Human T-Cell Leukemia Virus Type 1 (HTLV-1) bZIP Factor Upregulates the Expression of ICAM-1 To Facilitate HTLV-1 Infection

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) causes multiple pathological effects, ranging from a form of leukemia to a spectrum of inflammation-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. Lymphocyte functioning antigen 1 (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 an 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 intercellular adhesion molecule 1 (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.

HBZ upregulates myoferlin expression to facilitate HTLV-1 infection

“…The viral protein HBZ was recently shown to enhance HTLV-1 infection by activating ICAM-1 expression [31]. HBZ regulates transcription of many other cellular genes as well as transcription of the HTLV-1 provirus [32].…”

Collagen IV (COL4A1, COL4A2), a Component of the Viral Biofilm, Is Induced by the HTLV-1 Oncoprotein Tax and Impacts Virus Transmission

“…Tax regulates virus transmission by inducing and cooperating with intercellular adhesion molecule 1 (ICAM-1) and inducing polarization of the microtubule organizing center (MTOC), which leads to formation of the VS (Fukudome et al, 1992; Nejmeddine et al, 2005, 2009). Recent work suggests that next to Tax also HBZ contributes to HTLV-1-infectivity by upregulating ICAM-1 (Fazio et al, 2019). Use of single-cycle replication-dependent HTLV-1 reporter vectors revealed that Tax also enhances actin- and tubulin-dependent transmission of HTLV-1 virus-like particles (Mazurov et al, 2010).…”

Human T-Cell Leukemia Virus Type 1 Envelope Protein: Post-Entry Roles in Viral Pathogenesis

“…The primary mechanisms for infection via cell-to-cell contact involve the formation of a virological synapse (VS), driven by the polarization of the microtubule organizing center of an infected cell toward a target cell [61,62]. This polarization is triggered by virus-induced upregulation of intercellular adhesion molecule 1 (ICAM-1) on the infected cell and its interaction with lymphocyte function-associated antigen (LFA-1) on the target cell [52,63,64]. The accumulation of Env and other viral proteins, including p19 matrix and p15 nucleocapsid, as well as viral genomes, has been found at this cell-cell interface; therefore, it is thought that viral assembly is coordinated with VS formation and transmission [52,61].…”