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HIV-1LAI Nef blocks the development of hematopoietic stem/progenitor cells into T lymphoid cells.
Zou, Wei; Xing, Juanjuan; Wang, Fen; Chen, Xinping; Liu, Qian; Wang, Jinyong; Zou, Shijie; Chen, Limin; Fu, Xin; Zhou, Zhengping; Wan, Zhikai.
Affiliation
  • Zou W; Department of Infectious Diseases.
  • Xing J; Department of Burn.
  • Wang F; Department of Gynecology and Obstetrics.
  • Chen X; Department of Gynecology and Obstetrics.
  • Liu Q; Department of Gynecology and Obstetrics.
  • Wang J; Department of Infectious Diseases.
  • Zou S; Department of Infectious Diseases.
  • Chen L; Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University.
  • Fu X; Jiangxi Provincial Key Laboratory of Preventive Medicine, School of Public Health.
  • Zhou Z; Department of Clinical Medicine, Nanchang University, Nanchang, Jiangxi, China.
  • Wan Z; Department of Clinical Medicine, Nanchang University, Nanchang, Jiangxi, China.
AIDS ; 35(6): 851-860, 2021 05 01.
Article in En | MEDLINE | ID: mdl-33587447
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.
Subject(s)

Full text: 1 Database: MEDLINE Main subject: HIV Infections / HIV-1 / Hematopoietic Stem Cell Transplantation Type of study: Prognostic_studies Limits: Animals Language: En Year: 2021 Type: Article

Full text: 1 Database: MEDLINE Main subject: HIV Infections / HIV-1 / Hematopoietic Stem Cell Transplantation Type of study: Prognostic_studies Limits: Animals Language: En Year: 2021 Type: Article