Modes of Human T Cell Leukemia Virus Type 1 Transmission, Replication and Persistence

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that causes cancer (Adult T cell Leukemia, ATL) and a spectrum of inflammatory diseases (mainly HTLV-associated myelopathy-tropical spastic paraparesis, HAM/TSP). Since virions are particularly unstable, HTLV-1 transmission primarily occurs by transfer of a cell carrying an integrated provirus. After transcription, the viral genomic RNA undergoes reverse transcription and integration into the chromosomal DNA of a cell from the newly infected host. The virus then replicates by either one of two modes: (i) an infectious cycle by virus budding and infection of new targets and (ii) mitotic division of cells harboring an integrated provirus. HTLV-1 replication initiates a series of mechanisms in the host including antiviral immunity and checkpoint control of cell proliferation. HTLV-1 has elaborated strategies to counteract these defense mechanisms allowing continuous persistence in humans.

Keywords: HBZ; HTLV-1; Tax; viral persistence; viral replication.

Figure 1

Model of HTLV-1 replication (a) HTLV-1 transmission occurs by breastfeeding, sexual intercourse, or blood transfusion. Except for blood transfer, initial infection requires crossing of the mucosal barrier by several mechanisms: (i) transmigration of HTLV-1 infected macrophages, (ii) transcytosis of viral particles, (iii) release of newly produced virions from the basal surface of infected epithelial cell, (iv) bypass of HTLV-1 infected cells through a damaged mucosa. HTLV-1 can then infect mucosal immune cells directly (cis-infection) or via antigen-presenting cells (APCs); (b) APCs can either become infected or transfer membrane-bound extracellular virions to T-cells (trans-infection). Cell-to-cell transfer of virions involves different non-exclusive mechanisms: a virological synapse, cellular conduits, or extracellular viral assemblies. Infection of resident cells occurs either in the mucosa or in secondary lymphoid organs. Soon after primary infection, HTLV-1 replicates by cell-to-cell infection (i.e., the infectious cycle) or (c) by mitotic division of a cell containing an integrated provirus (clonal expansion). Since an antiviral immune response is quickly initiated, the efficacy of the infectious cycle is severely dampened down soon after infection.

Figure 2

Tax and HBZ promote proliferation and persistence of the infected cell. Tax activates survival pathways (CREB/Akt/NFkB), promotes mitosis (CDKs), and inhibits tumor suppressors (p53, TP53INP1, Bcl11B). Tax-mediated growth-promoting activities are counteracted by HBZ, mitigating unrestrained proliferation. The host immune response further controls infected cell proliferation. Tax-induced proliferation creates replicative stress and generates reactive oxygen species (ROS). Tax interacts with the mitotic checkpoint control protein Mad1 thereby inducing clastogenic damage. Tax attenuates the DNA damage response (DDR) induced by unscheduled cell proliferation. Inhibition of the DDR allows cells to accumulate DNA lesions and stabilize mutations. If uncontrolled by senescence or cell death mechanisms, growth-promoting mutations pave the way to disease development.