HTLV-1 bZIP factor upregulates the expression of ICAM-1 to facilitate HTLV-1 infection [Virus-Cell Interactions]

Human T-cell Leukemia Virus type 1 (HTLV-1) causes multiple pathological effects, ranging from a form of leukemia to a spectrum of inflammatory-mediated diseases. These diseases arise from one or several infected CD4+ T-cells among thousands acquiring proliferation and survival advantages and ultimately becoming pathogenic. Given the low incidence of HTLV-1-associated diseases among carriers, such cellular evolutionary processes appear to occur rarely. Therefore, infectious spread of HTLV-1 within the T-cell population may be one underlying factor influencing disease development. Free HTLV-1 virions are poorly infectious, so infection of T-cells relies on direct contact between infected and target cells. Following contact, virions pass to target cells through a virological synapse or cellular conduits, or are transferred to target cells within an extracellular matrix. LFA-1 on the surface of the target cell engaging with its ligand, ICAM-1, on the surface of the infected cell (effector cell) initiates and stabilizes cell-cell contact for infection. We found that stable expression of the HTLV-1 accessory protein, HTLV-1 bZIP factor (HBZ), in Jurkat T-cells increases homotypic aggregation. This phenotype was attributed to elevated ICAM-1 expression in the presence of HBZ. Using a single-cycle replication-dependent luciferase assay, we found that HBZ expression in Jurkat cells (used as effector cells) increases HTLV-1 infection. Despite this effect, HBZ could not replace the critical infection-related functions of the HTLV-1 regulatory protein, Tax. However, in HTLV-1-infected T-cells, knockdown of HBZ expression did lead to a decrease in infection efficiency. These overall results suggest that HBZ contributes to HTLV-1 infectivity.

Importance

Human T-cell Leukemia Virus type 1 (HTLV-1) causes a variety of diseases, ranging from a fatal form of leukemia to immune-mediated inflammatory diseases. These diseases occur rarely, arising from one or a small subset of virally-infected cells infrequently evolving into a pathogenic state. Thus, the process of HTLV-1 cell-to-cell transmission within the host helps influence the probability of disease-development. HTLV-1 primarily infects T-cells, and initially spreads within this cell population when virally-infected T-cells dock to uninfected target T-cells and then transfer HTLV-1 virus particles to the target cells. Here we found that the viral protein HTLV-1 bZIP factor (HBZ) promotes infectivity. HBZ accomplishes this task by increasing the surface abundance of a cellular adhesion protein known as ICAM-1, which helps initiate and stabilize contact (docking) between infected and target T-cells. These results define a novel and unexpected function of HBZ, diverging from its defined functions in cellular survival and proliferation.

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