Preferential Selection of Human T-Cell Leukemia Virus Type 1 Provirus Lacking the 5′ Long Terminal Repeat during Oncogenesis

Abstract

In adult T-cell leukemia (ATL) cells, a defective human T-cell leukemia virus type 1 (HTLV-1) provirus lacking the 5 long terminal repeat (LTR), designated type 2 defective provirus, is frequently observed. To investigate the mechanism underlying the generation of the defective provirus, we sequenced HTLV-1 provirus integration sites from cases of ATL. In HTLV-1 proviruses retaining both LTRs, 6-bp repeat sequences were adjacent to the 5 and 3 LTRs. In 8 of 12 cases with type 2 defective provirus, 6-bp repeats were identified at both ends. In five of these cases, a short repeat was bound to CA dinucleotides of the pol and env genes at the 5 end, suggesting that these type 2 defective proviruses were formed before integration. In four cases lacking the 6-bp repeat, short (6-to 26-bp) deletions in the host genome were identified, indicating that these defective proviruses were generated after integration. Quantification indicated frequencies of type 2 defective provirus of less than 3.9% for two carriers, which are much lower than those seen for ATL cases (27.8%). In type 2 defective proviruses, the second exons of the tax, rex, and p30 genes were frequently deleted, leaving Tax unable to activate NF-B and CREB pathways. The HTLV-1 bZIP factor gene, located on the minus strand, is expressed in ATL cells with this defective provirus, and its coding sequences are intact, suggesting its significance in oncogenesis.

Human T-Lymphotropic virus (HTLV) type I in vivo integration in oral keratinocytes

“…Although some failure during the PCR process could be responsible for a remote possible mistaken interpretation of results; however another real explanation is that defective proviruses would be generated during the infection process to oral keratinocytes. In order to support the last explanation, previous studies report the existence of defective HTLV-1 provirus in lymphocytic infections not only in ATL (9,20,11,15) but also in HAM/TSP patients (29,30,16,14). In this sense our results would be the first to document the existence of defective HTLV-1 provirus in infected oral keratinocytes.…”

“…Although not direct evidence have obtained, the presence of defective provirus not only in lymphocytes but in oral keratinocytes, strongly suggest the possibility that low levels of viremia and/or low efficiency in the contact cell-to-cell could possibly favor post integration process that increase the frequency of defective provirus (15); however this statement in oral mucosa keratinocytes needs to be tested. …”

Inhibition of the hTERT promoter by the proto-oncogenic protein TAL1

“…During later stages of infection, several arguments support a very low expression of Tax in ATL cells because of deletion or hypermethylation of the 5 0 LTR and even in some cases to the appearance of stop codons in the Tax coding sequence. [33][34][35] By contrast, the HBZ RNA is well expressed in ATL cells. 36,37 From these observations, it has been proposed that Tax by inhibiting hTERT favors an unstable genomic state at early steps of transformation, whereas at late stages HBZ would drive with JunD a high expression of hTERT and consequently a high telomerase activity.…”

Aspects moléculaires des lymphomes T périphériques (2)

“…Celle-ci est codée par le brin antisens du provirus HTLV-1 à partir de la région 3'LTR. Les ARN et protéines HBZ sont constitutivement exprimés tout au long du processus d'oncogenèse, probablement parce que les régions 3'LTR sont moins sensibles à la méthylation et/ou aux anomalies géné-tiques [60]. HBZ est importante dans la maintenance du phénotype tumoral des cellules infectées par HTLV-1 et ce même en l'absence de Tax [61][62][63].…”