APOBEC3G Splicing Defects in Nonhuman Primate Models Result in Disparate Viral Mutational Profiles Relative to Humans
Year: 2026
Type: preprint
Abstract: ABSTRACT Nonhuman primates (NHPs), particularly macaques, are indispensable models for studying human infectious diseases due to their close immunological and physiological similarities. Understanding species-specific molecular differences is essential for maximizing the translational value of these models. Here we report that APOBEC3G (A3G) , a potent antiviral restriction factor and the major source of genetic variations in HIV, exhibits a widespread mRNA splicing defect in the Cercopithecinae subfamily, which includes the commonly used NHP models. Driven by intronic polymorphisms, this splicing defect substantially reduces A3G protein levels and consequently results in a markedly reduced A3G-mediated mutation signatures, fewer defective viral genomes, and greater viral diversification in SIV compared to HIV. This species-specific effect is not restricted to lentiviruses: reduced A3G signatures have also been reported in simian foamy virus and simian T-cell leukemia virus, suggesting broader effects across primate retroviruses. These findings reveal a lineage-specific alteration in a major antiviral restriction factor, with important implications for viral restriction, evolution, drug resistance, and immune evasion. They also highlight the importance of incorporating naturally occurring genetic variation into NHP model selection to improve the reproducibility, translational fidelity, and biological relevance of preclinical research.
Authors: Armando D. Mendez, Rachael Springman-Rodriguez, Ayub Bokani, Fiona Carter-Tod, Niloofar Haghjoo, Margarita Rzhetskaya, Colin Rorex, Jake D. Lehle, Mohadeseh Soleimanpour, Luis Ferrández-Peral, Hanjing Yang, Michael A. Carpenter, Rajesh Thippeshappa, Sebla Kutluay, Rick N. McLaughlin, Mahesh Mohan, Binhua Ling, Luis D. Giavedoni, Maria Rodriguez-Barradas, Reuben S. Harris, Xiaojiang Chen, Susan T. Weintraub, Judd F. Hultquist, Diako Ebrahimi
Institutions: Texas Biomedical Research Institute, The University of Texas at San Antonio, Central Queensland University, Northwestern University, Institut de Biologia Evolutiva, University of Southern California, Howard Hughes Medical Institute, The University of Texas at San Antonio Health Science Center, Washington University in St. Louis, Trinity University, Michael E. DeBakey VA Medical Center, Baylor College of Medicine
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funders: Cancer Prevention and Research Institute of Texas, Houston Advanced Research Center, University of Texas at San Antonio, Third Coast Center for AIDS Research, National Institutes of Health, Center for AIDS Research, University of Washington, District of Columbia Developmental Center for AIDS Research, National Institute of Allergy and Infectious Diseases, National Center for Research Resources
Awards: Viral and host determinants of donor-specific anti-HIV/SIV immunity mediated by APOBEC3-enzyme, G1328727658, G1536689936, G1632606811, G2003430324, Donor-specific anti-HIV/SIV immunity mediated by APOBEC3 enzymes, G2616758173, G2692924352, G3209101793, G3395966601, Functionally Defining HIV-Host Interactions During the Early HIV-1 Lifecycle, G54487708, G619466266, Texas Developmental Center for AIDS Research, G7421301966, G867047700, G867868940, G9000026354, G9000097363, Deciphering the Role of CPSF6 in HIV Infection, The Southwest National Primate Research Center, HARC: HIV accessory and regulatory complexes, MMI-T32 Training Pre-doctoral Scientists in Molecular Microbiology and Immunology at UTSA
OpenAlex ID: W7202275476
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