HIV-1LAI Nef blocks the development of hematopoietic stem/progenitor cells into T lymphoid cells

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-1_LAI (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 TNF, TLR, and NOD-like receptor signaling pathways that are important for hematopoietic cell development. Conclusions: 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.