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Originally published online as doi:10.1189/jlb.0403177 on August 1, 2003

Published online before print August 1, 2003
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(Journal of Leukocyte Biology. 2003;74:667-675.)
© 2003 by Society for Leukocyte Biology

Specific CD4 down-modulating compounds with potent anti-HIV activity

Kurt Vermeire and Dominique Schols1

Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium

1Correspondence: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium. E-mail: dominique.schols{at}rega.kuleuven.ac.be


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 Targeting the gp120/CD4...
 CONCLUSION
 REFERENCES
 
Despite the availability of the current clinically approved anti-HIV drugs, new classes of effective antiviral agents are still urgently needed to combat AIDS. A promising approach for drug development and vaccine design involves targeting research on HIV-1 entry, a multistep process that comprises viral attachment, coreceptor interactions, and fusion. Determination of the viral entry process in detail has enabled the design of specific agents that can inhibit each step in the HIV entry process. Therapeutic agents that interfere with the binding of the HIV envelope glycoprotein gp120 to the CD4 receptor (e.g., PRO 542, PRO 2000, and CV-N) or the coreceptors CCR5 and CXCR4 (e.g., SCH-C and AMD3100) are briefly outlined in this review. The anti-HIV activity of cyclotriazadisulfonamides, a novel class of compounds with a unique mode of action by down-modulating the CD4 receptor in lymphocytic and monocytic cells, is especially highlighted. On the basis of the successful results of T-20, the first approved entry inhibitor, the development of effective antiretrovirals that block HIV entry will certainly be further encouraged.

Key Words: HIV entry inhibitors • CD4 receptor down-modulation • CADA • CCR5 • CXCR4 antagonists


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
Targeting the gp120/CD4...
 CONCLUSION
 REFERENCES
 
The introduction of highly active antiretroviral therapy (HAART), using cocktails of two or more different anti-HIV agents that usually come from two drug categories (RT inhibitors and protease inhibitors), has led to dramatically improved survival for HIV-1-infected patients. However, the emergence of drug-resistance and the problems of drug tolerability and toxic effects emphasize the need for new classes of effective antiviral drugs.

A promising approach for drug development and vaccine design is the blocking of the viral entry/fusion step. Identification and characterization of the molecular structure and biology of the virus and its cellular receptors, as well as the determination of the viral entry process in detail, have resulted in successful strategies that target HIV-1 entry. This review will focus on recent research on viral entry inhibitors, especially on those that interfere with the CD4 receptor and the HIV coreceptors, and also T-20 as the first approved HIV fusion inhibitor.


   Targeting the gp120/CD4 interactions
TOP
 ABSTRACT
 INTRODUCTION
 Targeting the gp120/CD4...
CONCLUSION
 REFERENCES
 
HIV-1 must enter a permissive host cell to replicate and produce new virions. The initial step in this complex multistep process is the attachment of HIV particles to the cell surface by the highly specific interaction between the HIV-1 envelope glycoprotein gp120 and its primary receptor, the cellular CD4 receptor [1 , 2 ]. Binding of the CD4 receptor induces a conformational change that brings gp120 into proximity with a cellular coreceptor, allowing them to bind. More than 10 years later, the chemokine receptors CCR5 and CXCR4 were identified as the principal coreceptors for viral entry into T lymphocytes and macrophages [3 , 4 ]. Following the interaction of the viral gp120 with the chemokine receptor, a more dramatic conformational change in the gp120-gp41 complex leads to the formation of the trimer-of-hairpins structure in gp41, enabling the viral envelope to fuse with the cell membrane and, subsequently, release the viral capsid into the cytoplasm of the target cell [5 ].

Only very few monoclonal antibodies (mAbs) are capable of neutralizing HIV-1 primary isolates, because of the various protective mechanisms of the virus to resist the binding of antibodies to its envelope glycoprotein complex. However, three human mAbs have been identified with effective neutralizing activity against a broad array of primary isolates in vitro and in vivo. The neutralizing mAbs IgG1 b12 [6 , 7 ] and IgG1 2G12 [8 , 9 ] react with independent epitopes on gp120, whereas IgG3 2F5 [10 , 11 ] reacts with gp41.

Preventing the attachment of the HIV envelope to cellular CD4 is an attractive therapeutic approach, since all HIV and SIV strains use the CD4 receptor for effective infection in vivo. CD4-based molecules can neutralize HIV by several mechanisms, including competitive inhibition of attachment, dissociation of the exterior envelope glycoprotein gp120, and inhibition of cell-to-cell transmission of the virus. Thus, soluble preparations of CD4 (sCD4) are a logical choice for antiviral therapy and proved to be excellent in vitro inhibitors of diverse strains of HIV and SIV [12 13 14 15 16 ]. However, recombinant sCD4 therapy in AIDS patients did not fulfill the high anti-HIV expectations [17 ], and only extremely high doses of recombinant sCD4 seemed to have short-term therapeutic utility [18 , 19 ]. Moreover, infection by some primary patient HIV-1 isolates, as well as HIV-2 and SIV isolates was even enhanced by the binding of subneutralizing concentrations of sCD4 [20 21 22 ]. This could be explained by the fact that primary HIV-1 isolates are much less sensitive to neutralization by sCD4 than are laboratory-adapted HIV-1 strains, probably resulting from the lower affinity for CD4 and the reduced sCD4-induced gp120 shedding from the virions [23 24 25 ]. In addition, several reports demonstrated that soluble CD4 could activate the envelope glycoprotein gp120, making it competent to interact with the coreceptor, and thus could promote fusion/entry [22 , 26 , 27 ].

To provide improved pharmacokinetics, greater avidity for HIV-1 gp120 and minimal immunogenic effects, CD4-immunoglobulin fusion proteins have been developed [28 , 29 ]. CD4-IgG2, a tetravalent fusion protein comprising human IgG2 in which the Fv portions of both heavy and light chains have been replaced by the D1 and D2 domains of human CD4 (i.e., the HIV binding region of CD4), has been demonstrated to neutralize diverse primary HIV-1 isolates in vitro [30 ] and ex vivo [31 ], and protect against infection by primary isolates in the hu-PBL-SCID mouse model [32 ]. In particular, CD4-IgG2 was even more potent when assayed on macrophages and cord blood mononuclear cells in vitro and proved to effectively block DC-mediated trans-infection [33 ]. Interestingly, combination of CD4-IgG2—renamed as PRO 542 (Progenics Pharmaceuticals, Tarrytown, NY)—and the fusion inhibitor T-20 potently and synergistically inhibited viral entry in preclinical models of HIV-1 infection [34 ]. Furthermore, in a single-dose phase I clinical trial, PRO 542 showed antiviral activity in patients and also a favorable safety and pharmacological profile [35 ]. In this study, HIV-infected adults were treated with one intravenous infusion of PRO 542 at doses of 0.2–10 mg/kg, and reductions in plasma levels of infectious HIV and viral RNA were observed [35 ]. In another phase I/II clinical trial in 18 HIV-1-infected children, single and multiple intravenous doses of PRO 542 also showed promising evidence for an antiviral effect [36 ].

Recently, a novel sCD4-based HIV-1 neutralizing agent has been reported [37 ]. This agent, designated sCD4-17b, is a recombinant chimeric protein containing sCD4 attached via a flexible polypeptide linker to a human mAb that targets a conserved CD4-induced epitope on gp120 overlapping the coreceptor-binding region. sCD4-17b can bind to gp120 simultaneously via two independent moieties (i.e., the CD4 binding site and the masked coreceptor binding site which is exposed only after a CD4-induced conformational change) and showed higher neutralizing activity against HIV-1 as compared with the neutralizing mAbs IgG1 b12, IgG1 2G12, and IgG3 2F5. However, several primary isolates appeared to be insensitive to sCD4-17b [37 ].

Sulfated polysaccharides, such as heparin, dextran sulfate, pentosan polysulfate, and sulfated polymers were described as potent inhibitors of HIV replication in vitro many years ago [38 39 40 ]. Their mechanism of action has been attributed to an inhibition of virus adsorption/binding to the cell membrane, very often targeting gp120 [41 ].

Another group of compounds that block gp120 binding to CD4 and suppress HIV-1 infection of T lymphocytes, macrophages, and cervical explant tissue in vitro are the naphthalene sulfonate polymers [42 , 43 ]. The synthetic naphthalene sulfonate polymer PRO 2000 binds to CD4 and has been shown to protect against vaginal HIV transmission in nonhuman primate models [44 ]. Furthermore, vaginal PRO 2000 gel was found to be generally well tolerated in a phase I clinical study [45 , 46 ] and is currently under investigation as a microbicidal agent.

Cyanovirin-N (CV-N) is a 11 kDa protein, originally purified from extracts of the cultured cyanobacterium Nostoc ellipsosporum, that exerts broad virucidal activity, at low nanomolar concentrations, against primary clinical isolates of HIV-1, as well as laboratory-adapted strains of HIV-1, HIV-2, SIV, and FIV [47 , 48 ]. The carbohydrate components of HIV envelope glycoproteins, especially the high-mannose oligosaccharides Man-8 and Man-9 of gp120, may be important for the glycosylation-dependent binding and antiviral activity of CV-N [49 50 51 52 ]. However, the mechanism underlying the HIV-inhibitory activity of CV-N has not been fully elucidated.

Finally, the down-modulation of the CD4 receptor can also be considered as an approach to prevent HIV infection of target cells. Prostratin, a nontumor-promoting phorbol ester, inhibits HIV replication by decreasing CD4 expression in T cell lines [53 ]. However, prostratin rapidly reduces cell surface expression of CXCR4, similar to PMA, and this internalization of CD4 and CXCR4 is mediated by the activation of protein kinase C enzymes [54 ].

CADA, a specific down-modulator of CD4
Cyclotriazadisulfonamide (CADA) is a synthetic macrocyle (Fig. 1 ) with a broad range of activity against several strains of HIV (i.e., laboratory-adapted HIV-1 and HIV-2 and primary clinical isolates of HIV-1) [55 ]. The anti-HIV activity of CADA was further enhanced when cells were pretreated for 24 h with the drug. In a previous report, the antiviral activity of CADA has been tentatively attributed to the specific CD4 down-modulating potency of this compound [55 ]. When a T cell line (MT-4) was treated with CADA for 24 h, a significant decrease in surface CD4 expression was observed (almost 90% reduction in CD4 receptor expression). Moreover, the antiviral activity of CADA correlated with its ability to down-modulate the CD4 receptor [55 ]. A close correlation could also be observed between the CD4 down-regulating and anti-HIV potencies of 17 CADA derivatives, further pointing to CD4 receptor down-modulation as the primary and unique mode of antiviral action for this novel group of compounds [56 ]. The CD4 down-modulating activity of CADA was detected in T cell lines (i.e., MT-4, SupT1, MOLT-4, and Jurkat), CD4-transfected U87 cells and in peripheral blood mononuclear cells (PBMCs) [55 ]. In addition to its novel mode of action, CADA was synergistic with all clinically approved antiretroviral drugs [57 ]. Interestingly, CADA did not alter the expression of any other cellular receptor (or HIV coreceptor) examined [55 ].



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  		Figure 1. Chemical structure of CADA (9-benzyl-3-methylene-1,5-di-p-toluenesulfonyl-1,5,9-triazacyclododecane) and 2 derivatives QJ023 and QJ028.

 
As three CD4 binding events are needed to efficiently activate HIV-1 Env trimers [58 ], multimeric CD4 binding is required for HIV infection, further implying that CD4 receptor density has a crucial role in effective HIV infection [59 60 61 62 63 64 ]. Chesebro et al. reported that the HIV titer in clones of human cervical carcinoma (HeLa) cells expressing different (low) levels of CD4 and infected with laboratory strains of HIV-1 increased with increasing CD4 expression [59 ]. Also primary HIV-1 isolates infected HeLa-CD4 cell clones that have distinct quantities of CD4 in direct proportion to cellular CD4 expression [60 ]. However, laboratory-adapted HIV-1 isolates infected these HeLa-CD4 cell clones with equal efficiencies regardless of the levels of CD4, with exception of the clone with the lowest CD4 expression [60 ]. It is worth mentioning that the CD4 expression in all of the HeLa-CD4 cell clones were higher than in those used in the study of Chesebro et al. and, probably, above a low threshold of CD4 expression, HIV titers do not significantly depend on CD4 levels. Furthermore, it has been shown that laboratory adaptation of T-tropic (X4) HIV-1 may involve corresponding increases in affinities for CD4 and in abilities to infect cells that have relatively little CD4 [61 , 62 , 64 ]. In addition, mutations that specifically reduce CD4 affinities of gp120 in a laboratory-adapted HIV-1 strain could convert viral infectivities from relative CD4 independence to the strong CD4 dependence described for X4 clinical isolates, which preferentially infect cells that coexpress CXCR4 and substantial amounts of CD4 [62 ]. Thus, drugs with CD4 down-modulating activity, such as CADA, can strongly inhibit virus entry by reducing the CD4 receptor density below a level that is required for efficient infection.

Results with macrophage-tropic (R5) HIV-1 were, at first sight, strikingly different in CD4 dependency. CCR5-transfected HeLa-CD4 cells could be infected by R5 HIV-1 isolates even if those cells had small amounts of CD4 [61 ], and the susceptibility of maturing monocytes to HIV-1 infection correlated with CCR5 expression [65 ]. Furthermore, the differences between neonatal and adult monocytes in susceptibility to primary clinical isolates may be related to the level of CCR5 expression [66 ]. However, the CD4 and CCR5 concentration requirements for efficient infections by R5 HIV-1 are interdependent: cells with a large amount of CD4 required only a trace amount of CCR5 for maximal susceptibility to infection by diverse isolates of R5 HIV-1, whereas cells with a low amount of CD4 required a much larger amount of CCR5 for infection [63 ]. Thus, the requirements for each receptor are increased when the other component is present in a limiting amount. Here, we show some evidence that the CD4 down-regulating activity of CADA has interesting antiviral potency also for the cells of the macrophage lineage. Figure 2 shows a flow cytometric analysis of PBMCs and reveals a marked CD4 down-regulating effect of CADA not only in lymphocytes but also in monocytes. The compound CADA also strongly affects the CD4 expression in the monocytic cell lines U937 and THP-1 (Fig. 2) . Furthermore, the CD4 down-modulation by CADA in purified monocytes/macrophages (M/M) results in a potent antiviral activity of this compound (Fig. 3 ). Indeed, when M/M were isolated from the blood of healthy donors and infected with the R5 HIV-1BaL strain, treatment with CADA (at a dose of 3.2 µM) completely blocked viral replication as evident from the undetectable HIV-1 p24 viral Ag production (Fig. 3) . The antiviral activity in M/M was even more pronounced for two derivatives of CADA (i.e., QJ023 and QJ028 (Fig. 1) , two analogs with stronger CD4 down-modulating potency and antiviral activity in T cells [56 ]) (Table 1 ). Comparable anti-HIV activity was also observed in PBMCs infected with HIV-1BaL (Table 1) .



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  		Figure 2. CD4 down-modulation in lymphocytes, monocytes and monocytic cell lines (U937 and THP-1) after incubation with CADA (2 µM) for 3 days. Cell surface CD4 expression of untreated and CADA-treated cells after staining with the specific anti-CD4 mAb (clone SK3) is shown. The mean fluorescence intensities are indicated between brackets. An isotype control is included to measure the background staining. Freshly isolated lymphocytes and monocytes were obtained from the blood of healthy donors and were treated with CADA for 3 days.

 


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  		Figure 3. Antiviral activity of CADA in purified monocytes/macrophages infected with HIV-1BaL. M/M were obtained from the blood of healthy donors. On the 5th day of culture, nonadherent cells were removed by repeated gentle washing with warm complete medium. Adherent cells obtained with this technique consisted of > 95% differentiated M/M. The M/M were cultured in a humidified chamber with 5% CO2 at 37°C in the presence of the same medium for another 5 days. Then, cells were pretreated with CADA for 2 h and infected with HIV-1BaL at 300 50% cell culture infective doses per ml in vitro in the presence of different concentrations of CADA. The cells were treated with the drug in triplicate wells of a 48-well plate and were washed and fed after 5 days with fresh medium and replenished with compound. After 12 days of incubation, supernatant was collected and analyzed for its p24 viral Ag content. For each dose of CADA, the vertical bar represents the p24 Ag production (mean+SEM) in the three wells. The IC50 value of CADA in this experiment is 0.62 µM, whereas the CC50 value of CADA in PBMC is 73 µM.

 

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  		Table 1. Antiviral Activity of CADA and 2 Derivatives In PBMCs and Purified Monocytes Infected With HIV-1BaLa

 
Although several CD4-independent HIV-1 strains have been described [67 68 69 70 ], these viruses show higher infectivity and replicative ability when CD4 is expressed on the cell surface. In addition, CD4 independence of HIV has been correlated with enhanced sensitivity to antibody mediated neutralization [68 , 71 , 72 ], which could explain the rarity of CD4-independent wild-type variants. Thus, a CD4-lowering drug could inhibit viral infection by not only blocking viral entry, but also making the virus more prone to elimination by the neutralizing action of antibodies. Furthermore, as several domains of CD4 play an important role in regulating HIV entry of cells [73 ], a specific down-modulator of the complete CD4 receptor may be considered as a more effective antiviral agent.

Targeting the HIV coreceptors
Since the discovery of the chemokine receptors (especially CCR5 and CXCR4) as coreceptors for HIV, these coreceptors have led to a new classification of HIV [74 ], but, more interestingly, they received considerable attention as new therapeutic targets for the treatment or prevention of HIV infection. In 1996, it was demonstrated that certain individuals with a mutation in both alleles for CCR5 ({Delta}32-CCR5) were highly resistant to HIV infection and importantly had no immunity defects [75 76 77 78 ]. In addition, it was reported that individuals who were heterozygous for the {Delta}32-CCR5 gene had a slower decrease in their CD4 T cell count and a longer AIDS-free survival for up to 11 years of follow-up [79 ]. Also the observation that exposed but uninfected individuals with a CCR5 wild-type (WT/WT) genotype have a low level of CCR5 expression and a high level of CCR5-binding chemokines [macrophage inflammatory protein (MIP)-1{alpha} (or CCL3, according to the new classification system of Zlotnik and Yoshie [80 ]), MIP-1ß (CCL4) and RANTES (CCL5) as natural ligands for CCR5] boosted the search for small-molecule chemokine receptor antagonists enormously. Several reports also showed that CCR5-binding chemokine levels were associated with lower levels of HIV-1 replication in vivo [81 82 83 84 ]. High-plasma SDF-1 (CXCL12) levels (the natural ligand for CXCR4) and low CXCR4 expression on T lymphocytes were associated with long-term nonprogression, whereas in advancing disease, expression of CXCR4 increased, accompanied by a decrease in plasma SDF-1 during the more advanced stages of HIV-1 infection [85 , 86 ].

Derivatives of the CC-chemokine RANTES (such as Met-RANTES and AOP-RANTES) have been described as CCR5 antagonists, possessing activity against CCR5-dependent (R5) HIV-1 strains [87 ]. However, only AOP-RANTES was capable of inhibiting viral infection of primary macrophages [87 ]. Several groups demonstrated that a non-allelic isoform of MIP-1{alpha}, termed LD-78ß, is the most active naturally occurring inhibitor of HIV entry described so far [88 89 90 91 ]. LD-78ß strongly down-regulated CCR5 expression in M/M, thereby explaining its potent antiviral activity [91 ]. Later on, it was shown that, like RANTES, the addition of AOP to this isoform of MIP-1{alpha} enhances its interactions with CCR1 and CCR5, allows more effective internalization of CCR5, and increases the ligand’s potency as an inhibitor of HIV entry through CCR5. Importantly, AOP-LD-78ß is ~10-fold more active than AOP-RANTES at inhibiting HIV entry, making it the most effective chemokine-based inhibitor of HIV entry through CCR5 described to date [92 ].

The first nonpeptidic CCR5 antagonist identified was called TAK-779. It inhibits [125I]-RANTES binding to CCR5-transfected cells with an IC50 of 1.4 nM. Although the compound did not inhibit [125I]-RANTES binding to CCR1-, [125I]-eotaxin (CCL11) binding to CCR3-, [125I]-SDF-1 binding to CXCR4-, or [125I]-TARC (CCL17) binding to CCR4-transfected cells, it inhibited the binding of [125I]-MCP-1 (CCL2) to CCR2b-transfected cells with an IC50 of 27 nM. Consequently, the compound was active against certain R5 viruses evaluated in PBMCs (IC50: 2-4 nM) but not against X4 viruses [93 ].

Another more recently described nonpeptidic CCR5 antagonist is SCH-C, which is specific for CCR5 as determined in multiple receptor binding and signal transduction assays [94 ]. This compound specifically inhibits R5 HIV-1 infection, but had no effect on infection of X4 HIV-1. SCH-C has broad and potent antiviral activity in vitro against primary R5 HIV-1 isolates evaluated in PBMCs, with IC50 values between 0.4 and 200 nM. Moreover, SCH-C strongly inhibited the replication of a R5 primary HIV-1 isolate in SCID-hu Thy/Liv mice.

Both compounds are also capable of inhibiting HIV-1BaL viral replication in M/M, with IC50 values of 90 nM and 40 nM for TAK-799 and SCH-C, respectively ([95 ] and Vermeire and Schols, unpublished results).

The first nonpeptidic, low-molecular-weight compounds shown to interact with CXCR4 were the bicyclams. These compounds had been known as potent and selective inhibitors of HIV-1 and HIV-2 replication for a number of years [96 , 97 ], before their direct target of interaction was unequivocally identified as the CXCR4 receptor [98 99 100 ]. This action targeted at CXCR4 is consistent with the initially proposed mode of interaction of the bicyclams with the virus-cell fusion/viral uncoating process [96 ]. The bicyclams can be described as two tetraazamacrocycles tethered by an aliphatic linker (i.e., propylene, as in AMD2763) [96 ] or an aromatic linker (i.e., 1,4-phenylenebis(methylene), as in AMD3100, previously referred to as JM3100) [97 ]. Whereas AMD2763 was found to inhibit HIV replication in various human T cells at a concentration of 0.14-1.4 µM [96 ], AMD3100 inhibited HIV replication within the nanomole range [97 ]. The inhibitory effects of AMD3100 on X4 HIV-1 strains have been demonstrated in a wide variety of cells expressing CXCR4, including PBMCs, and, vice versa, various X4, R5/X4 but not R5 HIV-1 viruses have proven sensitive to AMD3100 in PBMCs and M/M [99 , 101 102 103 ]. Recently, a follow-up drug has been reported. AMD070 is an orally available CXCR4 antagonist with potent anti-HIV activity and will be evaluated in a clinical trial in 2003 [104 ].

Entry inhibitors as effective antiviral agents
The first drug of a novel group of antiretroviral therapeutic agents that target entry of HIV-1 into cells is T-20, currently renamed as enfuvirtide (FuzeonTM). T-20 is a 36-amino acid peptide that binds to a highly conserved region of the HIV-1 envelope glycoprotein gp41. It interferes with the fusion of the virus with the cell membrane, resulting in potent inhibition of HIV-1 cell entry (for reviews of T-20, the reader is referred to [5 , 105 , 106 ]). On the basis of the marked antiviral activity in vitro, several clinical trials have been conducted, showing a significant virological advantage of T-20 treatment [105 ]. Recently, the addition of enfuvirtide has been studied in two large clinical trials phase III (TORO 1 and TORO 2) and proven to be successful, as evident from the significant antiretroviral and immunological benefit observed in patients with multidrug-resistant HIV-1 infection [107 , 108 ]. Furthermore, enfuvirtide is now approved in Europe, Australia, and the United States for clinical use.

The successful development and approval of the fusion inhibitor T-20 provide proof-of-principle in the development of entry inhibitors as practical and potent antiviral agents. Despite the requirements for subcutaneaous administration and the development of T-20 resistance, T-20 will give high hopes that new generation inhibitors of HIV entry can be used as a component of multidrug salvage therapy in extensively pretreated patients. This may open the door to the development of other agents that target the HIV entry process, especially the chemokine receptor antagonists and the compounds that interfere with the CD4 receptor. Interestingly, the combination of T-20 with other entry inhibitors (PRO 542 and AMD3100) resulted in a synergistic interaction in vitro [34 , 109 ]. Also, the use of the CD4 down-modulating compound CADA in combination with RT, protease or entry inhibitors (such as T-20) proved to be synergistic [57 ], providing a strong rationale for clinical trials to explore the use of entry inhibitors in combination therapy.

The development of entry inhibitors as therapeutics may be hampered by many challenges such as drug delivery, stability, and toxicity related to inference with cellular receptor expression. However, this has not been a general rule. Although some side effects of the CCR5 antagonist SCH-C and the CXCR4 antagonist AMD3100 were observed, the compounds were well tolerated and, significantly, showed antiviral efficacy [110 , 111 ]. Also, administration (i.p.) of the CD4 down-regulating compounds CADA, QJ023, and QJ028 (up to 2 mg/day) in mice was not associated with severe side effects (data not shown). In addition, CADA was found to be soluble in human, rat, and mouse plasma at 1.9–3.1 µM, to be stable in plasma (>200 h), and to be detectable in the bloodstream up to 2 h after intravenous injection in mice. However, further studies are needed to better define the role of CD4 down-modulating compounds in the complex interplay of the immune cells. Interestingly, the selection of an HIV-1 strain resistant to CADA by passing virus through T cells in the presence of increasingly progressive compound concentrations over a period of several months, is so far without success. Thus, resistance of HIV to CD4 down-modulators will develop slowly, as could be expected from the crucial role of the CD4 receptor in viral entry. A similar slow resistance development of HIV-1 against chemokine receptor antagonists, which target the cellular HIV coreceptors, has been observed [112 , 113 ].


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 Targeting the gp120/CD4...
 CONCLUSION
REFERENCES
 
New and diverse classes of compounds interfering with the HIV entry process into target cells are approaching clinical application. Several randomized clinical trials recently demonstrated the antiviral efficacy of the fusion inhibitor T-20, especially when given to HIV-infected subjects who harbor drug-resistant viruses and currently have limited therapeutic options. In addition, recent clinical studies with a small number of HIV-infected subjects provided proof-of-principle for the antiviral effectiveness of CCR5 and CXCR4 antagonists. Because, very often, mixed populations of viruses may be present in the same patient, CCR5 and CXCR4 antagonists very likely have to be administered in combination to show clinical efficacy. Furthermore, several groups have demonstrated synergy not only between viral entry inhibitors and RT or protease inhibitors, but also between different classes of virus entry inhibitors. These promising results will boost the design and development of agents capable of inhibiting HIV binding and subsequent viral entry. Also, compounds that specifically interact with the CD4 receptor, such as the cyclotriazadisulfonamides, deserve further attention as a novel class of potential antiretrovirals. Despite the many challenges of safety and clinical application, which are related to the development of such inhibitors, the possible use of these compounds to block HIV infection at a different step in the viral replication cycle will give us new hope to combat AIDS.


   ACKNOWLEDGEMENTS
 
We thank Erik Fonteyn for excellent technical assistance, especially for the isolation and the cultivation of the monocytes/macrophages. We also thank Sandra Claes for her invaluable assistance with the HIV experiments. Kurt Vermeire has a Postdoctoral Mandate from the Research Council K.U. Leuven.

Received April 24, 2003; revised June 19, 2003; accepted July 2, 2003.


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 Targeting the gp120/CD4...
 CONCLUSION
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