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Inhibitors that target gp120 interactions with coreceptor

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Entry Inhibitors in HIV Therapy

Part of the book series: Milestones in Drug Therapy ((MDT))

Abstract

Until 1996, when HIV-1 infection was discovered to involve chemokine receptors (reviewed in [1, 2]), virus isolates were characterized by biological assays on human cell lines as syncytium inducing (SI) or non-syncytium inducing (NSI) [3]. NSI viruses predominate early after transmission, are capable of growth in primary macrophages (macrophage tropism), and fail to grow in most established human T cell lines. SI viruses, by contrast, are found in only a subset of patients after chronic infection, are usually not macrophage tropic, and infect established T cell lines [4]. NSI viruses were found to use CCR5 as the coreceptor for virus entry into target cells, and SI viruses to use CXCR4 for entry, either alone or, more commonly, in addition to CCR5. Since CCR5 and CXCR4 are differentially expressed on the surface of naïve and memory T cells, dendritic cells, and macrophages, coreceptor preference largely explains cell tropism. The importance of CCR5 in viral transmission and as a target for therapeutic intervention was underscored by the discovery of a 32-base pair deletion in the human CCR5 coding region (Δ32 mutation) which, when homozygous, prevents CCR5 surface expression and HIV-1 infection [5, 6]. Individuals with the CCR5 Δ32/Δ32 genotype appear to suffer no clinically obvious detriment, although recent data suggest that they may be more susceptible to West Nile virus encephalitis [7]. The cell tropism of CCR5-using viruses (R5 isolates) probably helps explain their selective transmission [8], although it is still difficult to understand why R5 isolates predominate after parenteral exposure [9].

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Authors and Affiliations

  1. Department of Virology, Schering-Plough Research Institute, 2015 Galloping Hill Road, K15, E405C/4945, Kenilworth, NJ, 07033, USA

    Julie M. Strizki

  2. Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California, 92037, USA

    Donald E. Mosier

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  1. Julie M. Strizki
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  2. Donald E. Mosier
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Editors and Affiliations

  1. Monogram Biosciences, 345 Oyster Point Blvd., South San Francisco, CA, 94080, USA

    Jacqueline D. Reeves

  2. Department of Pathology and Laboratory Medicine, Emory Vaccine Center, Emory University, 954 Gatewood Rd, Suite 1024, Atlanta, GA, 30329, USA

    Cynthia A. Derdeyn

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© 2007 Birkhäuser Verlag/Switzerland

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Strizki, J.M., Mosier, D.E. (2007). Inhibitors that target gp120 interactions with coreceptor. In: Reeves, J.D., Derdeyn, C.A. (eds) Entry Inhibitors in HIV Therapy. Milestones in Drug Therapy. Birkhäuser Basel. https://doi.org/10.1007/978-3-7643-7783-0_5

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