The oral mucosa is directly challenged with Human Immunodeficiency Virus (HIV) by exposure of infants to HIV-carrying vaginal fluids at birth and to breast milk postnatally, and with passive oral sex among men. Exposures commonly include both X4 and R5 HIV, yet R5 viruses account for most primary systemic infections. When exposed to HIV and Porphyromas gingivalis cysteine proteases, we hypothesize that oral keratinocytes up-regulate expression of innate immune molecules, including alpha- and beta-defensins and other associated genes, to enhance HIV R5 transcytosis and intracellular resistance to HIV infection. To test this hypothesis, we will: 1. show that expression of CXCR4 and CCR5 by oral keratinocytes contribute to coreceptor-specific transcytosis of X4 and R5 HIV isolates; 2. determine if exposure to HIV regulates expression of the innate immune molecules calprotectin and alpha- and beta-defensins directly or in association with PAR signaling mediated by specific P. gingivalis protease mutants; 3. identify and profile oral keratinocyte innate immune-associated gene expression patterns, including known plausible HIV co-receptors and other innate immune molecules, which are regulated by HIV in the presence and absence of P. gingivalis proteases; and 4 show how innate immune molecules modulate transcytosis, translocation by paracellular routes, and anti-HIV resistance in oral keratinocytes in vitro. This project will show that oral keratinocytes express innate immune molecules to resist intracellular infection by X4 and R5 HIV. In the presence of cysteine proteases, innate immune molecules and genes required for transcytosis of R5 HIV expression will be up-regulated, increasing intracellular anit-HIV resistance and facilitating transfer R5 HIV-1 to initiate systemic infection. Innate immune factor-related genes may prove to be novel targets to prevent mucosal HIV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE015503-03
Application #
6899812
Study Section
Special Emphasis Panel (ZDE1-YL (39))
Program Officer
Mcinnes, Pamela M
Project Start
2003-08-01
Project End
2007-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
3
Fiscal Year
2005
Total Cost
$336,070
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Dentistry
Type
Schools of Dentistry
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Ross, Karen F; Herzberg, Mark C (2016) Autonomous immunity in mucosal epithelial cells: fortifying the barrier against infection. Microbes Infect 18:387-398
Dietrich, Elizabeth A; Gebhard, Kristin H; Fasching, Claudine E et al. (2012) Short communication: HIV type 1 escapes inactivation by saliva via rapid escape into oral epithelial cells. AIDS Res Hum Retroviruses 28:1574-8
Herzberg, M C; Vacharaksa, A; Gebhard, K H et al. (2011) Plausibility of HIV-1 Infection of Oral Mucosal Epithelial Cells. Adv Dent Res 23:38-44
Hiroshima, Yuka; Bando, Mika; Kataoka, Masatoshi et al. (2011) Regulation of antimicrobial peptide expression in human gingival keratinocytes by interleukin-1?. Arch Oral Biol 56:761-7
Giacaman, Rodrigo A; Asrani, Anil C; Ross, Karen F et al. (2009) Cleavage of protease-activated receptors on an immortalized oral epithelial cell line by Porphyromonas gingivalis gingipains. Microbiology 155:3238-46
Giacaman, Rodrigo A; Asrani, Anil C; Gebhard, Kristin H et al. (2008) Porphyromonas gingivalis induces CCR5-dependent transfer of infectious HIV-1 from oral keratinocytes to permissive cells. Retrovirology 5:29
Vacharaksa, Anjalee; Asrani, Anil C; Gebhard, Kristin H et al. (2008) Oral keratinocytes support non-replicative infection and transfer of harbored HIV-1 to permissive cells. Retrovirology 5:66
Bando, Mika; Hiroshima, Yuka; Kataoka, Masatoshi et al. (2007) Interleukin-1alpha regulates antimicrobial peptide expression in human keratinocytes. Immunol Cell Biol 85:532-7
Giacaman, Rodrigo A; Nobbs, Angela H; Ross, Karen F et al. (2007) Porphyromonas gingivalis selectively up-regulates the HIV-1 coreceptor CCR5 in oral keratinocytes. J Immunol 179:2542-50
Herzberg, M C; Weinberg, A; Wahl, S M (2006) (C3) The oral epithelial cell and first encounters with HIV-1. Adv Dent Res 19:158-66

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