Oral transmission of human immunodeficiency virus (HIV) as a potential risk factor for HIV/AIDS spread is being intensively investigated, but the mechanisms of HIV interaction with oral mucosal epithelium in vivo are not well understood. Analysis of HIV infection in clinical specimens of oropharyngeal mucosal epithelium and saliva showed that HIV can be detected in both, indicating a key role of the oral cavity in HIV transmission and dissemination. Primary oral keratinocytes in vitro also can be infected by HIV-1, and they can transfer virus to lymphocytes. Our preliminary data show that HIV- 1 transcytosis can occur across polarized Detroit pharyngeal epithelial cells, indicating that oral HIV transmission may occur by transepithelial transcytosis through the epithelial barrier without infecting the epithelial cells. We also found that interepithelial Langerhans cells (LCs) in the HIV/AIDS-associated oral lesion called hairy leukoplakia are infected simultaneously with HIV and EBV, suggesting a critical role of LCs and HIV-EBV interactions in HIV pathogenesis in the oral cavity. Since suitable in vivo and in vitro oral mucosal epithelial model systems for evaluation of HIV infection are not available, our goal in this proposal is to establish an in vitro organ culture system from oral mucosal tissue and to use it to investigate HIV-1 infection. This system will also be used to study HIV and EBV interaction, since both viruses can replicate in oropharyngeal mucosal epithelium.
The specific aims of the study are: (1) To establish an in vitro organ culture model derived from squamous oral tissue. (2) To investigate infection of HIV-1 in the organotropic oral mucosal epithelial cell culture. (3) To study the effect of EBV on HIV infection in Langerhans cells of the organotropic oral mucosal epithelial tissue model. The results of these studies will provide new and detailed information on the mechanisms of HIV infection of the oral mucosal epithelium and the role of HIV-EBV infection in oral interepithelial LCs in HIV pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DE016009-01
Application #
6802946
Study Section
Special Emphasis Panel (ZDE1-YL (22))
Program Officer
Nokta, Mostafa A
Project Start
2004-03-15
Project End
2006-02-28
Budget Start
2004-03-15
Budget End
2005-02-28
Support Year
1
Fiscal Year
2004
Total Cost
$227,250
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Sufiawati, Irna; Tugizov, Sharof M (2014) HIV-associated disruption of tight and adherens junctions of oral epithelial cells facilitates HSV-1 infection and spread. PLoS One 9:e88803
Tugizov, Sharof M; Herrera, Rossana; Chin-Hong, Peter et al. (2013) HIV-associated disruption of mucosal epithelium facilitates paracellular penetration by human papillomavirus. Virology 446:378-88
Tugizov, Sharof M; Herrera, Rossana; Palefsky, Joel M (2013) Epstein-Barr virus transcytosis through polarized oral epithelial cells. J Virol 87:8179-94
Tugizov, Sharof M; Herrera, Rossana; Veluppillai, Piri et al. (2012) Differential transmission of HIV traversing fetal oral/intestinal epithelia and adult oral epithelia. J Virol 86:2556-70
Tugizov, Sharof M; Herrera, Rossana; Veluppillai, Piri et al. (2011) HIV is inactivated after transepithelial migration via adult oral epithelial cells but not fetal epithelial cells. Virology 409:211-22
Xiao, Jianqiao; Palefsky, Joel M; Herrera, Rossana et al. (2009) EBV-positive human sera contain antibodies against the EBV BMRF-2 protein. Virology 393:151-9
Xiao, Jianqiao; Palefsky, Joel M; Herrera, Rossana et al. (2009) EBV BMRF-2 facilitates cell-to-cell spread of virus within polarized oral epithelial cells. Virology 388:335-43
Xiao, Jianqiao; Palefsky, Joel M; Herrera, Rossana et al. (2008) The Epstein-Barr virus BMRF-2 protein facilitates virus attachment to oral epithelial cells. Virology 370:430-42
Tugizov, Sharof; Herrera, Rossana; Veluppillai, Piri et al. (2007) Epstein-Barr virus (EBV)-infected monocytes facilitate dissemination of EBV within the oral mucosal epithelium. J Virol 81:5484-96
Xiao, Jianqiao; Palefsky, Joel M; Herrera, Rossana et al. (2007) Characterization of the Epstein-Barr virus glycoprotein BMRF-2. Virology 359:382-96