In vivo infection dynamics and human adaptive changes of SIVsm-derived viral siblings SIVmac239, SIVB670 and SIVhu in humanized mice as a paralog of HIV-2 genesis

James Z Curlin; Kimberly Schmitt; Leila Remling-Mulder; Ryan Moriarty; John J Baczenas; Kelly Goff; Shelby O'Connor; Mark Stenglein; Preston A Marx; Ramesh Akkina

doi:10.3389/fviro.2021.813606

In vivo infection dynamics and human adaptive changes of SIVsm-derived viral siblings SIVmac239, SIV_B670 and SIVhu in humanized mice as a paralog of HIV-2 genesis

Front Virol. 2021:1:813606. doi: 10.3389/fviro.2021.813606. Epub 2021 Dec 31.

Authors

Affiliations

¹ Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA.
² Antiviral Discovery, Evaluation and Application Research (ADEAR) Training Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
³ Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
⁴ Department of Tropical Medicine, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
⁵ Tulane National Primate Research Center, Covington, LA, USA.

Abstract

Simian immunodeficiency virus native to sooty mangabeys (SIVsm) is believed to have given rise to HIV-2 through cross-species transmission and evolution in the human. SIVmac239 and SIV_B670, pathogenic to macaques, and SIVhu, isolated from an accidental human infection, also have origins in SIVsm. With their common ancestral lineage as that of HIV-2 from the progenitor SIVsm, but with different passage history in different hosts, they provide a unique opportunity to evaluate cross-species transmission to a new host and their adaptation/evolution both in terms of potential genetic and phenotypic changes. Using humanized mice with a transplanted human system, we evaluated in vivo replication kinetics, CD4⁺ T cell dynamics and genetic adaptive changes during serial passage with a goal to understand their evolution under human selective immune pressure. All the three viruses readily infected hu-mice causing chronic viremia. While SIVmac and SIV_B670 caused CD4⁺ T cell depletion during sequential passaging, SIVhu with a deletion in nef gene was found to be less pathogenic. Deep sequencing of the genomes of these viruses isolated at different times revealed numerous adaptive mutations of significance that increased in frequency during sequential passages. The ability of these viruses to infect and replicate in humanized mice provides a new small animal model to study SIVs in vivo in addition to more expensive macaques. Since SIVmac and related viruses have been indispensable in many areas of HIV pathogenesis, therapeutics and cure research, availability of this small animal hu-mouse model that is susceptible to both SIV and HIV viruses is likely to open novel avenues of investigation for comparative studies using the same host.

Keywords: A dual purpose humanized mouse model for HIV and SIV research; HIV origins and evolution from SIV; SIV cross-species transmission; SIV evolution into HIV-2; SIVmac and SIVB670 pathogenesis and evolution in humanized mice; origin of human pathogens in NHP; origins of human pandemic viruses; viral adaptive changes and evolution.

Abstract

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