Progressive loss of CD3 expression after HTLV-I infection results from chromatin remodeling affecting all the CD3 genes and persists despite early viral genes silencing.
BACKGROUND
HTLV-I infected CD4+ T-cells lines usually progress towards a CD3- or CD3low phenotype. In this paper, we studied expression, kinetics, chromatin remodeling of the CD3 gene at different time-points post HTLV-I infection.


RESULTS
The onset of this phenomenon coincided with a decrease of CD3gamma followed by the subsequent progressive reduction in CD3delta, then CD3epsilon and CD3zeta mRNA. Transient transfection experiments showed that the CD3gamma promoter was still active in CD3- HTLV-I infected cells demonstrating that adequate amounts of the required transcription factors were available. We next looked at whether epigenetic mechanisms could be responsible for this progressive decrease in CD3 expression using DNase I hypersensitivity (DHS) experiments examining the CD3gamma and CD3delta promoters and the CD3delta enhancer. In uninfected and cells immediately post-infection all three DHS sites were open, then the CD3gamma promoter became non accessible, and this was followed by a sequential closure of all the DHS sites corresponding to all three transcriptional control regions. Furthermore, a continuous decrease of in vivo bound transcription initiation factors to the CD3gamma promoter was observed after silencing of the viral genome. Coincidently, cells with a lower expression of CD3 grew more rapidly.


CONCLUSIONS
We conclude that HTLV-I infection initiates a process leading to a complete loss of CD3 membrane expression by an epigenetic mechanism which continues along time, despite an early silencing of the viral genome. Whether CD3 progressive loss is an epiphenomenon or a causal event in the process of eventual malignant transformation remains to be investigated.
Akl
Haidar
H
Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), 121, Boulevard de waterloo, 1000, Brussels, Belgium. haidaakl@ulb.ac.be
Badran
Bassam
B
Dobirta
Gratiela
G
Manfouo-Foutsop
Germain
G
Moschitta
Maria
M
Merimi
Makram
M
Burny
Arsène
A
Martiat
Philippe
P
Willard-Gallo
Karen E
KE
D017252:CD3 Complex / Q000235:genetics* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly; D003850:Deoxyribonuclease I / Q000378:metabolism*; D015870:Gene Expression; D020868:Gene Silencing; D005814:Genes, Viral; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D011401:Promoter Regions, Genetic; D013601:T-Lymphocytes / Q000378:metabolism* / Q000502:physiology / Q000821:virology*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic