The baboon as a nonhuman primate model for the study of natural Zika virus infection

Abstract

Background: Zika virus (ZIKV) was first isolated from a sentinel rhesus macaque in the Zika forest of Uganda. Baboons are a nonhuman primate species widely distributed in Africa that could reasonably be a natural reservoir for ZIKV. We characterized the early phases of ZIKV infection in naïve captive baboons and tested immunity induced by primary infection against reinfection with a distant ZIKV strain. Methods & Materials: Four juvenile baboons were injected with 104 or 106 TCID50 of the Puerto Rico strain of ZIKV by the subcutaneous route. Viral loads were determined by RT-PCR in blood, urine, and mucosal swabs. Infection was followed by measuring fever and systemic cytokine changes, and by observing clinical signs. Humoral immune responses were determined by ELISA, and cellular responses by flow cytometry. Transcriptomic analysis was performed on days 0, 3 and 15. Six months after primary infection, the same animals were exposed to 104 TCID50 of the Uganda strain of ZIKV, and virological and immunological outcomes were performed as described before. Results: Viremia was present in all animals and lasted for about 5 days. Virus was transiently present in the urine of some animals. There were no clinical signs of infection, and body temperature was stable during the viremic phase. Cytokine analysis did not show evident peaks of inflammatory cytokines in circulation; however, RNAseq analysis showed a clear inflammatory antiviral response by day 3 PI that resolved by day 15 PI. All animals developed low levels of anti-ZIKV NS1 and crossreactive anti-Dengue GP antibodies, and there was also a detectable cell-mediated immune response to viral antigens. After challenge with ZIKV Uganda strain, there was no detectable viremia and this correlated with a lack of anamnestic humoral and cell-mediated immune response to the viral antigens. Conclusion: Similarl to the majority of human cases, ZIKV infection of baboons resulted in a subclinical infection. However, this infection was able to induce a protective immune response against re-exposure with a distant ZIKV. The baboon may be a useful NHP model of natural ZIKV infection in which to test antivirals and vaccines efficacy.