A Novel HIV-1 Nef Mutation in a Primary Pediatric Isolate Impairs MHC-Class I Downregulation and Cytopathicity

Ayub Ali; Robert L Furler; Livia Pedroza-Martins; Arnaud D Colantonio; Deborah Anisman-Posner; Yvonne Bryson; Otto O Yang; Christel H Uittenbogaart

doi:10.1089/AID.2019.0160

A Novel HIV-1 Nef Mutation in a Primary Pediatric Isolate Impairs MHC-Class I Downregulation and Cytopathicity

AIDS Res Hum Retroviruses. 2020 Feb;36(2):122-130. doi: 10.1089/AID.2019.0160. Epub 2019 Nov 4.

Authors

Ayub Ali^{1

2}, Robert L Furler³, Livia Pedroza-Martins⁴, Arnaud D Colantonio^{1

5}, Deborah Anisman-Posner^{1

5}, Yvonne Bryson^{1

6}, Otto O Yang^{1

2}, Christel H Uittenbogaart^{1

5

6

7}

Affiliations

¹ UCLA AIDS Institute, University of California, Los Angeles, Los Angeles, California.
² Division of Infectious Diseases, Department of Medicine, University of California, Los Angeles, Los Angeles, California.
³ Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, New York.
⁴ ANRS, French National Agency for Research on AIDS and Viral Hepatitis, Paris, France.
⁵ Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, California.
⁶ Department of Pediatrics, University of California, Los Angeles, Los Angeles, California.
⁷ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California.

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.

Keywords: HIV-1; MHC-I downregulation; Nef; cytopathicity; thymocyte.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cells, Cultured
Child, Preschool
Cytopathogenic Effect, Viral
Down-Regulation
Gene Deletion
HIV Infections / genetics*
HIV Infections / virology
HIV-1 / genetics
Histocompatibility Antigens Class I / genetics*
Humans
Infant, Newborn
Mice
Mice, SCID
Mutation
Thymocytes / pathology
Thymocytes / virology*
nef Gene Products, Human Immunodeficiency Virus / genetics*

Substances

Histocompatibility Antigens Class I
nef Gene Products, Human Immunodeficiency Virus
nef protein, Human immunodeficiency virus 1