Human T-cell Lymphotropic Viruses: Review and Prospects for Antiviral Therapy

Abstract

The human T-cell lymphotropic viruses types I and II (HTLV-I, II) pose challenges to researchers and clinicians who seek to unveil mechanisms of viral transformation and pathogenesis. HTLV-I infection in humans is associated with a wide array of primary and secondary diseases ranging from mild immunosuppression to adult T-cell leukaemia/lymphoma and HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a neurological degenerative syndrome. As retroviruses, HTLV-I and II share similar replicative cycles with human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome. However, in contrast to HIV-I which destroys CD4+ T cells, HTLV-I and II can preferentially transform a CD4+ T-cell subset to an unrestricted growth state. HTLV-I and II, along with simian T-lymphotropic virus (STLV) and bovine leukaemia virus (BLV), form a phylogenetic group which is distinct from ungulate, non-human primate and human lentiviruses such as visna, simian immunodeficiency virus (SIV), and human immunodeficiency viruses types 1 and 2. The proviral genome of HTLV-I is flanked at the 5′ and 3′ ends by long terminal repeats (LTR) and is further subdivided into structural gag and env genes, a pro gene encoding an aspartyl protease, a pol gene which encodes reverse transcriptase and endonuclease, and the regulatory gene elements tax and rex. Regions within the LTR contain recognition sites for cellular proteins and the tax gene product that collectively promote viral expression. Tax-mediated activation of cellular genes involved in growth and differentiation is suspected to play a dominant role in the leukaemogenic process associated with HTLV-I infection. Differential rex-regulated splicing of viral message gives rise to transcripts encoding the polyprotein precursor gag-pro-pol (unspliced), envelope (single spliced), or tax/rex (doubly spliced). The 100nm HTLV virion contains an electron-dense core surrounding a divalent-single stranded DNA genome. This core is in turn enclosed by concentric shells of matrix protein and an outer lipid bilayer, the latter acquired as the virus buds from the surface of the infected cell. Envelope glycoproteins associated with the outside of this lipid bilayer can interact with viral receptors on cells and mediate virus entry. Antiviral strategies have been directed at inhibiting viral entry into cells (sulphated and non-sulphated polysaccharides, vaccines), blocking of viral replication (AZT, suramin), intracellular immunization (transdominant repression of rex), and elimination of virus infected cells (IL-2 receptor-directed toxins). Serological screening of the blood supply and curtailing breast feeding of children by HTLV-I + mothers have likely had a major impact in preventing HTLV-I infection.

The solution structure of the bovine leukaemia virus matrix protein and similarity with lentiviral matrix proteins.

“…Despite this, both the HTLV/BLV group and the lentiviruses share a similar replicative life cycle. However, whereas HIV destroys CD4 T cells, HTLV can transform CD4 T cells to an unrestricted growth rate (Palker, 1992). Retroviral replication is initiated by the penetration of the virion core into the host cell.…”