Development of a Zika Virus Infection Model in Cynomolgus Macaques

Abstract

Limited availability of Indian rhesus macaques (IRM) is a bottleneck to study Zika virus (ZIKV) pathogenesis and evaluation of appropriate control measures in non-human primates. To address these issues, we report here the Mauritian cynomolgus macaque (MCM) model for ZIKV infection. In brief, six MCMs (seronegative for Dengue and ZIKV) were subdivided into three cohorts with a male and female each and challenged with different doses of Asian [PRVABC59 (Puerto Rico) or FSS13025 (Cambodia)] or African (IBH30656) lineage ZIKV isolates. Clinical signs were monitored; and biological fluids (serum, saliva, and urine) and tissues (testes and brain) were assessed for viral load by quantitative reverse transcription polymerase chain reaction and neutralizing antibodies (Nab) by 50% Plaque Reduction Neutralization Test (PRNT50) at various times post-infection (p.i). PRVABC59 induced viremia detectable up to day 10, with peak viral load at 2–3 days p.i. An intermittent viremia spike was observed on day 30 with titers reaching 2.5 × 103 genomes/mL. Moderate viral load was observed in testes, urine and saliva. In contrast, FSS13025 induced viremia lasting only up to 6 days and detectable viral loads in testes but not in urine and saliva. Recurrent viremia was detected but at lower titers compare to PRVABC59. Challenge with either PRVABC59 or FSS13025 resulted in 100% seroconversion; with mean PRNT50 titers ranging from 597 to 5179. IBH30656 failed to establish infection in MCM suggesting that MCM are susceptible to infection with ZIKV isolates of the Asian lineage but not from Africa. Due to the similarity of biphasic viremia and Nab responses between MCM and IRM models, MCM could be a suitable alternative for evaluation of ZIKV vaccine and therapeutic candidates.

Immune Cell Dynamics in Rhesus Macaques Infected with a Brazilian Strain of Zika Virus

“…Recent findings in experimental infections of macaque monkeys, show that ZIKV RNA is found in diverse fluids and tissues, but are short-lasting in blood. However, ZIKV loads may last longer in saliva, urine or semen and tissues (16–18, 21, 22). Recently, the extended persistence of ZIKV particles in the testes and epididymidis of IFNar1 KO infected mice was correlated with inflammation, damage of the male genital tract, culminating with lower testosterone levels and infertility (19, 21).…”

Animal Models of Zika Virus Infection, Pathogenesis, and Immunity

“…(i) Pathogenesis in immunocompetent adult macaques. Nonhuman primates (NHPs) also are being used to evaluate aspects of ZIKV biology and pathogenesis (38,(87)(88)(89)(90). Several groups have characterized ZIKV infection in pregnant and nonpregnant rhesus, cynomolgus, and pigtail macaques.…”

“…ZIKV RNA also was detected in the seminal fluid and vaginal secretions, albeit more sporadically (87,88). Using multiple approaches, including in situ hybridization for the ZIKV genome, immunohistochemistry with a cross-reactive flavivirus-specific MAb, and quantitative reverse transcription-PCR (RT-PCR) analysis for viral RNA in tissues, ZIKV infection was detected in a several tissues of rhesus and cynomolgus macaques, including secondary lymphoid organs, the male reproductive tract, the intestines, and the brain and spinal cord (38,88,90). These studies support the use of rhesus and cynomolgus macaques as models for improving our understanding of the cellular and tissue tropism of ZIKV infection.…”

Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14-22

“…Additionally, ZIKV strains isolated from Brazil and injected into nonhuman primates at high dosages were able to cause alterations in the fetal brain (19). On the other hand, studies using other strains at much lower doses were unable to show the same effect (33,34). The comparisons among the strains and their pathologies cannot be limited to the dosages used in different studies.…”