Inhibition of Human Immunodeficiency Virus Replication by a Dual CCR5/CXCR4 Antagonist

Princen, Katrien; Hatse, Sigrid; Vermeire, Kurt; Aquaro, Stefano; Clercq, Erik De; Gerlach, Lars‐Ole; Schwartz, Thue W.; Skerlj, Renato T.; Bridger, Gary; Schols, Dominique

doi:10.1128/jvi.78.23.12996-13006.2004

Cited by 87 publications

(69 citation statements)

References 61 publications

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“…The structure of AMD3465 may translate into oral delivery and potential clinical use (Hatse et al 2005). Another receptor antagonist, AMD3451, was shown to inhibit both X4 and R5 strains; however, more studies are needed to determine its therapeutic potential (Princen et al 2004). A number of CCR5 antagonists are in clinical trials (Julg and Goebel 2005;Princen and Schols 2005).…”

Section: Receptor Antagonistsmentioning

confidence: 99%

Neuroimmunity and the Blood–Brain Barrier: Molecular Regulation of Leukocyte Transmigration and Viral Entry into the Nervous System with a Focus on NeuroAIDS

Buckner

Luers

Calderon

et al. 2006

Jrnl NeuroImmune Pharm

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HIV infection of the central nervous system (CNS) can result in neurologic dysfunction with devastating consequences in a significant number of individuals with AIDS. Two main CNS complications in individuals with HIV are encephalitis and dementia, which are characterized by leukocyte infiltration into the CNS, microglia activation, aberrant chemokine expression, bloodbrain barrier (BBB) disruption, and eventual damage and/or loss of neurons. One of the major mediators of NeuroAIDS is the transmigration of HIV-infected leukocytes across the BBB into the CNS. This review summarizes new key findings that support a critical role of the BBB in regulating leukocyte transmigration. In addition, we discuss studies on communication among cells of the immune system, BBB, and the CNS parenchyma, and suggest how these interactions contribute to the pathogenesis of Neuro-AIDS. We also describe some of the animal models that have been used to study and characterize important mechanisms that have been proposed to be involved in HIV-induced CNS dysfunction. Finally, we review the pharmacologic interventions

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Section: Receptor Antagonistsmentioning

confidence: 99%

Neuroimmunity and the Blood–Brain Barrier: Molecular Regulation of Leukocyte Transmigration and Viral Entry into the Nervous System with a Focus on NeuroAIDS

Buckner

Luers

Calderon

et al. 2006

Jrnl NeuroImmune Pharm

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“…CXCR4 is expressed reasonably well on monocytes and macrophages, 6 and can be used by some SI and dual-tropic primary isolates. 15,17,28 Progression of acute HIV-1 infection to AIDS is accompanied by immune dysregulation and susceptibility to OIs. 4 Accompanying these events, a change in HIV-1 dynamics involves an increased representation of HIV-1 positive macrophages hosts, in addition to CD4+ T cells.…”

Section: Macrophage Tropism and Disease Progressionmentioning

confidence: 99%

Pathogenesis of HIV infection

Pattman¹,

Sankar²,

Elawad³

et al. 2010

Oxford Handbook of Genitourinary Medicine, HIV, and Sexual Health

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Over the past three decades of intense research on the contribution of viral and host factors determining the variability in HIV-1 infection outcome, HIV pathogenesis is still a fascinating topic that requires further study. An understanding of the exact mechanism of how these factors influencing HIV pathogenesis is critical to the development of effective strategies to prevent infection. Significant progress has been made in identifying the role of CCR5 (R5) and CXCR4 (X4) HIV strains in disease progression, particularly with the persistence of R5 HIV-1 strains at the AIDS stage. This indicates that R5 strains are as fit as X4 in causing CD4+ T cell depletion and in contribution to disease outcome, and so questions the prerequisite of the shift from R5 to X4 for disease progression. In contrast, the ability of certain HIV strains to readily use CXCR4 for infection or entry into macrophages, as the case with viruses are homozygous for tropism by CCR5delta32. This raises another major paradox in HIV pathogenesis about the source of X4 variants and how do they emerge from a relatively homogeneous R5 viral population after transmission. The interactions between viral phenotypes, tropism and co-receptor usage and how they influence HIV pathogenesis are the main themes addressed in this review. A better understanding of the viral and host genetic factors involved in the fitness of X4 and R5 strains of HIV-1 may facilitate development of specific inhibitors against these viral populations to at least reduce the risk of disease progression.

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“…AMD3451 also inhibited the SDF-1-and MIP-1␤-induced chemotaxis in a dose-dependent manner and was able to block the SDF-1-and LD78 ␤-induced endocytosis in CXCR4-and CCR5-transfected cells. Moreover, studies showed that the compound interacts in a different manner with CXCR4 then the specific CXCR4 antagonist AMD3100 since AMD3451 did not inhibit but enhanced the binding of anti-CXCR4 mAbs (such as clone 12G5) at the cell surface (Princen et al, 2004). The precise interaction sites of AMD3451 with CCR5 and CXCR4 is still under investigation, but it demonstrates that it is possible to develop compounds that interact with both HIV co-receptors.…”

Section: Ccr5/cxcr4 Antagonistmentioning

confidence: 99%

HIV co-receptor inhibitors as novel class of anti-HIV drugs

Schols

2006

Antiviral Research

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Entry inhibitors constitute a new class of drugs to treat infection by human immunodeficiency virus type 1 (HIV-1). The first member of this class, enfuvirtide, previously known as T-20 and targeting gp41, has now been licensed for therapeutic use. Several other entry inhibitors are in various stages of pre-clinical or clinical development. In this review we focus on the chemokine receptor inhibitors targeting CCR5 and CXCR4 that are the main HIV co-receptors for viral entry.

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Inhibition of Human Immunodeficiency Virus Replication by a Dual CCR5/CXCR4 Antagonist

Cited by 87 publications

References 61 publications

Neuroimmunity and the Blood–Brain Barrier: Molecular Regulation of Leukocyte Transmigration and Viral Entry into the Nervous System with a Focus on NeuroAIDS

Neuroimmunity and the Blood–Brain Barrier: Molecular Regulation of Leukocyte Transmigration and Viral Entry into the Nervous System with a Focus on NeuroAIDS

Pathogenesis of HIV infection

HIV co-receptor inhibitors as novel class of anti-HIV drugs

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