HIV-1 Nef protein expression in human CD34+ progenitors impairs the differentiation of an early T/NK cell precursor.
HIV-1 impairs the production of T cells, through mechanisms that are still unknown. Here, we investigated the effect of the expression of HIV-1 Nef on the T-cell potential of human hematopoietic CD34(+) precursors. Those progenitors were transduced by using lentiviral vectors expressing Nef and cultured on OP9-DL1 cells allowing the differentiation of T cell from human hematopoietic precursors. We demonstrate that Nef impairs the generation of a CD3epsilon(+)CD5(+) CD1a(+) precursor stage that has initiated a D-J rearrangement of the TCRbeta locus. Onward stages of T-cell development were also affected with a quantitative reduction of CD4(+) intraCD3epsilon(+) Immature single positive cells (ISP), Double Positive (DP) CD4(+)CD8(+) TCRalphabeta T cells and CD56(+) NK cells. But B cell production was not affected. Limiting dilution analyses demonstrated a significant reduction in the frequency of T/NK progenitors among Nef-expressing CD34(+) cells. Altogether, these data demonstrate that Nef interferes with the differentiation of a primitive lymphoid human precursor with a T/NK potential.
Dorival
Céline
C
INSERM U 841, Faculté de Médecine, Créteil, France.
Brizzi
Fanny
F
Lelièvre
Jean-Daniel
JD
Sol-Foulon
Nathalie
N
Six
Emmanuelle
E
Henry
Adeline
A
André-Schmutz
Isabelle
I
Cavazzana-Calvo
Marina
M
Coulombel
Laure
L
Estaquier
Jérôme
J
Schwartz
Olivier
O
Lévy
Yves
Y
D018952:Antigens, CD34 / Q000378:metabolism; D002454:Cell Differentiation; D015754:Genes, nef; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000473:pathology / Q000821:virology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology / Q000821:virology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology / Q000821:virology*; D014161:Transduction, Genetic; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000502:physiology*
D018952:Antigens, CD34; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1