Abstract
Current animal models of HIV-1 infection are either immunocompromised or rely on proxy viruses instead of HIV-1. Here, we establish an immunocompetent animal model for CXCR4-tropic HIV-1 in owl monkeys (Aotus nancymaae). Through analysis of 191 owl monkeys, genetic characterization and functional testing demonstrate that CD4 and Tetherin in this species support HIV-1 replication. Although owl monkeys do carry restrictive TRIMCyp and APOBEC3G alleles, small changes to the HIV-1 genome allow the virus to overcome these barriers. The resulting virus remains 93% wildtype HIV-1 in sequence. Fully immunocompetent owl monkeys can be infected with this virus, recapitulating key aspects of HIV-1 infection in humans: an initial surge of virus replication, subsequent establishment of a durable set point viremia, seroconversion, and the formation of a viral reservoir. The owl monkey model broadens the experimental options for HIV-1 research, and future studies will explore its utility for CCR5-tropic virus strains.