The mechanisms determining how virus is passed through the genital epithelium to underlying immune cells are poorly understood. Consequently, there is a need for a model to study the events of HIV-1 genital infection as well as evaluation of microbicides to inhibit HIV-1 transmission. Studies in nonhuman primates have provided insight into the role of the mucosa during SIV infection; however, use of a different retrovirus and the ensuing disease course, together with ethical issues and the high cost of animal husbandry, necessitate development of in vitro assays which better duplicate the human genital tract environment. Use of small animal models (mice and rabbits) for microbicide testing presents similar problems given the inability to infect these animals with HIV-1. The studies proposed in this application utilize an in vitro model that uses both primary cervical epithelial and stromal immune cells. Microbicide toxicity will be evaluated with primary epithelial cells in a transwell system and cervical epithelial sheets clamped into diffusion chambers. The ability of a microbicide to inhibit HIV-1 infection and replication in cultured mucosal immune cells will also be examined. Finally, the cervical explant model will be used to determine the ability of a microbicide to inhibit dissemination of HIV-1 to local cells during immune activation or degradation of the epithelial barrier by mucosal pathogens (T. pallidum and T. vaginalis). The proposed experiments will provide valuable insight into microbicide development and may obviate the need for small animal testing.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32HD040727-01
Application #
6340093
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
Kaufman, Steven
Project Start
2001-09-01
Project End
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
1
Fiscal Year
2001
Total Cost
$39,196
Indirect Cost
Name
U.S. Centers for Disease Control & Prev
Department
Type
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30333
Cummins Jr, James E; Denniston, Maxine; Mayer, Kenneth H et al. (2007) Mucosal innate immune factors in secretions from high-risk individuals immunized with a bivalent gp120 vaccine. AIDS Res Hum Retroviruses 23:748-54
Cummins Jr, James E; Guarner, Jeannette; Flowers, Lisa et al. (2007) Preclinical testing of candidate topical microbicides for anti-human immunodeficiency virus type 1 activity and tissue toxicity in a human cervical explant culture. Antimicrob Agents Chemother 51:1770-9
Cummins, James E; Christensen, Logan; Lennox, Jeffery L et al. (2006) Mucosal innate immune factors in the female genital tract are associated with vaginal HIV-1 shedding independent of plasma viral load. AIDS Res Hum Retroviruses 22:788-95
Abner, Sheila R; Guenthner, Patricia C; Guarner, Jeannette et al. (2005) A human colorectal explant culture to evaluate topical microbicides for the prevention of HIV infection. J Infect Dis 192:1545-56
Cummins Jr, James E; Boneva, Roumiana S; Switzer, William M et al. (2005) Mucosal and systemic antibody responses in humans infected with simian foamy virus. J Virol 79:13186-9
Cummins Jr, James E; Villanueva, Julie M; Evans-Strickfaden, Tammy et al. (2003) Detection of infectious human immunodeficiency virus type 1 in female genital secretions by a short-term culture method. J Clin Microbiol 41:4081-8