Anti-HTLV-1 immunity combined with proviral load as predictive biomarkers for adult T-cell leukemia-lymphoma.

Human T-cell leukemia virus type 1 (HTLV-1) establishes chronic infection in humans and induces a T-cell malignancy called adult T-cell leukemia-lymphoma (ATL) and several inflammatory diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Persistent HTLV-1 infection is established under the pressure of host immunity, and therefore the immune response against HTLV-1 is thought to reflect the status of the disease it causes. Indeed, it is known that cellular immunity against viral antigens is suppressed in ATL patients compared to HAM/TSP patients. In this study, we show that profiling the humoral immunity to several HTLV-1 antigens, such as Gag, Env, and Tax, and measuring proviral load are useful tools for classifying disease status and predicting disease development. Using targeted sequencing, we found that several carriers whom this profiling method predicted to be at high risk for developing ATL indeed harbored driver mutations of ATL. The clonality of HTLV-1-infected cells in those carriers was still polyclonal; it is consistent with an early stage of leukemogenesis. Furthermore, this study revealed significance of anti-Gag proteins to predict high risk group in HTLV-1 carriers. Consistent with this finding, anti-Gag cytotoxic T lymphocytes (CTLs) were increased in patients who received hematopoietic stem cell transplantation and achieved remission state, indicating the significance of anti-Gag CTLs for disease control. Our findings suggest that our strategy that combines anti-HTLV-1 antibodies and proviral load may be useful for prediction of the development of HTLV-1-associated diseases.

Prevention of acute graft-versus-host disease in adult T-cell leukemia-lymphoma patients who received mogamulizumab before allogeneic hematopoietic cell transplantation.

Mogamulizumab (Mog) is effective against adult T-cell leukemia-lymphoma (ATL), but as we reported previously, Mog increases the incidence of severe acute GVHD when administered before allogeneic hematopoietic cell transplantation (allo-HCT). Here, we report the cases of two ATL patients who did not develop acute GVHD despite receiving Mog before allo-HCT. Case 1: a 63-year-old female who underwent allo-HCT from an HLA-matched donor 2 months after the last dose of Mog. Case 2: a 47-year-old male with ATL that relapsed 3 months after first allo-HCT. He received eight doses of Mog and underwent a second allo-HCT from a haploidentical donor 4 months after the last dose of Mog. Mog blood levels were measured and lymphocytes analyzed by mass cytometry. Mog blood levels measured before starting the conditioning regimens were low. A small proportion of regulatory T cells (Tregs) was detected before and shortly after allo-HCT. When using Mog before allo-HCT, it is important to consider the number of Mog doses and the interval from the last dose of Mog to allo-HCT. Analyzing Mog blood levels and Treg counts before and after allo-HCT should also be useful.

New analogs of pochonicine, a potent ß-N-acetylglucosaminidase inhibitor from fungus Pochonia suchlasporia var. suchlasporia TAMA 87.

Three novel analogs of pochonicine (1) were isolated from a solid fermentation culture of the fungal strain Pochonia suchlasporia var. suchlasporia TAMA 87, and their structures were elucidated as 7-deoxypochonicine (2), 6-deoxypochonicine (3), and 6,7-dideoxypochonicine (4). These analogs were found to possess the same stereochemistry as pochonicine. Comparison of ß-N-acetylglucosaminidase (GlcNAcase) inhibitory activity between these analogs and pochonicine suggested that the C-6 hydroxy group of pochonicine was essential to its potent GlcNAcase inhibitory activity and that the C-7 hydroxy group also contributed to the activity, but to a lesser extent than the C-6 hydroxy group.

In vivo dynamics and adaptation of HTLV-1-infected clones under different clinical conditions.

Human T-cell leukemia virus type 1 (HTLV-1) spreads through cell contact. Therefore, this virus persists and propagates within the host by two routes: clonal proliferation of infected cells and de novo infection. The proliferation is influenced by the host immune responses and expression of viral genes. However, the detailed mechanisms that control clonal expansion of infected cells remain to be elucidated. In this study, we show that newly infected clones were strongly suppressed, and then stable clones were selected, in a patient who was infected by live liver transplantation from a seropositive donor. Conversely, most HTLV-1+ clones persisted in patients who received hematopoietic stem cell transplantation from seropositive donors. To clarify the role of cell-mediated immunity in this clonal selection, we suppressed CD8+ or CD16+ cells in simian T-cell leukemia virus type 1 (STLV-1)-infected Japanese macaques. Decreasing CD8+ T cells had marginal effects on proviral load (PVL). However, the clonality of infected cells changed after depletion of CD8+ T cells. Consistent with this, PVL at 24 hours in vitro culture increased, suggesting that infected cells with higher proliferative ability increased. Analyses of provirus in a patient who received Tax-peptide pulsed dendritic cells indicate that enhanced anti-Tax immunity did not result in a decreased PVL although it inhibited recurrence of ATL. We postulate that in vivo selection, due to the immune response, cytopathic effects of HTLV-1 and intrinsic attributes of infected cells, results in the emergence of clones of HTLV-1-infected T cells that proliferate with minimized HTLV-1 antigen expression.

Total synthesis of citridone A.

The first total synthesis of citridone A has been achieved through regioselective intramolecular iodocyclization and regio- and stereoselective Pd(0)-catalyzed coupling as key reactions.

The evolution of the phenylacetic acid degradation pathway in bacteria.

The phenylacetic acid (PhAc) degradation pathway becomes an interesting model for the catabolism of aromatic compounds. To determine the molecular basis for this environmentally important process, we did a phylogenic analysis based on the PhAc CoA ligase gene. It suggests that the PhAc CoA ligase genes are distributing widely and subject to frequent lateral gene transfer within and across bacterial phylum.