1. HIV-1LAI Nef blocks the development of hematopoietic stem/progenitor cells into T lymphoid cells
- Author
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Jinyong Wang, Zhengping Zhou, Shijie Zou, Zhikai Wan, Xinping Chen, Fen Wang, Juanjuan Xing, Limin Chen, Wei Zou, Qian Liu, and Xin Fu
- Subjects
CD4-Positive T-Lymphocytes ,0301 basic medicine ,humanized mouse model ,T lymphoid cells ,viruses ,Immunology ,Cell ,CD34 ,HIV Infections ,Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Basic Science ,medicine ,Animals ,Immunology and Allergy ,nef Gene Products, Human Immunodeficiency Virus ,030212 general & internal medicine ,Progenitor cell ,hematopoietic stem/progenitor cells ,Hematopoietic Stem Cell Transplantation ,virus diseases ,Cell biology ,LAI Nef ,Haematopoiesis ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,Cord blood ,Humanized mouse ,HIV-1 ,Tumor necrosis factor alpha ,RNA-seq ,CD8 - Abstract
Objective: Despite successful antiviral therapy, the recovery of CD4+ T cells may not be complete in certain HIV-1-infected individuals. In our previous work with humanized mice infected with CXCR4-tropic HIV-1LAI (LAI), viral protein Nef was found the major factor determining rapid loss of both CD4+ T cells and CD4+CD8+ thymocytes but its effect on early T-cell development is unknown. The objective of this study is to investigate the influence of LAI Nef on the development of hematopoietic stem/progenitor cells (HSPCs) into T lymphoid cells. Design: HSPC-OP9-DL1 cell co-culture and humanized mouse model was used to investigate the objective of our study in vitro and in vivo. RNA-seq was exploited to study the change of gene expression signature after nef expression in HSPCs. Results: Nef expression in HSPCs was found to block their development into T lymphoid cells both in vitro and in the mice reconstituted with nef-expressing HSPCs derived from human cord blood. More surprisingly, in humanized mice nef expression preferentially suppressed the production of CD4+ T cells. This developmental defect was not the result of CD34+ cell loss. RNA-seq analysis revealed that Nef affected the expression of 176 genes in HSPCs, including those involved in tumor necrosis factor, Toll-like receptor, and nucleotide-binding oligomerization domain-like receptor signaling pathways that are important for hematopoietic cell development. Conclusion: Our results demonstrate that Nef compromises the development of HSPCs into T lymphoid cells, especially CD4+ T cells. This observation suggests that therapeutics targeting Nef may correct HIV-1-associated hematopoietic abnormalities, especially defects in T-cell development.
- Published
- 2021