Role of Annexin A1 expression in HTLV-1-mediated pathogenesis. - PROJECT SUMMARY The complex retrovirus, human T-cell leukemia virus type 1 (HTLV-1) causes a fatal leukemia known as adult T-cell leukemia (ATL). In vivo, HTLV-1 primarily infects CD4+ T-cells, with ATL arising when one infected T-cell undergoes a series of events leading to its immortalization and subsequent transformation, and ultimately to the disease. This process is believed to be influenced by the genomic site where the provirus is integrated. Thus, the efficiency of viral infection within the T-cell population is believed to relate to the risk of developing ATL. Two viral proteins, Tax and HBZ, promote ATL development and maintenance of the malignant phenotype, and also viral infection. While both proteins regulate transcription, they frequently impart their effects on the cell by modulating expression of separate sets of genes. In lieu of this pattern, we found that both Tax and HBZ repress ANXA1 expression, which coincides with repressed ANXA1 expression in HTLV-1-infected T-cell lines. ANXA1 encodes annexin A1 (AnxA1) a phospholipid-binding protein that, upon secretion or translocation to the cell surface, acts to counteract inflammation during innate immune responses. Separately, AnxA1 facilitates early stages of chemotherapy-induced immunogenic cell death (ICD), a process in which dying cancer cells expose a specific set of damage-associated molecular patterns (DAMPs). These DAMPs orchestrate signaling that leads to an adaptive immune response to tumor-associated antigens produced by the cancer cells. Through ICD, cancer cells that have survived chemotherapy are eliminated by the immune system. We believe repression of AnxA1 expression imparts effects on viral infection and the chemotherapeutic resistance of ATL. Viral infection requires contact between infected and target T-cells, which is facilitated by overexpression of specific surface adhesion molecules on infected T-cells that serve as ligands for integrin complexes on target T-cells. Vascular cell adhesion molecule 1 (VCAM-1) is one adhesion molecule abnormally expressed by infected T-cells. During innate immune responses, VCAM-1 is upregulated on endothelial cells to promote stable binding of leukocytes and their subsequent trans-endothelial migration. AnxA1 binds and blocks access to VCAM-1 to inhibit adhesion between endothelial cells and leukocytes. Given these observations, Specific Aim 1 characterizes the influence of abnormal VCAM-1 expression in conjunction with repressed AnxA1 expression by HTLV-1-infected T-cells on viral infection. During early ICD, AnxA1 is a dual functioning DAMP in that it promotes recruitment of dendritic cells to tumor cell corpses and also serves as an “eat me” signal for phagocytosis of corpse material. Given these functions, Specific Aim 2 analyzes early ICD-mediated events initiated by anthracycline-induced death of HTLV-1-transformed T-cells, comparing repressed versus restored AnxA1 expression. Addressing Aim 1 may help establish therapeutic approaches to reduce the risk of HTLV-1-mediated pathogenesis through inhibition of viral infection. Addressing Aim 2 may help render chemotherapy for ATL patients efficacious and less toxic.
