Ken-ichiro Etoh

Involvement of IL-2/IL-2R system activation by parasite antigen in polyclonal expansion of CD4(+)25(+) HTLV-1-infected T-cells in human carriers of both HTLV-1 and S. stercoralis.

The intermediate state of HTLV-1 infection, often found in individuals dually infected with Strongyloides stercoralis (S. stercoralis) and HTLV-1, is assumed to be a preleukemic state of adult T-cell leukemia (ATL). To investigate the effects of S. stercoralis superinfection on the natural history of HTLV-1 infection, we characterized peripheral blood samples of these individuals in Okinawa, Japan, an endemic area for both HTLV-1 and S. stercoralis and we studied effects of the parasite antigen on T-cells. The dually infected individuals showed a significantly higher provirus load and an increase in CD4+25+ T cell population, with a significant, positive correlation. This increase was attributable to polyclonal expansion of HTLV-1-infected cells, as demonstrated by inverse-long PCR analysis of the integration sites. S. stercoralis antigen activated the IL-2 promoter in reporter gene assays, induced production of IL-2 by PBMC in vitro, and supported growth of IL-2 dependent cell lines immortalized by HTLV-1 infection or the transduction of Tax. Taken collectively, these results indicate that S. stercoralis infection induces polyclonal expansion of HTLV-1-infected cells by activating the IL-2/IL-2R system in dually infected carriers, an event which may be a precipitating factor for ATL and inflammatory diseases.

Rapid quantification of HTLV-I provirus load : Detection of monoclonal proliferation of HTLV-I-infected cells among blood donors

In this report, we quantified HTLV‐I provirus load using the AmpliSensor system, which utilizes fluorescence to measure PCR products. With this method, provirus loads could be measured within 6 hr, and the results obtained correlated well with those obtained by other methods. Samples from 256 blood donors, who were positive for antibodies against HTLV‐I, were analyzed, showing that provirus load ranged from less than 0.1% to 56% among carriers. We analyzed the association between provirus load and the biomarkers age and sex and found that it was not influenced by either. Provirus load was better correlated with soluble interleukin‐2 receptor (sIL‐2R) levels than with antibody titer against the virus. Among 18 blood donors with high provirus load (more than 10%), Southern blotting detected monoclonal integration of HTLV‐I in infected cells in 2 cases, both of them showing high sIL‐2R levels (more than 900 U/ml). Sequential analyses of provirus load showed stable levels of provirus in the same carriers, suggesting that some factors other than age or sex determined provirus load in infected individuals. Thus, this rapid method is a useful tool for the early detection of adult T‐cell leukemia and other HTLV‐I‐associated diseases. Int. J. Cancer 81:859–864, 1999.

Random integration of HTLV-I provirus; increasing chromosomal instability

Adult T-cell leukemia/lymphoma (ATLL) is a neoplasm of mature helper (CD4) T-lymphocytes. Human T-cell lymphotropic virus type-I (HTLV-I) is etiologically considered to cause ATLL. It has been suggested that HTLV-I integrates its provirus into random sites in host chromosomal DNA after infection. Clonal integration has been observed in patients with ATLL, including smoldering, chronic and acute leukemia states. Almost all cases with ATLL demonstrate clonal chromosome abnormalities, with karyotypes being very complicated in both number and structure. However, there are no specific karyotype abnormalities in ATLL. In order to examine the role of HTLV-I in the pathogenesis of ATLL, we investigated whether or not HTLV-I randomly integrates and whether the integration site in the human genome is associated with any chromosomal abnormality. We analyzed 18 cases with ATLL, which included 15 cases with acute states, two cases with chronic states and one case with a smoldering state. In four of the 18 cases, the HTLV-I provirus integrated into the 9th chromosome, while in three cases, it integrated into the 1st or 10th chromosome. However, the integrated site in the chromosome varied in each case and the random integration was considered to be true. All 15 cases with acute ATLL had complicated chromosomal abnormalities and two cases with chronic and smoldering ATLL showed simple abnormal karyotypes, while one case with chronic ATLL showed a normal karyotype. In 15 of the 18 cases, the chromosomes with HTLV-I integration showed abnormalities. In particular, in two cases with simple chromosome abnormalities, HTLV-I integrated into the abnormal chromosome, but not into the normal chromosome. The HTLV-I proviral integration thus seems to be associated with chromosome abnormalities. In the multistage leukemogenesis of ATLL, these findings indicate that HTLV-I integration might play an important role in the induction of chromosomal instability.