Perturbation of the viral co-receptor CCR5 by NB325 inhibits HIV-1 infection
Despite the successes achieved using the latest therapies effective against HIV-1-associated immunopathogenesis, neurological disease associated with HIV-1 infection of the central nervous system remains a pressing problem. For this reason, the development of compounds effective against HIV-1, speci...
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Published in | Journal of neurovirology Vol. 13; p. 99 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
01.01.2007
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Subjects | |
Online Access | Get full text |
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Summary: | Despite the successes achieved using the latest therapies effective against HIV-1-associated immunopathogenesis, neurological disease associated with HIV-1 infection of the central nervous system remains a pressing problem. For this reason, the development of compounds effective against HIV-1, specifically the CCR5-utilizing strains predominant in the brain, remains a high priority. Our efforts in this area focus on compounds that inhibit HIV-1 infection by interfering with the role of CCR5 in viral binding and entry. NB325, which is a biguanide-based compound, is characterized by low toxicity and notable activity against HIV-1 BaL, a CCR5-utilizing viral strain. Results from flow cytometric analyses of primary human peripheral blood mononuclear cells (PBMCs) demonstrated increased CCR5 detection following exposure to NB325 despite effective inhibition of HIV-1 BaL infection. Differences in CCR5 detection were also noted between quiescent PBMC sub-populations and cells activated with PHA-P. We hypothesize that inhibition of HIV-1 BaL infection by NB325 may involve perturbation of CCR5 within the plasma membrane. These changes interfere with interactions with HIV-1, and make CCR5 more accessible to detection by CCR5-specific antibodies. Our current mechanism of action studies are building on the observation that NB325 also interacts specifically with CXCR4 extracellular loop 2 (ECL2). Ongoing investigations are exploring similar interactions between NB325 and CCR5 that may cause changes in co-receptor availability, localization, and/or conformation that result in inhibition of HIV-1 infection. These studies are being used to facilitate the development of novel compounds that can be used safely to inhibit HIV-1 CNS infection. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 content type line 23 ObjectType-Feature-2 |
ISSN: | 1355-0284 |