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Introduction
Acquired immunodeficiency syndrome (AIDS) was
recognized in 1981, and the first human immunodeficiency
virus (HIV) was isolated 2 years later, heralding a new era in
the fight against pathogenic
viruses[1,2]. Since then, HIV infection has become a major public health problem
worldwide, with an estimated 39.4 million infected people as
at the end of 2004 (Table 1)[3]. According to the Joint United
Nations Programme on HIV/AIDS (UNAIDS) epidemic update, in 2004 there were more than 3.1 million AIDS deaths,
including 500000 children under 15 years of
age[4]. The prevalence of HIV-1 is greater in developing countries, and
especially in Sub-Saharan Africa, where the infrastructure to
prevent and treat the infection is
limited[5]. These ※hotspots§ absorb most of the attention of international committees and
organizations, and a significant part of the funding for AIDS
prevention and treatment goes towards attempting to scale
up antiretroviral (ARV) therapy in developing and transitional
countries[6].
HIV is a lentinovirus that is predominantly transmitted
by sexual contact, as virus particles can cross the mucosal
epithelium and infect specific
cells[7,8] expressing the CD4 receptor. Cells bearing CD4 receptors on their membrane
belong to the macrophage/monocyte lineage and to a
subset of T-cells[9,10]. Initial indications were that HIV-1 used
only CD4 to identify and enter the target cells. Soon, however,
it became apparent that additional co-receptors were
probably required in order for the virus to complete cell entry.
Subsequently, several such potential co-receptors were
proposed[11,12], but the CCR5 and CXCR4 chemokine receptors
are today considered to be the major co-receptors for HIV-1
entry[13每15]. T-cell tropic HIV strains use mainly CXCR4 as a
co-receptor and are called X4 strains, whereas
macrophage-tropic strains, responsible for host-to-host transmission, use
CCR5 as a co-receptor, and are referred to as R5 strains.
Thus, macrophages are the principal targets for the
establishment of the infection in new
individuals[16]. Although it is not always the
case[17,18], the transition from viral isolates
that use the CCR5 receptor to isolates that use the CXCR4
receptor has been linked with the transition from the latent
asymptomatic phase to the clinical manifestations
associated with AIDS[19,20].
The most striking feature of HIV-1 infection is the gradual
depletion of circulating CD4+ T cells, which leads to increased
sensitivity of the patient to opportunistic and chronic
infections and to oncogenesis. The cause of the
CD4+ T cell depletion is still under
debate[21每23]. It is generally accepted,
however, that during the asymptomatic phase the daily replenishment rate of CD4+ T cells is much higher than the
turnover of infective virus particles for the cytopathicity
model to explain the progressive depletion of
CD4+ T cells from
circulation[24]. An alternative hypothesis proposes that
certain viral components contribute to dysfunction of a vital
immune mechanism[25].
Over the past 23 years, the main objective in the field of
HIV research has been the discovery of drugs that will
combat the disease. Satisfactory progress has already been made
and there are now more than 20 anti-HIV drugs approved by
the American Food and Drug Administration
(FDA)[26]. ARV drugs are categorized according to their mode of action into
three main groups: 1) the nucleoside reverse transcriptase
inhibitors (NRTI); 2) the non-nucleoside reverse transcriptase
inhibitors (NNRTI)[27,28]; and 3) the protease inhibitors
(PI)[29]. ARV drugs from these categories are now administered in
combination (as cocktails) to produce more efficient
treatment[30]. This type of therapy, termed ※highly active
antire-troviral therapy§ or HAART, has markedly decreased
morta-lity and morbidity in the developed world. Efforts have been
made by the World Health Organization (WHO) and UNAIDS
to substantially increase the number of people on HAART
in developing and transitional
countries[6].
Despite the fact that current antiviral treatments have
improved prognosis, drug resistance and high toxicity are
serious limitations to current treatments that justify the
continuation of research efforts for new strategies and
interventions[31,32]. Today, AIDS
is treatable, and patients can have a good prognosis, but it is still not curable. A new generation
of drugs was recently introduced that inhibit viral cell entry
(to be discussed later). HIV entry inhibitors appear to be a
rational step forward in ARV therapy, because they prevent
the virus from infecting new host cells, and may potentially
stop or significantly limit HIV
transmission[33每35]. In order to rationally design effective drugs, the pathophysiology of
HIV must be better understood for ARV therapy research to
target specific events in the biology of the virus within the
host cell[36,37].
HIV entry
HIV-1 predominately infects cells that have the CD4
receptor on their surface membrane, although this is not
always the case[38,39]. Achievement of infection of these cells
involves three discrete steps: viral attachment, then
co-receptor binding, and finally fusion (see Figure 1).
Recognition of the ※correct§ target cell and attachment to it is
primarily achieved through envelope glycoprotein gp120, which
binds to CD4 molecules. Gp120 is generated within the in
fected host cell after cleavage of gp160 by cellular proteases
into two functional proteins: gp120 and gp41. It consists of
5 variable (V1-V5) and 5 conserved (C1-C5)
regions[40]. Gp120 and gp41 are glycosylated in the Golgi apparatus, and then
transported to the membrane that is later incorporated in the
viral envelope during the budding of the viral particles to
form mature viruses[41]. The envelope membrane is studded
with trimers of gp120-gp41 heterodimers, where gp41 forms
the cytosolic part and gp120 the extracellular
part[42].
Binding of viral gp120 to host cell CD4 is achieved through
interactions of several conserved gp120 residues with the
second complementarity-determining region (CDR2) of
CD4[43,44]. This interaction alone is not sufficient to achieve
cell entry, but it is necessary in order to identify the target
cell and also to increase the affinity of other viral
components for the co-receptor molecules. Indeed, binding of
gp120 to CD4 causes conformational changes to the variable
loop regions V1/V2 and V3 of gp120, causing the V3 loop to
evaginate, thus becoming exposed to the
co-receptors[45] (Figure 1). The major co-receptors that HIV-1 uses are the
CCR5 and CXCR4 chemokine receptors. The exact
mechanism of interaction between the variable loop regions V1/V2
and V3 and the chemokine receptors is not well understood
and it merits a more detailed investigation. It has been
suggested, however, that the interaction between V3 and
CCR5 is ionic in nature, and results in enhancement of the
process of activation-induced cell death of responding
effector CD4+ T cells during antigen
presentation[22,46,47].
The final step for viral entry requires fusion of the viral
envelope components with the target surface membrane; this
is achieved with the use of gp41, which is a glycoprotein
consisting of 3 main domains: an intracellular domain
(endodomain), a transmembrane anchor and an extracellular
domain (ectodomain). The ectodomain is the key structure
responsible for fusion and consists of a hydrophobic fusion
peptide sequence at the N-terminal, two hydrophobic
heptad repeats (HR1 and HR2) at the C-terminal, and a hinge
region, where a disulfide-bond loop is formed between the
two heptad repeats during fusion[48,49]. On binding of gp120
to CD4 and subsequently to the co-receptor, further
conformational changes occur that lead to gp41 dissociation from
gp120. The gp41 unfolds and the hydrophobic fusion
peptide sequence extends out of the viral membrane towards the
host cell membrane. Insertion of the fusion peptide into the
host cell membrane leads gp41 to fold into a hairpin-like
structure where the two hydrophobic heptad repeats (HR1 and
HR2) lie antiparallel, forming a 6-helix
bundle[50,51]. This hairpin structure is believed to be responsible for the fusion of
the HIV envelope to the host cell membrane.
Enfuvirtide: the first FDA-approved fusion inhibitor
Enfuvirtide (formerly known as T-20) is the first fusion
inhibitor approved by the FDA and the European
Commission for the Treatment of AIDS, and is available under the
trade name Fuzeon (Trimeris and Roche). It is a 36 amino
acid synthetic peptide homologous to the HR2 region of
gp41 (residues 127-162) [52,53], that has the ability to interfere
with the fusion pathway by mimicking the HR2
domain[54]. The accepted mode of action proposes that enfuvirtide
targets conformational changes during fusion by binding to
the HR1 domain. Recent evidence indicates that enfuvirtide
interacts with multiple sites in gp41 and
gp120[55]. This binding prevents the formation of the 6-helix bundle by
preventing HR2 from refolding antiparallel to
HR1[56,57]. Thus, inhibition of fusion of the viral envelope to cell membranes is
achieved by blocking a critical step in the fusion pathway
(Figure 2).
In the initial stages of discovery, enfuvirtide appeared to
inhibit HIV-1 replication very effectively in various cell types
and clinical trials proved to be very promising. Phase I/II
trials provided proof that HIV entry was inhibited after
treating patients with 100 mg enfuvirtide twice daily for 14 d. The
levels of plasma HIV RNA after 14 d of treatment
demonstrated a 1.96 lg median
decline[58]. Phase II clinical trials were performed on 71 HIV-infected individuals who were
treated with 50 mg enfuvirtide together with other ARV drugs
for 48 weeks. There was a 1.0 log10 decline from baseline in
HIV RNA and a median gain of CD4 cell counts of 84.9
cells/mL, with no significant
toxicity[59].
Furthermore, two TORO (T-20 vs Optimized Regimens
Only) Phase III clinical trials were performed in America
(TORO 1) and in Europe and Australia (TORO 2). The trials
had similar protocols: they compared the efficacy and safety
of enfuvirtide plus an optimized antiretroviral regimen with
the efficacy and safety of an optimized antiretroviral regimen
alone[60,61]. In both studies the least-squares mean change
from baseline in the plasma viral load indicated a significant
difference in the decrease in the enfuvirtide group compared
with the control (P<0.01). In the same way, the mean count
of CD4 cells/mL was significantly greater in the enfuvirtide
group compared with the controls (P<0.01).
Further studies are currently being performed on the
exact metabolic pathway of enfuvirtide, potential drug
resistance problems, and identification of synergistic interactions
with other drugs. Several reports concluded that enfuvirtide
does not appear to interfere with the activities of cytochrome
P450, probably because it is a peptide and is easily
hydrolyzed in the body[62,63]. Enfuvirtide was found to act
synergistically with other potential entry inhibitors
in vitro, such as AMD3100 and PRO542, producing results that
encouraged the use of combinations of entry inhibitors as part of a
new generation of ARV strategies[64,65]. However, HIV
resistance has been reported in patients treated with enfuvirtide,
indicating a hotspot from codons 36 to 38 of the HR1
domain[66], as well as other sites in
gp41[67每69]. Additionally, primary resistance has been reported, which appears to be more
frequent than predicted[70], indicating that more research is
needed in this field.
Enfuvirtide obtained accelerated approval by the FDA in
2003 and became the 17th licensed ARV drug and the first to
inhibit HIV entry. The drug is supplied as a lyophilized
powder in single-dose vials containing 108 mg of the drug.
Reconstitution of the powder in 1.1 mL sterile water for
injection produces a single dose of 90
mg/mL[71] that is injected subcutaneously. Enfuvirtide has two currently known
major drawbacks. First, being a peptide, it can only be
administered by injection and not orally. This makes usage more
difficult, because patients must be educated for
self-administration. Second, the cost of enfuvirtide is high,
because it is a synthetic peptide that is manufactured by a
highly complicated process involving large amounts of raw
materials[72,73]. It is estimated that the annual cost of
enfuvirtide therapy is approximately US$20 000 per patient,
and if taken in combination with other ARV drugs then the
cost of therapy could approach US$30 000.
Potential drugs targeting entry and fusion
Attachment inhibitors Current novel antiretroviral drugs
aim to interfere with the crucial HIV entry steps: viral
attachment, co-receptor binding and fusion. One approach
for interfering with viral attachment involves the use of a
tetravalent fusion protein construct, consisting of a human
IgG2 in which the Fv portions of both the heavy and light
chains have been replaced with the D1 and D2 domains of
human CD4[74,75]. This CD4-immunoglobulin fusion
construct, called PRO 542, is suggested to bind to the viral
gp120 and thus prevent the virus from interacting with
CD4-bearing host cells. Phase I clinical trials indicated that PRO
542 has a half-life of 3每4 d when a relatively high dose was
used (10 mg/kg), and no dose-limiting toxicities were
observed[76]. In addition, in phase II clinical trials, 12
HIV-infected patients were treated with 25 mg/kg single-dose PRO
542. The drug was well tolerated and the acute reduction
caused in the HIV-1 RNA was statistically significant, even
in patients with advanced AIDS[77].
In the same way, several other compounds target either
the gp120 or the CD4 receptor and interfere with HIV
attachment. FP-21399 is a bis(disulfonapthelene) derivative
that binds to gp120, most probably near the third variable
domain, because interactions with antibodies against the V3
loop region were blocked[78]. A phase I study showed that it
caused an increase in CD4 cell counts, and a significant
decrease in viral load and minor side
effects[79]. BMS-378806, a 4-methoxy-7-azaindole derivative, is a compound that can
be administered orally, and was developed by Bristol Myers
Squibb[80,81]. Despite the fact that phase I and II studies
showed promising results, Bristol Myers Squibb decided to
investigate similar drugs such as BMS-488043, an analogue
of BMS-378806, in order to optimize its
effectiveness[82]. A series of polyanionic compounds, for example
dextrin-2-sulfate, Carraguard and PRO 2000 are in clinical trials, and
are designed to be topically
administered[83每85]. Finally, TNX-355, a humanized anti-CD4 mAB that binds to CD4 without
interfering with its biological function, significantly
decreased viral load and increased CD4 cell counts in a phase
I trial[86].
Co-receptor binding inhibitors The most interesting
target in HIV entry is the co-receptor binding phase. Current
drug research is focused on designing compounds that
prevent the virus interacting with the chemokine receptors. The
CCR5 receptor is the principal target, and a number of
potential drugs are currently being studied. SCH-C is a small
mo-lecule that inhibits the binding of gp120 to CCR5, and initial
in vitro experiments have indicated good inhibitory activity
against R5 viruses as well as synergistic effects with several
ARV drugs, including enfuvirtide[87,88]. Although it can be
administered orally and clinical studies showed decreased
viral loads, electrocardiographic anomalies due to
arrhy-thmias were reported at high
dosages[89]. Another compound, SCH-D, has been found to have greater
in vitro and in vivo antiviral properties, with no apparent side effects. Clinical
studies for this drug are still
ongoing[90]. Interestingly, it was recently reported that V3-like peptides from X4 strains
with more electropositive V3 domains were effective
antagonists and potential infectivity blockers of R5
variants[91].
TAK-779 was the first non-peptidic molecule found to
inhibit co-receptor attachment by binding to CCR5 at
transmembrane helices 1, 2, 3, and
7[92,93]. It has the disadvantage of intravenous administration and because of irritations
observed at the injection site, its development
was discontinued. It was replaced by another compound, T-220, which can be
administered orally, and shows promising anti-R5 HIV
acti-vity[94]. Similarly, UK-427,857 is a novel CCR5 inhibitor that
has acceptable pharmacokinetic and metabolic rates in mice,
rats, dogs and humans, and can be administered
orally[95]. Finally, PRO 140 is one of the few monoclonal
antibodies that has been used as an entry inhibitor and has been reported to
block co-receptor attachment without down-modulating or
inducing signaling of the CCR5 chemokine
receptor[96,97].
CXCR4, the second major HIV co-receptor, is also a
target for current drug research. AMD-3100, one of the first
entry inhibitors, was found to inhibit viral entry well before
the discovery of co-receptor usage by
HIV[98]. It is a bicyclam compound of low molecular weight that inhibits the
electrostatic interaction between CXCR4 and gp120 by ionic
binding to the second extracellular loop (ECL2) and the adjacent
membrane-spanning domain (TM4) of the CXCR4
receptor[99]. Despite the fact that in phase I and II clinical trials,
intravenous administration of AMD-3100 significantly reduced the
viral load[100], it was later replaced by an orally available
compound, AMD-070. A non-peptidic compound, KRH-1636,
which is absorbed through the duodenum, had similar
efficacies to AMD-3100[101]. Finally, T-22 and ALX40-4C are
positively charged peptides that occupy the V3 region and
competitively inhibit binding of gp120 to the negatively
charged amino acid residues on
CXCR4[102每104].
In conclusion, the role of the V3 region in the mechanism
of cell attachment and entry in relation to the major
co-receptors is being actively pursued. In addition to biological
studies, physicochemical studies on the interacting protein
domains are being carried out in an attempt to decipher the
interface conformations between the virus and the
cell[105].
Fusion inhibitors Understanding the mechanism of
fusion of the viral envelope with the host membrane played a
crucial role in the development of new generation ARV drugs.
This became apparent when enfuvirtide was licensed as the
first viral entry inhibitor, and it is currently used in HAART.
Resistance to enfuvirtide has been reported, which has led
to the design of a second generation HR2 mimetic peptide.
T-1249 is a 39-L-amino acid synthetic peptide that contains a
pocket-binding sequence that makes the HR1 and HR2
interaction more stable. Studies on T-1249 showed that it has
greater efficacy and longer half-life than enfuvirtide.
Additionally, efficacy against enfuvirtide-resistant viruses
has been reported, indicating that this second generation
fusion inhibitor is a step
forward[106,107]. However, Roche and Trimeris decided to halt clinical development due to
formulation concerns[108].
5-Helix is a newly designed recombinant C-peptide that
consists of 5 of the 6 helices that are formed during the
fusion phase. A CHR domain is missing for the 6-helix bundle
formation, and thus there is one exposed groove. This groove
binds to a CHR domain in gp41 and inhibits fusion of the
viral membrane to the host
membrane[109]. Because it is a recombinant peptide, it has a much lower cost of production
compared with the synthetic enfuvirtide. Initial studies
demonstrated potent antiretroviral activity, with
IC50 values in the low nanomolar
range[110].
Finally, N-peptides represent another group of peptides
with potential inhibitory effects against HIV entry. Initial
studies have indicated that they are weaker inhibitors than
the C-peptides, with IC50 values in the micromolar range.
However, chimeric molecules composed of soluble trimeric
coiled coils have shown promising results. IQN17 is one of
the first such peptides with potent inhibitory effects, and
the current most potent chimeric N-peptide, IQN23, is
reported to have an IC50 value of 15
nmol/L[111].
Conclusion
Antiretroviral chemotherapy has recently acquired a new
※weapon§ in the fight against AIDS. Enfuvirtide is the first
HIV entry inhibitor that was approved by FDA, and it is
currently used in combination with other ARV drugs.
Results from clinical trials indicated that it had potent activity
against HIV strains that are resistant to other ARV drugs,
although some resistance to enfuvirtide has been reported.
The design of other entry inhibitors has moved forward, and
every phase of HIV entry is actively pursued as a target for
potential inhibitors. Probably the most exciting prospect is
potential interference with co-receptor usage, particularly
that of CCR5.
ARV drug development aims to produce drugs with
potent antiretroviral activity, with
IC50 values in the nanomolar range, with no or limited toxicity and that can be
administered orally. Several compounds are currently in clinical trials,
and we are optimistic that new, more effective drugs will be
added to the ARV armory.
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