Infection Dynamics of Sylvatic Dengue Virus in a Natural Primate Host, the African Green Monkey

Abstract

Abstract. The four serotypes of mosquito-borne dengue virus (DENV-1, -2, -3, and -4) that circulate in humans each emerged from an enzootic, sylvatic cycle in non-human primates. Herein, we present the first study of sylvatic DENV infection dynamics in a primate. Three African green monkeys were inoculated with 10 5 plaque-forming units (pfu) DENV-2 strain PM33974 from the sylvatic cycle, and one African green monkey was inoculated with 10 5 pfu DENV-2 strain New Guinea C from the human cycle. All four monkeys seroconverted (more than fourfold rise in 80% plaque reduction neutralization titer [PRNT 80 ]) against the strain of DENV with which they were inoculated; only one (33%) of three monkeys infected with sylvatic DENV showed a neutralizing antibody response against human-endemic DENV. Virus was detected in two of three monkeys inoculated with sylvatic DENV at low titer ( 1.3 log 10 pfu/mL) and brief duration ( 2 days). Clinical signs included rash and elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels.Mosquito-borne dengue virus (DENV; genus Flavivirus) is one of only two arthropod-borne viruses to have established a transmission cycle endemic to humans that is ecologically and evolutionarily distinct from its enzootic ancestors.1 In its human transmission cycle, the virus comprises four antigenically and genetically distinct serotypes (DENV-1, -2, -3, and -4); infection with one serotype conveys lifelong protection against homologous challenge but only transient protection against heterologous infection with another serotype.2,3 Although most infections are subclinical, a fraction results in classical dengue fever (DF), a self-limited febrile illness, and some of these patients progress to severe dengue disease. 4 The lack of an animal model that recapitulates human dengue disease has been a major barrier to the development of DENV vaccines and therapeutics. Replication of human-endemic DENV in non-human primates (NHPs) 5 is muted in intensity and duration relative to replication in humans, 6 and infection with human-endemic DENV produces disease in NHPs only when administered at doses that greatly exceed those delivered by the mosquito. 1Each of four human-endemic DENV serotypes emerged from enzootic ancestors maintained in a sylvatic cycle between NHPs and canopy-dwelling Aedes mosquitoes.1,7 These sylvatic cycles remain active in the forests of southeast Asia and west Africa. Spillover of sylvatic DENV into humans, sometimes causing severe disease, has been repeatedly documented. [8][9][10][11][12][13][14][15] Thus, continued circulation of sylvatic DENV may threaten future control of human DENV when a DENV vaccine becomes available. 7 Because the replication and immunogenicity of sylvatic DENV in its NHP hosts have not previously been investigated, some mathematical models of sylvatic DENV population dynamics and spillover risk have used infection parameters derived from studies of humanendemic DENV in NHPs. 16 However, infection dynamics of arboviruses in reservoir a...

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