1. A Novel HIV-1 Nef Mutation in a Primary Pediatric Isolate Impairs MHC-Class I Downregulation and Cytopathicity
- Author
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Arnaud D. Colantonio, Otto O. Yang, Ayub Ali, Robert L. Furler, Deborah J. Anisman-Posner, Yvonne J. Bryson, Livia Pedroza-Martins, and Christel H. Uittenbogaart
- Subjects
Pediatric AIDS ,HIV Infections ,Pathogenesis ,Mice, SCID ,nef Gene Products ,medicine.disease_cause ,Mice ,Cytopathogenic Effect, Viral ,2.1 Biological and endogenous factors ,2.2 Factors relating to the physical environment ,Viral ,Aetiology ,Child ,Cells, Cultured ,Pediatric ,Mutation ,Cultured ,Thymocytes ,biology ,virus diseases ,Thymocyte ,Infectious Diseases ,Child, Preschool ,HIV/AIDS ,Infection ,Human Immunodeficiency Virus ,Cells ,Immunology ,Clinical Sciences ,Down-Regulation ,cytopathicity ,Major histocompatibility complex ,SCID ,Downregulation and upregulation ,In vivo ,Virology ,MHC class I ,medicine ,Animals ,Humans ,nef Gene Products, Human Immunodeficiency Virus ,Preschool ,MHC-I downregulation ,Nef ,Histocompatibility Antigens Class I ,Infant, Newborn ,Infant ,thymocyte ,Newborn ,In vitro ,biology.protein ,HIV-1 ,Cytopathogenic Effect ,Gene Deletion - Abstract
HIV-1-induced cytopathicity of thymocytes is a major cause of reduced peripheral T cells and rapid disease progression observed in HIV-1-infected infants. Understanding the virulence factors responsible for thymocyte depletion has paramount importance in addressing the pathogenesis of disease progression in children. In this study, thymocyte depletion was analyzed following infection with two primary CXCR4-tropic HIV-1 pediatric isolates (PI), PI-2 and PI-2.1, which were serially derived from an in utero-infected infant. Although highly similar to each other, PI-2 showed markedly decreased thymocyte depletion in vitro compared with PI-2.1. Further analysis showed a novel deletion in the Nef protein (NefΔK7S) of PI-2, which was absent in PI-2.1. This deletion inhibited Nef-mediated major histocompatibility complex class I (MHC-I) downregulation in infected thymocytes in vitro and in vivo; in contrast, the mutated Nef continued to downregulate CD4 surface expression in vitro. These results suggest that HIV-1 Nef contributes to thymic damage in infants through selective functions.
- Published
- 2020