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.
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.
Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA. pgupta1+@pitt.edu
Phalguni
P
Gupta
Kelly B
KB
Collins
Deena
D
Ratner
Simon
S
Watkins
Gregory J
GJ
Naus
Daniel V
DV
Landers
Bruce K
BK
Patterson
D000163:Acquired Immunodeficiency Syndrome / Q000635:transmission*; D019380:Anti-HIV Agents / Q000494:pharmacology; D001706:Biopsy; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D002584:Cervix Uteri / Q000821:virology*; D005260:Female; D005434:Flow Cytometry; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007156:Immunologic Memory; D009924:Organ Culture Techniques
D019380:Anti-HIV Agents