The mammalian cells. This wide variety of

The growing research on the pathogenesis of HTLV-1 reveals the
importance of T cell function. CD4+ T-cells are the main targets of HTLV-1
infection. However, HTLV-1 has the potential to infect a broad range of
cells, including CD8+ T-cells, B-lymphocytes, fibroblasts, endothelial
cells, myeloid cells, as well as other mammalian cells. This wide variety of
target cells is due in part to the ability of the virally encoded envelope
glycoprotein (Env) to bind to various membrane-associated receptors on the
target cells 65. HTLV-I Env is synthesized as a precursor gp6l protein which is proteolytically
cleaved into the gp46 and gp21 glycoproteins. The gp46 surface subunit (SU) and
gp21, the transmembrane region (TM), are non-covalently
linked with each other 66. Similar to their HIV counterparts, it is believed the SU and TM of
HTLV-1 play a crucial role during the
entry process 67. Once HTLV-1 has attached to the host
cell membrane, the fusion process initiates through sequential events between the SU and the cell membrane receptors, including
the glucose transporter (GLUT1), heparin sulfate proteoglycan (HSPG), and the vascular endothelial growth
factor (VEGF)-165 receptor neuropilin-1 (NRP-1). The HTLV-1 SU forms complexes
with the HSPGs, NRP-1, and GLUT1 to trigger fusion of the retroviral and
cellular membranes, which allows releasing the retroviral capsid core into the
cytoplasm of the host cell 5.

The entry process is an important step in the retroviral replication
cycle, and thus can be a promising strategy for antiviral therapy. Several
HIV-1 inhibitors have been described to inhibit HIV entry into target cells,
some of which are FDA approved or in clinical trials. There are no approved therapeutic agents targeting the HTLV-1 entry
process; however, it was reported that synthetic
peptides which could interfere with the
conformational changes of TM subunits potently inhibit Env-mediated membrane
fusion and HTLV-1 entry into host cells 68-70. For example, Mirsaliotis et al. (2008) reported that synthetic peptides based on the leash and ?-helical
region (LHR) of gp21 are potent inhibitors of membrane fusion and HTLV-1
entry 69.

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It has
been shown that some sulfated
polysaccharides such as heparin have inhibitory activities against several retroviruses.
Chondroitin sulfate type E (CSE) and heparin exhibited anti-HTLV-1 activity 71-72. CSE interacts directly with
recombinant Env proteins of HTLV-1 at the C-terminal portion of SU and blocks
the virus binding to a human T cell line (MOLT-4 cells) 71.

1.       Tax

Tax is a 40 kDa phosphoprotein encoded
by an open reading frame in the pX region of the HTLV-1 genome. This viral
regulatory protein plays an essential role in the induction of T-cell
transformation through modulating host signaling pathways and also regulates
viral gene expression. The precise mechanism of HTLV-1 pathogenicity is not yet
clearly understood. It is believed that Tax plays a central role in enabling
the cells to overcome apoptosis and
senescence. Tax increases viral replication by transactivation of
the HTLV-1 promoter in the 5´ LTR region. Also,
Tax modulates the transcription of numerous target genes and also interacts with many host cell proteins involved in cell cycle, cell proliferation, p53 dependent
apoptosis, and DNA repair 73-74 via activating the NF-?B pathway and inducing I?B-? degradation. Tax
expression plays an important role in
initiating cell transformation but it is not essential afterward, and the HBZ protein drives the maintenance of the transformed cells 74-75.

Valproate (2-n-propylpentanoic acid) is a histone deacetylase
inhibitor that stimulates histone hyperacetylation and activation of the HTLV-1
5´ LTR promoter. In 2011, Belrose and colleagues investigated the effect of valproate
on Tax production in cultured lymphocytes from HTLV-1 carriers. They reported valproate
enhanced and prolonged Tax-mRNA expression during short-term culture of
HTLV-1-infected cells 76.

Due to its role in
transformation, Tax was considered as a
potential therapeutic target in ATL. However, Tax transcripts are detected in only 40% of patients with ATL. Thus, the therapeutic
benefit of Tax targeting in HTLV-1-associated diseases may be limited. Cyclosporin
A, a natural cyclic polypeptide from
an extract of soil fungi, is a powerful
immunosuppressant that inhibits cytokine production and T cell activation 77. Ozaki
et al. (2007) observed that cyclosporine A inhibited the production of Tax in HTLV-1
infected T-cells and Tax cDNA transfected cells 78. Niclosamide,
an anti-helminthic drug that is FDA approved for the treatment of
tapeworms, induced degradation of the Tax protein in the proteasome and subsequently inhibited the viral
gene transcription of HTLV-1 79.

2.      
Monoclonal antibodies

The first clinical trial that
tested the efficacy of the anti-CD52 antibody alemtuzumab on 19 patients with
ATL was conducted by Waldmann et al. The authors achieved two complete and four partial responses with the duration of the responses from 9
weeks to more than three years 80. CD25 is an alpha chain of
human interleukin-2 (also called the TAC antigen), which is expressed on ATL
cells 80-81 and the cells infected by HTLV-1. Therefore,
treatment with blocking monoclonal antibodies concomitant with anti-cancer
agents had encouraging results 34, 82.

Monoclonal antibodies against interleukin
15 (IL-15) or its
receptor also suppressed the spontaneous proliferation of peripheral blood
mononuclear cells  (PBMCs) from patients
with HTLV-I-associated myelopathy 83. Humanized
monoclonal antibodies directed to CD52 (Campath-1H or alemtuzumab) and CD2
(siplizumab or MEDI-507) have shown activity in a murine model of ATL or
lymphoma 84-85.

A24 is a neutralizing monoclonal
antibody against the transferrin receptor that induces internalization of the receptor and therefore blocks iron entry into
the cells. Iron deficiency induces cell-cycle arrest and apoptotic processes in
ATL cell lines and primary ATL cells 86.

The CC chemokine receptor 4
(CCR4) is a G-protein-coupled receptor which is preferentially
expressed on the
surface of T-helper
2 and regulatory T-cells. Many T-cell lymphomas such
as ATL display potent
CCR4 expression. Thus, it is a potential
target for antibody-based therapy in the treatment of T-cell neoplasms, especially in ATL. Mogamulizumab (KW-0761) is an anti-CCR4
monoclonal antibody with
a defucosylated Fc region,
which shows marked
antitumor activity in ATL patients 87-88. Ishida et al. reported
results of a follow?up analysis of prior clinical phase I and II studies of
mogamulizumab treatment in
patients with relapsed ATL. They reported that mogamulizumab
monotherapy may improve overall survival in these patients 89.

3.       Cellular proteins

3.1.    
NF-?B inhibitors

The NF-?B pathway is chronically
activated in HTLV-1-transformed
cell lines and freshly isolated ATL cells, even
in the presence of low Tax expression levels. This transcription factor
plays a crucial role in the protection of
the leukemia cells from apoptosis and also their proliferation 90-91. Bay
11-7082 is an NF-?B inhibitor that completely
and specifically abrogated NF-?B DNA
binding 92. The inhibition of NF-?B production
induced apoptosis of HTLV-1-infected T-cells
and prevented primary tumor growth and leukemic infiltration in various organs
in an in vivo mouse model of ATL 93.

The fungal-derived molecule dehydroxymethylepoxyquinomycin (DHMEQ: a
5-hydroxymethyl derivative of epoxyquinomicin
C) is another NF-?B inhibitor. It induced apoptosis in primary ATL cells and cell lines derived
from patients with ATL by blocking NF-?B
activation. DHMEQ also selectively targeted
HTLV-1–infected cells in the peripheral blood of virus carriers in vitro,
resulting in a decreased number of infected cells 94. Indole-3-carbinol (I3C), a naturally occurring component
of Brassica vegetables, is also reported to inactivate NF-?B and is considered a potentially useful therapeutic agent for ATL patients
94.

3.2.    
Histone deacetylases inhibitors

Histone deacetylases (HDACs) catalyze deacetylation of the lysine residues
in histone
amino termini, leading to the condensation of chromatin and repression of
transcription. Inhibition of HDAC activity induces differentiation, cell-cycle
inhibition, and apoptosis in a variety of transformed cells in vitro and
in vivo. Studies indicated that the transformed cells might be more sensitive to HDAC inhibitors
compared with normal cells 95-96. Romidepsin
(depsipeptide, FK228, FR901228), is a member of the cyclic peptide class of
HDAC inhibitors effective in patients
with cutaneous T-cell lymphoma (CTCL) and T-cell
lymphoma 97. It induced apoptosis of HTLV-1-infected T-cell lines and primary ATL cells and suppressed
the expression of NF-?B and AP-1. Additionally,
in vivo use of romidepsin partly inhibits the growth of tumors of
HTLV-1-infected T cells transplanted subcutaneously in severe combined immunodeficiency (SCID) mice 98-99. Several other
HDAC inhibitors such as vorinostat (SAHA), panobinostat (LBH589) and MS-275 have also shown promising
results in preclinical and/or clinical studies against T-cell malignancies.
Vorinostat and romidepsin are FDA-approved drugs
for the treatment of refractory and relapsed CTCL. LBH589 induced apoptosis in ATL-related cell lines, primary
ATL cells and reduced the size of tumors inoculated in SCID mice 100.

3.3.    
DNA replication and repair inhibitors

 Targeting of
DNA replication and repair processes has been proposed as a promising strategy
for cancer therapy 101-102. Recent studies
indicate that HTLV-1-derived cell lines and Tax-expressing cells exhibit defects
in both DNA replication and DNA damage response 103. Moreover, it has been shown that Werner syndrome
ATP-dependent helicases (WRN), which play important roles in replication fork
progression and participate in DNA repair, are highly expressed in human leukemia
cell lines 104-105. In line
with these findings, Moles et al. indicated that WRN activity is
essential for survival of ATL cells. In addition, the WRN inhibitors NSC 19630
and NSC 617145 induce cell cycle arrest and apoptosis, which led to cell death
in HTLV-1-transformed and patient-derived cells 106.

3.4.    
Proteasome inhibitors

 Bortezomib (PS-341), a
peptidyl boronic acid inhibitor of the proteasome, inhibits the function of the
26S proteasome complex 107. In ATL cells, bortezomib inhibits the degradation of I?B-? and prevents translocation of the NF-?B
protein into the nucleus and transcription of its
target genes. This results in suppression
of the NF-?B signaling pathway and induction of ATL cell death 108-109. However,
further investigations are required to clarify clinical utility of such
inhibitors in patients with ATL.

3.5.    
Survivin inhibitors

YM155 (serpantronium
bromide) suppresses survivin, which is an inhibitor of apoptosis and is considered
to play a role in oncogenesis 110. Inhibition of survivin by YM155 suppresses cell proliferation and
induces apoptosis in ATL cells 111-112. In addition, the combination of YM155 with
anti-CD52 monoclonal antibodies was shown
an effective treatment in prolonging survival in a murine model of human ATL
cells 113.

3.6.    
PARP inhibitors

 Poly (ADP-ribose) polymerase (PARP) plays a key role in some
cellular processes including DNA repair 114. A PARP inhibitor, PJ-34, was
shown to induce cell cycle arrest in various human cancers, including acute
myeloid leukemia (AML). In addition to cell cycle inhibition, Bai et al demonstrated that  PJ-34 activates p53 and caspase-3-dependent
apoptosis in HTLV-I-transformed and ATL-derived cell lines 115.

3.7.    
Retinoids

A synthetic
retinoid, ST1926, was recently tested for treating HTLV-1 infection.
Growing evidence indicated that ST1926 downregulates the oncoprotein
Tax, upregulates p53 proteins, and induces cell cycle arrest as well as massive
apoptosis in HTLV-1-infected cell lines 116-117.