Abstract
Defining the complex dynamics of Zika virus (ZIKV) infection in pregnancy and during transmission between vertebrate hosts and mosquito vectors is critical for a thorough understanding of viral transmission, pathogenesis, immune evasion, and potential reservoir establishment. Within-host viral diversity in ZIKV infection is low, which makes it difficult to evaluate infection dynamics. To overcome this biological hurdle, we constructed a molecularly barcoded ZIKV. This virus stock consists of a “synthetic swarm” whose members are genetically identical except for a run of eight consecutive degenerate codons, which creates approximately 64,000 theoretical nucleotide combinations that all encode the same amino acids. Deep sequencing this region of the ZIKV genome enables counting of individual barcodes to quantify the number and relative proportions of viral lineages present within a host. Here we used these molecularly barcoded ZIKV variants to study the dynamics of ZIKV infection in pregnant and non-pregnant macaques as well as during mosquito infection/transmission. The barcoded virus had no discernible fitness defects in vivo, and the proportions of individual barcoded virus templates remained stable throughout the duration of acute plasma viremia. ZIKV RNA also was detected in maternal plasma from a pregnant animal infected with barcoded virus for 67 days. The complexity of the virus population declined precipitously 8 days following infection of the dam, consistent with the timing of typical resolution of ZIKV in non-pregnant macaques and remained low for the subsequent duration of viremia. Our approach showed that synthetic swarm viruses can be used to probe the composition of ZIKV populations over time in vivo to understand vertical transmission, persistent reservoirs, bottlenecks, and evolutionary dynamics.
Highlights
Zika virus (ZIKV; Flaviviridae, Flavivirus) infection during pregnancy can cause congenital Zika syndrome (CZS)—a collection of neurological, visual, auditory, and developmental birth defects—in at least 5% of babies [1]
Understanding the complex dynamics of Zika virus (ZIKV) infection during pregnancy and during transmission to and from vertebrate host and mosquito vector is critical for a thorough understanding of viral transmission, pathogenesis, immune evasion, and reservoir establishment
We infected rhesus macaques with this virus to study the dynamics of ZIKV infection in nonhuman primates as well as during mosquito infection/transmission
Summary
Zika virus (ZIKV; Flaviviridae, Flavivirus) infection during pregnancy can cause congenital Zika syndrome (CZS)—a collection of neurological, visual, auditory, and developmental birth defects—in at least 5% of babies [1]. The frequency of vertical transmission is not known, data suggest that it may be very common, especially if infection occurs during the first trimester [2]. For both pregnant and nonpregnant women, it was previously thought that ZIKV caused an acute self-limiting infection that was resolved in a matter of days. Unusually prolonged maternal viremia has been noted, with viral RNA detected in maternal blood up to 107 days after symptom onset [8,9,10,11]. The source of virus responsible for prolonged viremia is not known, though it has been speculated that this residual plasma viral load could represent virus genome release from maternal tissues, the placenta, and/or the fetus
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