic, Sierra Leone and Gabon, and parts of Asia including India, Malaysia, the Philippines, Thailand, Vietnam and Indonesia. Clinically, Zika virus infections seemed fairly benign, causing a mild fever, usually with a rash, often with pruritus and conjunctivitis, that resolved in a few days. Zika virus infections did not appear to pose a serious public health threat at that time.

ZIKV spreads to Pacific islands, Americas

The first surprise was a major geographic jump outside its usual range in 2007, with the appearance of a Zika virus (ZIKV) outbreak on the island of Yap in the Federated States of Micronesia — the first occurrence of the virus outside of Africa or Asia. The symptoms were mild and generally lasted 4 to 7 days. Probable cases were identified in the neighboring islands of Ulithi, Fais, Eauripik, Woleai and Ifalik.

The second surprise was the appearance and rapid spread of ZIKV infections in French Polynesia in 2013, with an indication that more than just mild disease was occurring. Cases were reported in the Society, Marquesas and Tuamotu islands. The outbreak became extensive, and health providers indicated that nearly 8% of the population sought medical attention. WHO reported that during the 2013-2014 French Polynesia outbreak, 74 patients presented with neurological or autoimmune syndromes after having symptoms consistent with ZIKV infections. Of these, 42 had Guillain-Barré syndrome. Health authorities of French Polynesia reported an unusual increase of at least 17 cases of central nervous system malformations in fetuses and infants during the 2013-2014 outbreak. The cases were reported from pregnant women whose maternal ZIKV infection occurred at a gestational age of less than 6 months. The infants’ infection most likely occurred by transplacental transmission or during delivery but might have occurred from consumption of breast milk with virus. The ZIKV in this outbreak was of the Asian lineage.

The virus spread to other Pacific islands, initiating local transmission, including New Caledonia, Cook Islands and Easter Island, one of the most remote inhabited islands in the world. Later, the virus appeared on the Vanuatu Islands. The spread among islands was no doubt by viremic travelers.

The biggest surprises of all were yet to come. In February 2015, hundreds of cases of fever with rash and joint pains were reported in a number of northeastern states of Brazil, including Bahia, Maranhão, Paraiba, Pernambuco and Piauí. A Brazilian research group reported identifying the cause as ZIKV, the first time that this virus had been found in the Americas. Because the virus is efficiently transmitted by A. aegypti mosquitoes, there were no barriers to prevent its spread throughout Brazil and beyond in tropical and subtropical Americas where this mosquito is abundant and is transmitting dengue and chikungunya viruses. The virus that came to Brazil was genetically identical to the ZIKV circulating in French Polynesia.

Reports of congenital malformations

The next surprise began to appear in late October 2015, in Pernambuco, when it was suspected that cases of microcephaly were caused by maternal ZIKV infections during pregnancy. The number of suspected ZIKV-related microcephaly cases grew steadily and by May 14, there were 3,332 cases of microcephaly and other congenital malformations of the central nervous system under investigation; 1,384 cases were confirmed in 499 municipalities in 26 states, whereas in a normal year Brazil reports 139 to 167 microcephaly cases.

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Evidence for ZIKV infection as the cause of teratogenic effects began to mount with the identification of the ZIKV genome in the amniotic fluid of two pregnant women who showed clinical signs compatible with those of symptomatic infection with ZIKV. Their fetuses showed signs of microcephaly in prenatal exams, indicating that the virus could cross the placental barrier. The pathological picture became more complicated when on Jan. 11, 55 suspected microcephalic babies were examined, of whom 40 had microcephaly related to ZIKV infections. Of these, about 40% had retinal atrophy and pigment alteration. One of the microcephalic infants had a loss of hearing in his left ear. A recent study from Brazil reported that hearing loss was found in 6% of 70 infants born with microcephaly.

Additional evidence of ZIKV as the cause of teratogenic effects was provided by a retrospective study of 23 children in Pernambuco with a diagnosis of congenital infection presumably associated with ZIKV during the Brazilian microcephaly epidemic. Six of the 23 children tested positive for immunoglobulin M antibodies to ZIKV in cerebrospinal fluid. The other 17 children met the protocol criteria for congenital infection presumably associated with the ZIKV. Severe cerebral damage was found on imaging in most of the children with presumed congenital ZIKV infections. An additional study in Pernambuco found seven children with arthrogryposis and a diagnosis of congenital infection presumably caused by ZIKV during the Brazilian microcephaly epidemic.

On Feb. 1, WHO Director-General Margaret Chan, MD, declared a Public Health Emergency of International Concern based on the recommendation of a committee of 18 experts and advisers who had looked in particular at the strong association, in time and place, between infection with ZIKV and a rise in detected cases of congenital malformations and neurological complications.

In the Americas, serious disease resulting from ZIKV infections was not just in fetuses. More cases of GBS after ZIKV infections were diagnosed in Brazil, and researchers indicated ZIKV infection as the causal factor. Between January and July 2015, 121 cases with neurological symptoms or with GBS were reported by states in northeastern Brazil. Subsequently, ZIKV-associated cases of GBS were found in seven countries by mid-May. A study in Salvador, Brazil, showed that the number of GBS cases peaked after a lag of 5 to 9 weeks from the acute illness peak. ZIKV infection was the cause of two cases of encephalopathy in adults — one young and the other aged in his 70s.

Previously, ZIKV infections in adults were not considered fatal. In Brazil, three adult deaths were attributed, at least in part, to ZIKV infections. In Colombia, an otherwise healthy 15-year-old girl died.

Although direct, nonsexual person-to-person transmission was not believed to occur, an elderly man with comorbidities became infected with ZIKV in a country where transmission was occurring, returned home to Utah and died. His son, who had not traveled, cared for him during his illness and became infected. The elderly man had extremely high viremia and doubtless was shedding virus in urine, tears and probably saliva, exposing the caretaker son.

Recent in vitro studies with ZIKV infection added pathophysiologic evidence for ZIKV as a teratogenic agent. One study of human embryonic stem cell-derived cerebral organoids identified “a link between ZIKV-mediated TLR3 activation, perturbed cell fate, and a reduction in organoid volume reminiscent of microcephaly.” Another study showed that ZIKV can infect and replicate in primary human placental macrophages, and an additional study showed that ZIKV has a selective tropism of infection for neural stem cells in the mouse developing neocortex.

Changing pathogenicity

Why are some cases of ZIKV infection so severe in the Americas? Recent experiments suggest that pre-existing anti-dengue antibodies may increase disease severity through antibody-dependent enhancement (ADE) of the infection. A study showed that most antibodies that reacted to DENV envelope protein also reacted to ZIKV. Antibodies to linear epitopes were able to bind ZIKV but were unable to neutralize the virus and instead promoted ADE. This could lead to more disease severity in the Americas, where a significant number of people have had dengue infections and have anti-dengue antibodies that cross-react with ZIKV

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There was an early clue that nonarthropod, sexual transmission of ZIKV could occur. In 2008, a scientist became infected by ZIKV while working in Senegal and became ill 6 to 9 days after his return home to the United States. His wife also became infected, although she had not traveled away from the U.S., suggesting direct person-to-person virus transmission, possibly sexual. Alternatively, direct contact and exchange of other bodily fluids, such as saliva, could have resulted in ZIKV transmission. As of August, there were 21 cases of sexual transmission in which the infection was acquired outside the U.S. and then transmitted inside the country. One case was male-to-male, one was female-to-male, and the remainder were male-to-female. Research has demonstrated that the virus can persist in semen for as long as 188 days, leading to CDC and WHO recommendations for men to avoid unprotected sex for at least 6 months after the onset of symptoms.

The first reported cases of ZIKV infection due to blood transfusion in Brazil occurred in Sao Paulo on Dec. 16, 2015, when two cases of likely ZIKV transmission by blood transfusion were linked to a presymptomatic, infected person who donated platelets. Although there have not been additional reports of transfusion transmission, several national agencies responsible for the safety of blood and blood products have issued warnings about this risk and the need for testing.

Accurate diagnosis of ZIKV infection has posed a challenge as the clinical picture, especially early in the course of the disease, is similar to that of infection with dengue and chikungunya viruses. Now, the CDC recommends that ZIKV rRT-PCR be performed on urine collected less than 14 days after the onset of symptoms in patients with suspected ZIKV infections. ZIKV rRT-PCR testing of urine should be performed together with serum testing if specimens are collected less than 7 days after the onset of symptoms.

Control of transmission of the virus has been attempted through reduction of vector mosquitoes. Both A. aegypti and A. albopictus have been shown to be capable of transmitting the virus. A. aegypti appears to be the main vector, which is distributed in the U.S. from the Southeastern states, across the southern tier of states to Southern California. Populations of this species have been successfully reduced in field trials in other countries by the release of genetically modified male mosquitoes. While the release of modified mosquitoes in Florida has been approved, it is encountering resistance from local residents. Another approach to reduce transmission involves bacteria. Using A. aegypti infected with Wolbachia, investigators report that these mosquitoes have reduced vector competence for ZIKV in Colombia.

The mosquito vector picture may have become more complicated. In January, Brazilian entomologists found ZIKV in Culex quinquefasciatus mosquitoes, which would increase its chances of spreading around the world. However, neither C. quinquefasciatus nor C. pipiens were able to transmit the virus in recent experiments because the virus was not present in the saliva of these mosquitoes. Two recent reports indicate that C. quinquefasciatus is refractory to ZIKV infection or that the virus replicates poorly, making this species an ineffective vector. However, another recent report from China indicates that this mosquito species can become infected and transmit the virus.

What does the future hold for ZIKV?

ZIKV likely will become endemic in the tropical and subtropical Americas, but would probably persist as sporadic outbreaks. In the U.S., 42 locally acquired cases have occurred in Florida as of late August. It would not be surprising to see similar local cases across the Southern and Western states where A. aegypti is found and ZIKV viremic travelers arrive from countries with active transmission. As of Sept. 14, 3,132 infected travelers have arrived in the U.S. However, the kind of massive outbreaks that have occurred in the American tropics are unlikely in the U.S. because screened windows and doors and air conditioning are not conducive to large populations of vector mosquitoes. Meanwhile, several groups are developing ZIKV vaccines. An affordable, effective vaccine is the measure most likely to bring ZIKV transmission under control.

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References:
Amraoui F, et al. Eurosurveillance. 2016;doi:10.2807/1560-7917.ES.2016.21.35.30333.
Ayres CFJ. Lancet Infect Dis. 2016;doi:10.1016/S1473-3099(16)00073-6.
Brasil P, et al. Lancet. 2016;doi:10.1016/S0140-6736(16)30058-7.
CDC. Update: Interim Guidance for Prevention of Sexual Transmission of Zika Virus — United States, July 2016. http://www.cdc.gov/mmwr/volumes/65/wr/mm6529e2.htm?s_cid=mm6529e2_w. Accessed September 15, 2016.
Dang J, et al. Cell Stem Cell. 2016;doi:10.1016/j.stem.2016.04.014.
Dejnirattisai W, et al. Nat Immunol. 2016;doi:10.1038/ni.3515.
de Souza Campos Fernandes RC, et al. Lancet Infect Dis. 2016;doi:10.1016/S1473-3099(16)30079-2.
Faria NR, et al. Science. 2016;doi:10.1126/science.aaf5036.
Jouannic J-M, et al. Lancet. 2016;doi:10.1016/S0140-6736(16)00625-5.
Lanteri MC, et al. Transfusion. 2016;doi:10.1111/trf.13677.
Pan American Health Organization. Epidemio-logical Update: Neurological syndrome, congenital anomalies, and Zika virus infection, 17 January 2016. http://www.paho.org/hq/index.php?option=com_docman&task=doc_view&Itemid=270&gid=32879&lang=en. Accessed September 20, 2016.
Swaminathan S, et al. N Engl J Med. 2016;doi:10.1056/NEJMc1610613.
Teixeira MG, et al. Am J Public Health. 2016;doi:10.2105/AJPH.2016.303113.
Watrin L, et al. Medicine (Baltimore). 2016;doi:10.1097/MD.0000000000003257.
Wikan N, et al. Lancet Infect Dis. 2016;doi:10.1016/S1473-3099(16)30010-X.
Zanluca C, et al. Mem Inst Oswaldo Cruz. 2015;doi:10.1590/0074-02760150192.

For more information:
Donald Kaye, MD, MACP, is a professor of medicine at Drexel University College of Medicine, associate editor of the International Society of Infectious Diseases’ ProMED-mail, section editor of news for Clinical Infectious Diseases and an Infectious Disease News Editorial Board member.
Thomas M. Yuill, PhD, is a ProMED virus diseases moderator and professor emeritus, department of pathobiological sciences and department of forest and wildlife ecology, University of Wisconsin-Madison.

Disclosures: Kaye and Yuill report no relevant financial disclosures.