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Journal of Virology, October 2002, p. 9868-9876, Vol. 76, No. 19
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.19.9868-9876.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Memory CD4+ T Cells Are the Earliest Detectable Human Immunodeficiency Virus Type 1 (HIV-1)-Infected Cells in the Female Genital Mucosal Tissue during HIV-1 Transmission in an Organ Culture System

Phalguni Gupta,1* Kelly B. Collins,1 Deena Ratner,1 Simon Watkins,2 Gregory J. Naus,3 Daniel V. Landers,3 and Bruce K. Patterson4

Department of Infectious Diseases and Microbiology, Graduate School of Public Health,1 Department of Cell Biology and Physiology, School of Medicine,2 Departments of Pathology and Obstetrics, Gynecology and Reproductive Sciences, Magee Women's Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania,3 Department of Pediatrics, Division of Infectious Diseases, Children's Memorial Hospital, Northwestern University Medical School, Chicago, Illinois4

Received 9 April 2002/ Accepted 25 June 2002

The virologic and cellular factors that are involved in transmission of human immunodeficiency virus type 1 (HIV-1) across the female genital tissue are poorly understood. We have recently developed a human cervical tissue-derived organ culture model to study heterosexual transmission of HIV-1 that mimics the in vivo situation. Using this model we investigated the role of phenotypic characteristics of HIV-1 and identified the cell types that are first infected during transmission. Our data indicate that the cell-free R5 HIV-1 was more efficiently transmitted than cell-free X4 HIV-1. Cell-free and cell-associated HIV-1 had comparable transmission efficiency regardless of whether the virus was of R5 or X4 type. We have demonstrated that memory CD4+ T cells and not Langerhans cells were the first HIV-1 RNA-positive cells detected at the epithelial-submucosal junction 6 h after virus exposure. Multicolor laser confocal microscopy demonstrated a globular distribution of HIV-1 gag-pol mRNA in the cytoplasm, and the distribution of CD4 and the CD45RO isoform was irregular on the cellular membrane. At 96 h postinoculation, in addition to memory CD4+ T cells, HIV-1 RNA-positive Langerhans cells and macrophages were also detected. The identification of CD4+ T cells in the tissue at 6 h was confirmed by flow cytometric simultaneous immunophenotyping and ultrasensitive fluorescence in situ hybridization assay on immune cells isolated from disaggregated tissue. Furthermore, PMPA {9-[2-(phosphonomethoxy)propyl] adenine}, an antiretroviral compound, and UC781, a microbicide, inhibited HIV-1 transmission across the mucosa, indicating the utility of the organ culture to screen topical microbicides for their ability to block sexual transmission of HIV-1.

* Corresponding author. Mailing address: 426 Parran Hall, University of Pittsburgh, Graduate School of Public Health, 130 DeSoto St., Pittsburgh, PA 15261. Phone: (412) 624-7998. Fax: (412) 624-4953. E-mail: pgupta1+{at}pitt.edu.

Journal of Virology, October 2002, p. 9868-9876, Vol. 76, No. 19
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.19.9868-9876.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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