Abstract
Human T-cell leukemia virus type 1 (HTLV-1) was the first human retrovirus discovered. Studies on HTLV-1 have been instrumental for our understanding of the molecular pathology of virus-induced cancers. HTLV-1 is the etiological agent of an adult T-cell leukemia (ATL) and can lead to a variety of neurological pathologies, including HTLV-1-associated-myelopathy/tropical spastic paraparesis (HAM/TSP). The ability to treat the aggressive ATL subtypes remains inadequate. HTLV-1 replicates by (1) an infectious cycle involving virus budding and infection of new permissive target cells and (2) mitotic division of cells harboring an integrated provirus. Virus replication initiates host antiviral immunity and the checkpoint control of cell proliferation, but HTLV-1 has evolved elegant strategies to counteract these host defense mechanisms to allow for virus persistence. The study of the molecular biology of HTLV-1 replication has provided crucial information for understanding HTLV-1 replication as well as aspects of viral replication that are shared between HTLV-1 and human immunodeficiency virus type 1 (HIV-1). Here in this review, we discuss the various stages of the virus replication cycle—both foundational knowledge as well as current updates of ongoing research that is important for understanding HTLV-1 molecular pathogenesis as well as in developing novel therapeutic strategies.
Highlights
Human T-cell leukemia virus type 1 (HTLV-1) was independently discovered in 1980 by two research groups and identified as the etiological agent of an adult T-cell leukemia (ATL) [1,2].As the first human retrovirus discovered, research on HTLV-1 laid the foundational framework for subsequent studies of human immunodeficiency virus type 1 (HIV-1), infectious causes of cancer, and the molecular mechanisms of leukemogenesis [3].Shortly after the discovery of HTLV-1, another human retrovirus was discovered—human T-cell leukemia virus type 2, HTLV-2—which closely resembled HTLV-1 in genome structure and nucleotide sequence [4]
How HTLV-1 RNA traffics through the cytoplasm in order to get to the plasma membrane is poorly understood, but a recent study with HIV-1 genomic RNA (gRNA) suggests that the viral gRNA diffuses through the cytoplasm to the membrane [93]
It is likely that the emergence of human T-cell leukemia virus type 3 (HTLV-3) and human T-cell leukemia virus type 4 (HTLV-4) may be attributable to recent STLV zoonotic transmission events, as STLV-4 is known to be endemic in African gorillas, and phylogenetic analyses have shown that HTLV-4 is not an ancient human virus but recently emerged in the human population [120]
Summary
Human T-cell leukemia virus type 1 (HTLV-1) was independently discovered in 1980 by two research groups and identified as the etiological agent of an adult T-cell leukemia (ATL) [1,2]. HTLV-1 is the etiological agent of ATL as well as a variety of neurological pathologies, primarily HTLV-1-associated-myelopathy/tropical spastic paraparesis (HAM/TSP) [10]. ATL generally presents after a long latency in patients infected during childhood This is in contrast to HAM/TSP, which is associated with infection later in life [13]. Unlike ATL, which appears to have a complex and multi-faceted pathology, the incidence of HAM/TSP has been shown to correlate with HTLV-1 proviral loads as well as the site of proviral integration [20,21]. The recent advances help to provide further reason for hope in effective therapeutic options for HTLV-1-infected individuals
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