Two types of defective human T-lymphotropic virus type I provirus in adult T-cell leukemia

Abstract

Adult T-cell leukemia (ATL), an aggressive neoplasm of mature helper T cells, is etiologically linked with human T lymphotropic virus type I (HTLV-1). After infection, HTLV-I randomly integrates its provirus into chromosomal DNA. Since ATL is the clonal proliferation of HTLV-I-infected T lymphocytes, molecular methods facilitate the detection of clonal integration of HTLV-I provirus in ATL cells. Using Southern blot analyses and long polymerase chain reaction (PCR) we examined HTLV-I provirus in 72 cases of ATL, of various clinical subtypes. Southern blot analyses revealed that ATL cells in 18 cases had only one long terminal repeat (LTR). Long PCR with LTR primers showed bands shorter than for the complete virus (7.7 kb) or no bands in ATL cells with defective virus. Thus, defective virus was evident in 40 of 72 cases (56%). Two types of defective virus were identified: the first type (type 1) defective virus retained both LTRs and lacked internal sequences, which were mainly the 5′ region of provirus, such as gag and pol. Type 1 defective virus was found in 43% of all defective viruses. The second form (type 2) of defective virus had only one LTR, and 5′-LTR was preferentially deleted. This type of defective virus was more frequently detected in cases of acute and lymphoma-type ATL (21/54 cases) than in the chronic type (1/18 cases). The high frequency of this defective virus in the aggressive form of ATL suggests that it may be caused by the genetic instability of HTLV-I provirus, and cells with this defective virus are selected because they escape from immune surveillance systems.

NF‐κB activation in development and progression of cancer

“…However, we cannot exclude the possibility that polyubiquitination may have nothing to do with NF-κB activation because the introduced mutations could alter the conformation of Tax rendering it inactive. Many proviruses in ATL cells isolated from patients lack 5′-long-terminal repeat (LTR), (58) or maintain LTR but heavily methylated. (59) Therefore, Tax cannot be expressed in leukemic cells although NF-κB is usually constitutively activated.…”

Identification of differentially expressed molecules in adult T‐cell leukemia cells proliferating in vivo

“…Inverse polymerase chain reaction (inverse PCR). To amplify the genomic DNA flanking the integration sites of the HTLV-I provirus, inverse PCR was performed using a previously described method 15) with some modification. Genomic DNA (500 ng) was digested with PstI (Toyobo, Osaka) and then ligated with T4-DNA ligase (New England Biolabs, Beverly, MA).…”

Defective human T‐lymphotropic virus type 1 provirus in asymptomatic carriers

“…Schemas of the structure of complete, Type 1 defective and Type 2 defective HTLV-1 provirus are shown in Figure 1. 16 The nucleotide position number of HTLV-1 provirus was according to Seiki et al (accession no. J02029).…”

“…5,13 It has been reported that defective provirus was detectable in approximately half of patients with ATL. [14][15][16][17][18] Tamiya et al reported two types of genome deletion in defective provirus. 16 One form (i.e., Type 1) retains both LTRs and lacks internal sequences, such as the gag and pol regions.…”

“…[14][15][16][17][18] Tamiya et al reported two types of genome deletion in defective provirus. 16 One form (i.e., Type 1) retains both LTRs and lacks internal sequences, such as the gag and pol regions. The other form (i.e., Type 2) has only the 3 0 LTR, and the 5 0 LTR and its flanking internal sequences are preferentially deleted.…”