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Primary intestinal epithelial cells selectively transfer R5 HIV-1 to CCR5+ cells

Nature Medicine volume 8, pages 150–156 (2002)Cite this article

Abstract

The upper gastrointestinal tract is a principal route of HIV-1 entry in vertical transmission and after oral–genital contact. The phenotype of the newly acquired virus is predominantly R5 (CCR5-tropic) and not X4 (CXCR4-tropic), although both R5 and X4 viruses are frequently inoculated onto the mucosa. Here we show that primary intestinal (jejunal) epithelial cells express galactosylceramide, an alternative primary receptor for HIV-1, and CCR5 but not CXCR4. Moreover, we show that intestinal epithelial cells transfer R5, but not X4, viruses to CCR5+ indicator cells, which can efficiently replicate and amplify virus expression. Transfer was remarkably efficient and was not inhibited by the fusion blocker T-20, but was substantially reduced by colchicine and low (4 °C) temperature, suggesting endocytotic uptake and microtubule-dependent transcytosis of HIV-1. Our finding that CCR5+ intestinal epithelial cells select and transfer exclusively R5 viruses indicates a mechanism for the selective transmission of R5 HIV-1 in primary infection acquired through the upper gastrointestinal tract.

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Figure 1: Characteristics of primary IECs isolated by neutral protease from jejunal mucosa.
Figure 2: IECs express GalCer and CCR5, but not CXCR4.
Figure 3: IECs do not express SDF-1.
Figure 4: IECs preferentially transfer R5 virus to indicator cells.
Figure 5: Direct relationship between the duration of IEC–indicator-cell contact and HIV-1 production.
Figure 6: Sequence of gp41 and V3 regions of indicator-cell output virus was identical to input BaL but not IIIB HIV-1.

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Acknowledgements

This study was supported NIH grants and contracts DK-47322, DE-72621, AI-41530, HD-41361, AI-35467, CA-73470, AI-28147, DK34151; the Central AIDS Virus Core of the Birmingham Center for AIDS Research (P30-AI-27767); and the Research Service of the Department of Veterans Affairs.

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Authors and Affiliations

  1. Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Gang Meng, Xiaoyun Wu, John C. Kappes & Phillip D. Smith

  2. Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Marty T. Sellers

  3. Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Zina Moldoveanu, John C. Kappes & Jiri Mestecky

  4. Veterans' Administration Medical Center, Birmingham, Alabama, USA

    John C. Kappes & Phillip D. Smith

  5. Howard Hughes Medical Institute, Birmingham, Alabama, USA

    Xiping Wei, Julie M. Decker & George M. Shaw

  6. Department of Pathology, George Washington University Medical Center, Washington, D.C., USA

    Jan M. Orenstein

  7. Department of Pediatrics, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, USA

    Martin F. Graham

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Correspondence to Phillip D. Smith.

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Meng, G., Wei, X., Wu, X. et al. Primary intestinal epithelial cells selectively transfer R5 HIV-1 to CCR5+ cells. Nat Med 8, 150–156 (2002). https://doi.org/10.1038/nm0202-150

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