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.
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Data availability
All data are available within this manuscript or its supporting files. Sequencing data generated in this study have been deposited in the GenBank database under accession numbers PX876883-PX877642, PX877926-PX878685, PX911634-PX912013, PX925169-PX925171. Source data are provided with this paper.
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Acknowledgements
We thank Greg Del Prete for valuable conversations, Jiro Wada for help with data visualization, and Anya Crane for critically editing the manuscript. Hut78 cells stably expressing human CCR5 were a gift from Vineet KewalRamani. This work was funded by grants from the National Institutes of Health (DP1-AI-175471, DP1-DA-046108, R01-AI-137011, R01-OD-034046 to SLS); by NIAID through two contracts, Simian Vaccine Evaluation Unit (SVEU) (75N93020D00007) to Tulane National Biomedical Research Center and the Virology Core Laboratory (75N93025C00002) to Duke University; by the University of Colorado Flow Cytometry Shared Facility in JSCBB (RRID:SCR_019309), supported by NIH grant S10OD021601. This work was supported in part through the prime contract of Laulima Government Solutions, LLC, with NIAID under contract no. HHSN272201800013C. J.H.K. performed this work as an employee of Tunnell Government Services (TGS), a subcontractor of Laulima Government Solutions, LLC, under contract no. HHSN272201800013C. The views and conclusions contained in this document are those of the authors and should not be interpreted as necessarily representing the official policies or positions, either expressed or implied, of the US Department of Health and Human Services, or any of the institutions and companies affiliated with the authors.
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N.R.M., V.L.B., C.J.W., A.B.-G., M.J.W., P.N.N., K.A.S., P.P.A., R.S.V., S.M.K., G.K.W., and S.L.S. conceived and designed the experiments. N.R.M., V.L.B., W.T.F., C.J.W., A.B.-G., M.J.W., O.Dirasantha, B.L.B., A.S.A., J.L.T., E.R.F., R.T.F., P.G., A.F., K.A.S., A.G., G.W.T., P.J.K., M.D.S., O.Davila, E.I.L., S.E.C., M.L.G., C.T.D., S.R.S., T.N.D., S.M.K., and G.K.W. performed the experiments. N.R.M., V.L.B., W.T.F., C.J.W., A.B.-G., M.J.W., O.Dirasantha, B.L.B., A.S.A., J.L.T., E.R.F., R.T.F., P.G., A.F., A.G., O.Davila, R.S.V., G.K.W., and S.L.S. analyzed the data. P.N.N. contributed materials and analysis tools. N.R.M., V.L.B., J.H.K., G.K.W., and S.L.S. wrote the manuscript. All authors edited and approved the final manuscript.
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NRM, WTF, and SLS are employees of, or hold financial interests in, Darwin Biosciences in Boulder, CO, USA. The remaining authors declare no competing interests. A patent application is related to this work; PCT Application No. PCT/US2023/082939 for “Novel HIV-1 Variants and their Methods of Use in an Animal Challenge Model.”
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Meyerson, N.R., Bauer, V.L., Fattor, W.T. et al. CXCR4-tropic HIV-1 infection in an immunocompetent monkey model. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70209-5
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DOI: https://doi.org/10.1038/s41467-026-70209-5
