In potential targets for antiretroviral therapy. These

In the absence of an
effective vaccine against HTLV-1 infections 5, drugs are the only tools
that can be used to treat infected patients. Antiretroviral therapy does not
eliminate viral reservoirs, but it does disrupt the virus life cycle and reduce
the viral replication rate. Effective antiretroviral therapy for other
retroviruses was reported to result in indefinite viral suppression,
immunological recovery and improved the overall
quality of life in the patients. Several
steps in the retrovirus replication cycle are potential targets
for antiretroviral therapy. These steps can
be divided into entry steps and post-entry steps. The viral envelope
glycoproteins and their receptors are involved in entry steps, and post-entry steps involve viral replication
enzymes, accessory gene products and the cellular proteins with which they
interact 18.

Entry inhibitors are a class
of antiretroviral drugs that block retrovirus entry into target cells. The
success of human immunodeficiency virus (HIV) entry inhibitors suggests that envelope glycoproteins of HTLV-1
also could be attractive targets for
antiviral therapy. All human retroviruses, including HTLV and HIV, encode three
enzymes, PR, RT and IN required for viral
replication. These key enzymes are
attractive targets for antiviral therapy and have been successfully targeted in HIV-1 infection. Based on the successful
use of inhibitors of these enzymes in HIV-1 therapy, the enzymes involved in HTLV-1
replication are also the primary targets for drug design 5, 19. Moreover, accessory
proteins including Tax and HBZ might also serve as targets for antiretroviral chemotherapy.

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1.       Inhibition of HTLV-1 enzymes

1.1.     Reverse transcriptase

Once the retrovirus has attached to the cell surface, retroviral
infection is initiated by fusion of the
viral and cellular membranes. Membrane fusion allows for the retroviral core,
which contains the retroviral RNA genome along with retroviral proteins, to be released into the cytoplasm of the cell.
After the retroviral core components entered the cytoplasm of the host cell,
the next step is a reverse transcription
of the retroviral RNA. Reverse transcription is a unique process that is
responsible for the conversion of single-stranded RNA (ssRNA) to double-strand
DNA (dsDNA) 20-21. Reverse transcription is catalyzed by the multifunctional, retrovirally
encoded enzymes designated as RTs, discovered in 1970 by Temin and Baltimore 22-23. These enzymes possess two
enzymatic functions, an RNA-dependent DNA
polymerase activity, and a ribonuclease H (RNase H) activity responsible for
the hydrolysis of RNA in an RNA/DNA
duplex 20, 24.

Since RT
has no cellular counterpart, each of the RT activities, DNA polymerase, and RNase H, are essential for
replication of retroviruses, but not for eukaryotic cells, and thus they are
appropriate therapeutic targets 25-26. At present, many inhibitors
have been reported for HIV-1 RT,
and the current knowledge on the mechanism of action of retroviral RTs is based on biochemical studies and crystal
structures of HIV RT. To date, there is neither a specific inhibitor nor a published crystal structure for HTLV-1 RT.

HIV-1 RT is the target for
two distinct major classes of the enzyme inhibitors
that block reverse transcription activity: the nucleoside/nucleotide RT inhibitors
(NRTIs) and the non-nucleoside RT inhibitors (NNRTIs). NNRTIs interact with an
allosteric binding site located a short distance away from the polymerase
catalytic site of HIV-1 RT. Binding of an NNRTI
to the allosteric pocket alters the structural conformation of the enzyme and
inhibits the catalytic steps of the polymerization activity rather than interfering
in the nucleic acid or deoxynucleoside
triphosphate (dNTP) substrates binding 21, 27-28. The NRTIs are nucleoside analogs that need to be phosphorylated to their
triphosphate derivatives by host-cell kinases before exerting an antiretroviral
effect. NRTIs, in contrast to NNRTIs, compete with a dNTP in binding to the
catalytic site and interfere directly with the polymerization process. NRTIs
inhibit viral DNA synthesis in retrovirally
infected cells by competing with endogenous nucleotides for the catalytic
binding site of RT enzymes. Lack of a functional 3′-hydroxyl group in the ribose
ring of the NRTIs prevents the formation of a phosphodiester bond between the
NRTI and the subsequent nucleotide, resulting in chain termination during DNA
synthesis 29-30. The NNRTI binding site is
unique to HIV-1 RT. Thus, NNRTIs are very
specific for HIV-1 RT, with the majority of them having very low or no activity
at HTLV-1 RT, for example, nevirapine
(ART) was found to be inactive at HTLV-1
RT 31.

At present, there
are eight FDA-approved nucleoside analogues including zidovudine (AZT), emtricitabine
(Emtriva, FTC), didanosine (Videx, ddI), lamivudine (Epivir, 3TC), stavudine
(Zerit, d4T), abacavir (Ziagen, ABC), zalcitabine (Hivid, ddC), and Tenofovir
(Viread, TDF).
Evidence indicates that a limited number of HIV-1 NRTIs can inhibit viral
replication in HTLV-1 infected cells in single
or in combination therapy 32 (Table 1).

In vitro studies have shown that NRTIs can prevent
HTLV-1 replication 33-34. Based on in vitro experiments, the pyrimidine nucleoside analog AZT can efficiently inhibit HTLV-1 transmission to target
cells 35. It was also shown that the active triphosphate forms of AZT, ddI, ddC, and d4T could
partially inhibit HTLV-1 RT function 31. TDF inhibits the enzymatic
activity of HTLV-1 RT at lower concentrations than AZT 34, 36. Both TDF and AZT were
capable of blocking primary infection in human peripheral blood mononuclear
cells-NOG (huPBMC-NOG) mice. Taylor et al
observed a 10-fold reduction in HTLV-1 viral load during treatment with 3TC in
HAM/TSP patients 37. Conversely, others reported
that HTLV-1 RT is highly resistant to 3TC and so it is unlikely to have direct antiretroviral
efficacy in HTLV-1-infected patients 31, 38-39. PBMC cells from healthy
donors were cocultured with MT-2 cell
lines in the presence of cyclic
nucleoside phosphonate (PCOAN) compounds. In
this experiment, PCOANs inhibited RT activity
and also the growth of HTLV-1
infected cells 100 to 200 times more effectively
than TDF 40.