Human T-cell lymphoma virus (HTLV) or T-lymphotropic virus type 1 is a member of the deltaretrovirus family, which includes the simian T-lymphotropic virus type 1 (STLV-1) and bovine leukemia virus (BLV). There are four known strains of HTLV: HTLV-1, HTLV-2, HTLV-3, and HTLV-4. HTLV-1 and -2 are prevalent around the globe while HTLV-3 and -4 have been reported only in Central Africa. HTLV-1 and STLV-1 are highly related to STLV-2 and -3 respectively. It is believed that HTLVs evolved through interspecies transmission between monkeys and humans. Genetic variation among HTLV-1 strains is reported to be less than 8% while HTLV-1 and HTLV-2 shows 70% nucleotide homology. HTLV-1 is the first retrovirus to be described and it is estimated that about 20 million people are infected with it worldwide. HTLV-1 is the direct cause of Adult T cell leukemia/lymphoma (ATLL) and also causes many other chronic inflammatory diseases such as myelopathy/ tropical spastic paraparesis (HAM/ TSP), chronic renal failure, and monoclonal gammopathy due to the induction of immunodeficiency. The virus mainly infects CD4+ T lymphocytes without evidence of neuronal infection. HTLV-2 is rarely pathogenic and is associated with sporadic neurological disorder. No disease is associated with HTLV-3 and HTLV-4.
Epidemiologically, the virus is endemic in Southwestern Japan, Central Africa, the Caribbean Islands, and Australia (among the Aborigines). Available data shows that the virus prevalence has some ethnic distribution. In these endemic areas, the seroprevalence rate ranges from 0.1 to 30%. After a long period of latency, an estimated 5% of people infected with HTLV-1 will develop ATL. HTLV-2 is prevalence among IDUs in the USA, Europe, South America, and Southeast Asia. HTLV-1 is transmitted through three main routes: 1. Breastfeeding from mother-to-child, 2. Sexual contact from males to females, and 3. Needle sharing mediated by exposure to contaminated blood. The mother-to-child transmission is the predominant mode of transmission. This chapter will review viral genes associated with HTLV pathogenesis.
3.1 Genomic Description of HTLV and Infectivity: The HTLV-1 is a single-stranded diploid RNA virus with a proviral genome of 9,030-9,040 nucleotide long containing two flanking long terminal repeat (LTR) sequences. The LTRs is made up of 3 components: a unique 3’ (U3) region, a repeated (U) region, and a unique 5’ region (U5). The HTLV-1 genome (figure 1) is packed in the viral core with the viral nucelocapsid protein (NC, p15), which is surrounded by capsid (CA, p24), and matrix (MA, p19) proteins. The virus encodes the structural protein Gag (NC, CA, and MA) and Env and the enzymes RT, RNase H (RH), integrase, and protease. The env gene encodes the surface unit (SU) gp46 and transmembrane unit (TM) gp 21 proteins. The pX region also encodes the accessory proteins as well as regulatory proteins Tax and Rex.
Figure1: Structure of HTLV-1 genome: The gag gene encodes the matrix (MA),capsid (CA), and nucelocapsid (NC) proteins. The pol gene encodes reverse transcriptase (RT), RNase H (RH), and integrase (IN). The pX region encodes p13, p12, and p30, etc. HBZ is encoded by the antisense frame of the provirus.
The accessory proteins are spliced alternatively and translated into different initiation sites. These genes encode novel proteins such as p12/p8, p30, and p13. The anti-sense region corresponds to the px region. The env gene encodes HBZ. The roles of these proteins will be discussed in details. The envelope protein of the virus interacts with glucose transporter GLUT-1, heparin sulfate proteoglycans (HSPGS) and neuropilin -1 (NRP1) to promote viral entry into the cells. Productive infected HTLV-1 cells establish viral synapse through cell to cell contact with uninfected T cells mediated by interaction between ICAM-1 and LFA-1 adhesion molecule. The virological synapse mediates the accumulation and spread of the core complex of the virus and genome to uninfected cells.
3.2 Tax Protein: Transactivator/oncoprotein, Tax is a regulatory protein that immortalizes human CD4+ memory T cells but when expressed alone, they rarely transform T- cells. This means there should a co-factor which helps facilitate transformation. A study found that Tax proteins displayed differential ability to immortalize human CD4+Foxp3 T cell with characteristic expression of CTLA-4 and GITR. Tax impact quite a number of cellular processes. All these activities have been implicated in the development of HTLV-1. These cellular factors include CREB and CREM proteins, NF-kB p50, p65, and C-Rel proteins and SRF. In addition to these transcription factors, Tax also binds to NK-kB p105, p100, and IKR proteins which are inhibitors of NF-kB. The Tax binding domain (Figure 2) is the IKB proteins which were identified as ankyrin motifs.
Figure 2: A. Schematic representation of Tax protein-protein interaction domains. B, Schematic representation of known ubiquitination SUMOylation and acetylation of Tax (Source: Lavorgna and Harhaj, 2014)
The ankyrin motif are also found in other proteins involves in cell cycle control and tissue differentiation. This suggests that there is possible interaction between these proteins and Tax.
Tax is concentrated in different compartment of the cell including cytosol, nucleus, Golgi apparatus and endoplasmic reticulum (ER) which assist the virus to replicate and persist. Tax activates the transcription factor NF-kB in the cytoplasm and cis- Golgi while also regulating viral gene expression in the nucleus. To coordinate these highly essential functions, Tax forcefully moves between different sub cellular compartments through nuclear localization sequences (NLS) and nuclear export sequence (NES). Tax localization can be influenced by specific stimuli like genotoxic stress which triggers Tax nuclear export. Tax can be secreted into the extracellular compartment where cell-free Tax can play a role inflammation and pathogenesis. The large number of cellular proteins and dynamic localization patterns suggests that Tax has an effect on cell proliferation, survival, and pathogenesis. Tax perturbs signaling pathways leading to Upregulation of host cell factors. Amongst these is the actin-bundng protein Fascin, a major marker of several types of cancer. The role of Fascin has been elucidated in a study by Mohr et al. They identified a triple mode of transcriptional induction of Fascin which requires NF-KB dependent promoter activation, a Tax-responsive region in the Fascin promoter, and a promoter-independent inhibitor of PP2. From this, they concluded that Tax regulated Fascin by a multitude of signals. The NK-kB pathway is also a key cellular target. Tax interacts with specific components of NF-kB pathways to drive proliferation, survival, and transformation of HTLV-1 infected T cells. NF-kB is a family of transcription factors that regulates diverse function such as cell cycle, apoptosis, inflammation, development of lymphoid organogenesis. It also causes the activation of the canonical NF-kB pathway. Furthermore, Tax activates host E3 ligase (TRAF6) to help stabilize MCL-1 and reduce the number of cell death triggered by genotoxic stress agents and chemotherapy drugs. Tax inactivates a number of DUBS that opposes NF-kB activation. Although Tax disturbs the host ubiquitin- proteasome pathway for NF-kB activation and cell transformation, there is still lot to be done to understand the precise mechanisms. We still do not a clue as to the identity of the K63-U6 specific E3/ or E4 or the potential roles of the E2s and/ or E3s. As a result, mass-spectrometry- based proteomic screening or yeast two-based hybrid screening has a role in identifying ubiquitin-proteasome components that interacts with Tax. In addition, the screening of E2 and E3 enzyme siRNA libraries might identify key component that regulate Tax function, stability, and or trafficking. Elucidating the complex interplay between Tax and the host ubiquitin-proteasome mechanism might go a long way to identify drug targets against Tax which will be useful in HTLV-1-associated diseases.
3.3 The HBZ Gene: The HTLV-1 bZIP factor (HBZ) just like Tax is found in the pX region and it is encoded in the plus- and minus- tail of the pX region. It has a number of functions on the T-cell signaling pathway and associated with HTLV-1 pathogenesis. The HBZ gene (figure 2) has 2 transcripts: a spliced form (sHBZ) and an unspliced form (usHBZ). The protein of the spliced and unspliced HBZ transcripts does not have TATA and contained initiators and downstream promoter elements. The spliced and unspliced HBZ genes are translated into a polypeptide of 206 and 209 amino acids respectively. Both forms are made of 3 domains: N-terminal activation domain (AD), central domain (CD), and basic ZP domain (bZIP) in the C-terminal. There are two LXXLL-like motifs found within the N-terminal AD domain of HBZ.
Figure 3: Schematic representation of HBZ domain
Both are important for the binding of p300/CBP. The HBZ protein is localized in the nucleus in a speckled manner. Three nuclear localization signals (NGLs) were identified with two regions in the CD of HBZ and a basic region of the bZIP domain. The different between the two transcripts are 7 amino acids in their N-terminal which causes significant difference in the two proteins. The half-life of usHBZ protein is much shorter than that of sHBZ in ATL. This is attributed to the fact the sHBZ gene is more dominant than suHBZ.
A number of studies have characterized the role of HBZ in HTLV-1-associated pathogenesis. In a study Mitagami et al found that HBZ transgenic (HBX-Tg) mice that express HBX-CD4+ T cells developed systemic inflammatory disease, cellular immunodeficiency , and T-cell lymphomas. This suggests that HBZ plays important role in HTLV-1 mediated pathogenesis. In HBZ- Tg, the numbers of CD4+ CD25+ T cells and effector /memory CD4+ T-cells were increase as in ATL cases. In another study, Mitobe et al reported that the transduction of mouse T-cells with specific mutants of HBZ that distinguished between its RNA and protein activity resulted in differential effects on T-cell proliferation and survival. The HBZ RNA increase cell number by attenuating apoptosis BZ while HBZ protein induced apoptosis. However both HBZ RNA and protein promoted S-phase entry of T-cells. They identified a HBZ 50bp coding sequence that was essential for RNA-mediated cell survival. When they profiled T-cells expressing wild-type HBZ, or protein, they found that HBZ RNA was associated with genes that promote cell cycle proliferation and survival. HBZ protein was however more closely associated with immunological properties of T-cells. They reported of survivin which inhibits apoptosis. Inhibition of survivin led to impaired proliferation of several ATL cells. This means that HBZ is essential in the pathogenesis of ATL. Furthermore, HTLV-1 infection is associated with chronic inflammation in the CNS, skin, and lungs. Because HTLV-1 directly infects CD4+ T cells, it should modulate the host immune response not only via viral antigen stimulation but also via CD4+ T cell-mediated immune deregulation. Earlier it was reported that Foxp3+ CD4+ T cells are increased in HTLV-1 infection. One of the central questions asked in relation to HTLV-1 pathogenesis is why HTLV-1 induces inflammation despite the increase in Foxp3+ cells. A study found that most increase in Foxp3+ cells in HBZ-Tg mice or HAM/TSP patients were not naturally derived Treg cells but rather induced Treg cells since iTreg cells could serve as source of proinflammatory CD4+. Therefore Yamamoto-Taguchi et al concluded that HTLV-1 causes abnormal CD4+ T cells differentiation by expressing HBZ which is believed to play a crucial role in chronic inflammation associated with HTLV-1. This study further highlights the role of HBZ in the pathogenesis of HTLV-1-associated diseases. HBZ can therefore serve as a novel target for therapeutic interventions.
3.4 Rex protein : HTLV Rex is a trans-acting regulatory protein responsible for the nuclear export of unspliced gag/pol and incompletely spliced env mRNAs into the cytoplasm. It binds to the Rex responsive element (RxRE) found on the viral mRNAs and to the chromosome maintenance region 1 (CRM1) cellular export factor. Mutational analysis of HTLV-1 and HTLV-2 showed that Rex has several domains within the protein necessary for its function. These include the arginine-rich- N-terminal RNA binding domain (RBD) that overlaps with the nuclear export signal (NES), and two regions that flank the NES which has been shown to be important for Rex-Rex multimerization. A novel carboxyl terminal domain containing key phosphorylation sites essential for function has been described for HTLV-2 Rex. Rex therefore function includes regulating the cytoplasmic levels of genomic RNA and expression of the structural as well as enzymatic gene products that are critical for production of virus progeny. It has therefore been suggested that Rex plays an essential role in the transition from early to late stage of HTLV-1 infection and is required for efficient spread of the virus. It has also been suggested that Rex function’s modulation may determine whether a productively infected cell becomes latent. Therefore HTLV-1 absolutely requires Rex for efficient persistent infection in vivo.
3.5 Env protein: Like other retroviruses, HTLV-1 virion is surrounded by a proteo-lipid envelope made of protein with transmembrane (TM) and surface (SU) subunits. The most important factor in HTLV-1 pathogenesis is the product of the viral env gene (Figure 4) which is cleaved by cellular protease into non-covalently linked TM subunit gp21 and extracellular subunit gp46, with the later made of an N-terminal Receptor-Binding Domain (RBD), a mid Proline Rich Region (PRR), and a C-terminal domain.
Figure 4: The structure of Env protein (Source: Hoshino, 2012)
HTLV-1 env gene is encoded by 488 amino acid precursor protein which generates a 62kDa protein (gp62) after the addition of five N-glycan chains. Four are in the SU. The gp62 is cleaved at a trypsin-like proteolytic site spanning residues 309-312 into gp46 and gp21 subunit. The SU is entirely extracellular and remain linked to the virus through binding to TM which is embedded in the viral envelope.
3.6 Mechanism of HTLV-1 entry: Just like all retroviruses, HTLV-1 entry into target cells involves interaction between the viral envelope glycoprotein, SU, TM, and host cell receptors. The SU protein is involved in receptor recognition while the TM protein triggers the fusion of viral and cellular membranes thereby allowing entry of viral particles. With some retroviruses such as ecotropic murine leukemia virus, a single molecule is enough for attachment and entry while with others such as HIV, multiple molecules are required. Our current understanding of HTLV-1 entry is based on data from several researchers which showed that entry into host cell is multi-receptor dependent involving glucose transporter I (GLUT I), neuropilin-I (NRP-I), and heparan sulfate proteoglycans (HSPG). GLUT-I specifically bind to a truncated soluble form of HTLV-I and HTLV-2 SU proteins. Studies showed that over expression of GLUT-I in an HTLV-1 resistant cell line was associated with increased HTLV-1 titer. The HSPG is a glycosamine-glycine consisting of a core protein and heparan sulfate (HS) polysaccharide chains. Studies showed that enzymatic reduction of the cell surface levels of HSPG led to reduction of both the binding of soluble HTLV-1 SU and the titer of HTLV-1 Env pseudotype viruses in non T-cell lines. Jones et al also showed that HSPG is also involved in the binding and entry of HTLV-1 into CD4+ T cells. The NRP-1 is a cell surface protein known to function as co-receptors for some heparin-binding pro-angiogenic cytokines, principally members of vascular endothelial growth factor (VEGF) family, and class 3 semaphorins. Studies have shown that NRP-1 binds HTLV-1 SU and necessary for efficient HTLV-1 entry. The study also showed that NRP-1, GLUT1, and HTLV-1 SU form stable tripartite complex when co expressed in cells.
HTLV-1 entry is through viral attachment and virus/cell fusion. The initial attachment is mediated by the interaction between the C-terminal domain of the virus gp46 and HS moieties of cell surface HSPG, of activated CD4+ T cells or DC. It has been found that the length of HS plays a role in the susceptibility of cells to HTLV-1 entry; with shorter chains facilitating closer attachment of the virus to the target cells. This leads to viral binding to NRP-1. The viral gp46 RBD domain contains KPxR motif which has been identified as NRP-1 binding site. The NRP-1 b-domain binds to VEGF and is required for HTLV-1 entry. HTLV-1 utilizes HSPG and NRP-1 complex through molecular mimicry of VEGF. After stable binding of HTLV-1 to HSPG and NRP-1, GLUT-1 binding sites are exposed. This might be due to conformational changes in gp46. The HTLV-1 binds to GLUT-1 at its large extracellular loop (ECL1). The amino acids residues found in the RBD of gp46 that are essential for GLUT-1 binding are distinct from the binding sites of NRP-1 and HSPGs, indicating that a multi-receptor complex is formed. Antibodies to GLUT-1 alter HTLV-1 fusion and infection but not binding to CD4+ T cells. This means GLUT-1 is important for fusion. For cell-to-cell transmission to be effected, there is the need for cell contact between an infected cell and uninfected cell as well as the formation of Virological synapse (VS). In a study, Igakura et al reported that infected T-cell formed conjugate with neighboring uninfected cell resulting in the polarization of the microtubule organization center (MTOC) to the point of contact. This polarization of MTOC is promoted by the interaction of intercellular adhesion molecules -1 or -3 (ICAM-1, ICAM-3) or the vascular cell adhesion molecule-1 (VCAM-1) on infected cells with β-integrins, such as lymphocyte function associated antigen-1 (LFA-1) or uninfected cells. The HTLV-1 genome, Env, and Gag protein accumulate at the point of contact and then egress into the VS and interact with receptor on the conjugated, uninfected cell. Studies have shown that NRP-1 and GLUT-1 co-localize at the point of contact and presumably promote the formation of the VS which is also facilitated by HTLV-1 Tax. Although little is known about this mechanism, it is believed that it occurs through endocytosis of the virus as found in HIV.
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