Strong in Vitro Synergy Between the Fusion Inhibitor T-20 and the CXCR4 Blocker AMD-3100

Tremblay, Cécile; Kollmann, Christopher; Giguel, Françoise; Chou, Ting‐Chao; Hirsch, Martin S.

doi:10.1097/00126334-200010010-00001

Cited by 71 publications

(43 citation statements)

References 11 publications

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“…Thus, the use of a coreceptor antagonist in conjunction with T-20 may act to additively or synergistically inhibit HIV infection. Indeed, the CXCR4 ligand AMD3100 and CCR5 ligand SCH-C have been shown to act synergistically with T-20 to inhibit infection of peripheral blood mononuclear cells in vitro (34,35).…”

Section: Discussionmentioning

confidence: 99%

Sensitivity of HIV-1 to entry inhibitors correlates with envelope/coreceptor affinity, receptor density, and fusion kinetics

Reeves

Gallo

Ahmad

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

370

408

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HIV entry inhibitors include coreceptor antagonists and the fusion inhibitor T-20. T-20 binds the first helical region (HR1) in the gp41subunit of the viral envelope (Env) protein and prevents conformational changes required for membrane fusion. HR1 appears to become accessible to T-20 after Env binds CD4, whereas coreceptor binding is thought to induce the final conformational changes that lead to membrane fusion. Thus, T-20 binds to a structural intermediate of the fusion process. Primary viruses exhibit considerable variability in T-20 sensitivity, and determinants outside of HR1 can affect sensitivity by unknown mechanisms. We studied chimeric Env proteins containing different V3 loop sequences and found that gp120͞coreceptor affinity correlated with T-20 and coreceptor antagonist sensitivity, with greater affinity resulting in increased resistance to both classes of entry inhibitors. Enhanced affinity resulted in more rapid fusion kinetics, reducing the time during which Env is sensitive to T-20. Reduced coreceptor expression levels also delayed fusion kinetics and enhanced virus sensitivity to T-20, whereas increased coreceptor levels had the opposite effect. A single amino acid change (K421D) in the bridging sheet region of the primary virus strain YU2 reduced affinity for CCR5 and increased T-20 sensitivity by about 30-fold. Thus, mutations in Env that affect receptor engagement and membrane fusion rates can alter entry inhibitor sensitivity. Because coreceptor expression levels are typically limiting in vivo, individuals who express lower coreceptor levels may respond more favorably to entry inhibitors such as T-20, whose effectiveness we show depends in part on fusion kinetics.

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Section: Discussionmentioning

confidence: 99%

Sensitivity of HIV-1 to entry inhibitors correlates with envelope/coreceptor affinity, receptor density, and fusion kinetics

Reeves

Gallo

Ahmad

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

370

408

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“…It is currently in phase III clinical trials without evidence of any serious systemic toxicity. 2 Interestingly, strong in vitro synergy has been observed between T-20 and AMD3100 (26) suggesting that a possible combination of gp41 and CXCR4 inhibitors may provide significant therapeutic advantages in HIV treatment. This possibility further establishes the need for an approach that minimizes the toxic effects of AMD3100 and other CXCR4 antagonists.…”

Section: Discussionmentioning

confidence: 99%

Identification of Allosteric Peptide Agonists of CXCR4

Sachpatzidis¹,

Benton²,

Manfredi³

et al. 2003

Journal of Biological Chemistry

119

126

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The chemokine receptor CXCR4 is a co-receptor for T-tropic strains of HIV-1. A number of small molecule antagonists of CXCR4 are in development but all are likely to lead to adverse effects due to the physiological function of CXCR4. To prevent these complications, allosteric agonists may be therapeutically useful as adjuvant therapy in combination with small molecule antagonists. A synthetic cDNA library coding for 160,000 different SDF-based peptides was screened for CXCR4 agonist activity in a yeast strain expressing a functional receptor. Peptides that activated CXCR4 in an autocrine manner induced colony formation. Two peptides, designated RSVM and ASLW, were identified as novel agonists that are insensitive to the CXCR4 antagonist AMD3100. In chemotaxis assays using the acute lymphoblastic leukemia cell line CCRF-CEM, RSVM behaves as a partial agonist and ASLW as a superagonist. The superagonist activity of ASLW may be related to its inability to induce receptor internalization. In CCRF-CEM cells, the two peptides are also not inhibited by another CXCR4 antagonist, T140, or the neutralizing monoclonal antibodies 12G5 and 44717.111. These results suggest that alternative agonist-binding sites are present on CXCR4 that could be screened to develop molecules for therapeutic use.

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“…In vitro data indicate synergy between enfuvirtide and inhibitors of the CXCR4 and CCR5 coreceptor interactions. 27,28 Combination strategies, using multiple agents directed against discrete molecular targets associated with host cell recognition, attachment, and fusion, warrant further clinical evaluation. This approach is likely to yield potent suppression of plasma HIV RNA and may be especially important in treating patient populations exhibiting drug resistance to existing classes of antiretroviral agents.…”

Section: Discussionmentioning

confidence: 99%

The Safety, Plasma Pharmacokinetics, and Antiviral Activity of Subcutaneous Enfuvirtide (T-20), a Peptide Inhibitor of gp41-Mediated Virus Fusion, in HIV-Infected Adults

Kilby

Lalezari

Eron

et al. 2002

AIDS Research and Human Retroviruses

181

112

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Enfuvirtide (T-20) is a novel antiretroviral agent that blocks HIV-1 cell fusion. A 28-day randomized dose-comparison study was conducted to determine the safety, pharmacokinetics, and antiviral activity of enfuvirtide in 78 HIV-infected adults, most with extensive treatment experience. Patients received enfuvirtide, added to a failing regimen, either by continuous subcutaneous infusion (CSI: 12.5, 25, 50 or 100 mg/day) or by subcutaneous (SC) injection (50 or 100 mg twice daily). Dose-related decreases in viral load were observed, with a maximum mean reduction from baseline of 1.6 log(10) copies/ml (p< 0.001) seen in the 100 mg bid SC group. Most responses diminished by 28 days. Plasma pharmacokinetics and antiviral responses were more consistent for SC injection than for CSI because of technical difficulties experienced with CSI. Injection site reactions were common but generally mild. These results indicate that enfuvirtide is a promising new therapeutic agent for HIV-infected patients, including those with prior antiretroviral treatment.

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Strong in Vitro Synergy Between the Fusion Inhibitor T-20 and the CXCR4 Blocker AMD-3100

Cited by 71 publications

References 11 publications

Sensitivity of HIV-1 to entry inhibitors correlates with envelope/coreceptor affinity, receptor density, and fusion kinetics

Sensitivity of HIV-1 to entry inhibitors correlates with envelope/coreceptor affinity, receptor density, and fusion kinetics

Identification of Allosteric Peptide Agonists of CXCR4

The Safety, Plasma Pharmacokinetics, and Antiviral Activity of Subcutaneous Enfuvirtide (T-20), a Peptide Inhibitor of gp41-Mediated Virus Fusion, in HIV-Infected Adults

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