Journal article
Inhibition of HIV-1 infection by NB325 may be independent of the neuroglial functions of the chemokine receptor CXCR4
Journal of neurovirology, Vol.13, pp.129-129
01 Jan 2007
Abstract
Within the central nervous system (CNS), CXCR4 and its ligand SDF-1alpha (stromal cell derived factor-lalpha) participate in neurogenesis, neuronal survival, and axonal pathfinding; inhibition of HIV-1 infection by a CXCR4 inhibitor may adversely affect normal neuronal functions. For this reason, chemokine receptor (CCR) inhibitors developed for use in the CNS should specifically inhibit HIV-1 infection while permitting normal CCR functions. Our efforts in this area have focused on compounds that inhibit HIV-1 infection by interfering with interactions between the virus and cell surface proteins. NB325 (a biguanide-based compound) is characterized by low toxicity and considerable activity against HIV-1 IIIB, which uses CXCR4 as a viral co-receptor. The particular potency of NB325 in the presence of both virus and target cells led us to hypothesize that NB325 may interfere with viral binding and entry mechanisms. Flow cytometric assays demonstrated that NB325 altered the detection of CXCR4 on activated primary human CD4+ T lymphocytes in an epitope-specific manner. Further mechanistic studies demonstrated that NB325 (i) did not inhibit CXCR4 binding by its sole ligand, SDF-1alpha, (ii) did inhibit SDF-1alpha-induced chemotaxis, (iii) was competitively inhibited from binding CXCR4 by a pep-tide derived from CXCR4 extracellular loop 2 (ECL2), and (iv) did not induce CXCR4 internalization. Ongoing investigations will further explore the mechanism of NB325 activity and its impact on normal CXCR4 functions in both immune and neuroglial cells. These studies will facilitate the development of novel compounds that can be used safely in the CNS to inhibit HIV-1 infection.
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Details
- Title
- Inhibition of HIV-1 infection by NB325 may be independent of the neuroglial functions of the chemokine receptor CXCR4
- Creators
- N ThakkarS PassicT Kish-CataloneB WigdahlR RandoM LabibF Krebs
- Publication Details
- Journal of neurovirology, Vol.13, pp.129-129
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Identifiers
- 991019170495404721