HIV-1LAI Nef blocks the development of hematopoietic stem/progenitor cells into T lymphoid cells. (1st May 2021)

• Record Type: Journal Article
• Authors: Zou, Wei; Xing, Juanjuan; Wang, Fen; Chen, Xinping; Liu, Qian; Wang, Jinyong; Zou, Shijie; Chen, Limin; Fu, Xin; Zhou, Zhengping; Wan, Zhikai
• Is Part Of: AIDS. Volume 35:Number 6(2021)
• Publication Date: 2021-05-01
• Subjects: hematopoietic stem/progenitor cells -- humanized mouse model -- LAI Nef -- RNA-seq -- T lymphoid cells; AIDS (Disease) -- Periodicals; Acquired Immunodeficiency Syndrome; AIDS (Disease); Periodicals; Periodicals; 616.9792005
• DOI: 10.1097/QAD.0000000000002837
• Languages: English
• ISSNs: 0269-9370

Abstract

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 n ef -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. Abstract : Supplemental Digital Content is available in the text