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HIV-1 pathogenesis differs in rectosigmoid and tonsillar tissues infected ex vivo with CCR5- and CXCR4-tropic HIV-1

Grivel, Jean-Charlesa; Elliott, Julieb; Lisco, Andreaa; Biancotto, Angèliquea; Condack, Cristiana; Shattock, Robin Jc; McGowan, Ianb; Margolis, Leonida; Anton, Peterb

doi: 10.1097/QAD.0b013e3281864667
Basic Science

Gut-associated lymphoid tissue (GALT) has been identified as the primary target of HIV-1 infection. To investigate why GALT is especially vulnerable to HIV-1, and to determine whether the selective transmission of CCR5-using viral variants (R5) in vivo is the result of a greater susceptibility of GALT to this viral variant, we performed comparative studies of CXCR4-using (X4) and R5 HIV-1 infections of human lymphoid (tonsillar) and rectosigmoid tissues ex vivo under controlled laboratory conditions. We found that the relative level of R5 replication in rectosigmoid tissue is much greater than in tonsillar tissue. This difference is associated with the expression of the CCR5 co-receptor on approximately 70% of CD4 T cells in rectosigmoid tissue, whereas in tonsillar tissue it is expressed on fewer than 15% of CD4 T cells. Furthermore, tonsillar tissue responds to X4 HIV-1 infection by upregulating the secretion of CC-chemokines, providing a potential CCR5 blockade and further resistance to R5 infection, whereas gut tissue failed to increase such innate immune responses. Our results show that rectosigmoid tissue is more prone than tonsillar lymphoid tissue to R5 HIV-1 infection, primarily because of the high prevalence and availability of R5 cell targets and reduced chemokine blockade. The majority of CD4 T cells express CXCR4, however, and X4 HIV-1 readily replicates in both tissues, suggesting that although the differential expression of co-receptors contributes to the GALT vulnerability to R5 HIV-1, it alone cannot account for the selective R5 infection of the rectal mucosa in vivo.

From the aNational Institute of Child Health and Human Development, Bethesda, Maryland, USA

bCenter for Prevention Research, UCLA AIDS Institute, David Geffen School of Medicine at UCLA, Los Angeles, California, USA

cSt George's University of London, London, UK.

Received 24 July, 2006

Revised 16 October, 2006

Accepted 5 March, 2007

Correspondence to Leonid Margolis, 10 Center Drive, NIH Building 10, Room 9D58, Bethesda, MD 20892, USA. Tel: +1 301 5942476; fax: +1 301 4800857; e-mail:

© 2007 Lippincott Williams & Wilkins, Inc.