Oral manifestations of HIV have been documented since the initial presentation of the HIV/AIDS epidemic of the 80's. The most common oral complication was candidiasis, and was associated with a reduction in CD4+T cells. Oral candidal infection was a hallmark indicator of immune dysfunction. The increased incidence of opportunistic infections was related to immune suppression as evidenced by a reduction in number and functional activity of CD4 + T cells. The frequency and type of oral complication has changed since the initial description of the 80s. With the initiation of HAART therapies the constellation of oral manifestations has changed. The incidence of HPV associated warts and severe aphthous ulcer stomatitis has increased, whereas oral candidal infection and oral hairy leukoplakia has declined. In addition, not all patients develop these pathologies. The variation in disease presentation and concomitant response to therapy may be related to genetic predisposition of innate immune genes and variation in epithelial barrier function. Innate immunity is increasingly being recognized as playing a critical role in host defense against infectious diseases, including HIV. The defensin peptides have antimicrobial properties and are major protective components of the epithelial mucosal barrier. Genetic variation of the defensin genes in the form of SNPs and CNVs has been shown to be associated with disease susceptibility. Toll-like receptors (TLRs), a family of evolutionary conserved receptors on host cells including human oral epithelial cells, recognize specific microbial structures, leading to the up-regulation of inflammatory mediators and recruitment of inflammatory cells. Multiple interactions of microbes and host tissues and secreted antimicrobial molecules such as beta-defensins are involved in the maintenance of the homeostatic environment of the healthy mouth, however, little is known about the role of TLRs in this process or the impact of HIV disease on these processes. Polymorphisms in the TLR family and the common adaptor Tirap/Mal have been associated with many human infectious and autoimmune diseases. We hypothesize that host variation in TLRs and their signaling components contribute to the variability in oral infections seen in HIV disease by altering host/microbe interactions at the mucosal surface. We will decipher the relationship of genetic variations in both the defensin gene cluster and toll-like receptors TLR1 and 2 with oral manifestations of HIV/AIDS. We will define and correlate specific complex haplotypes with the frequency and occurrence of oral lesions in the HIV population. We hypothesize that susceptibility, prognosis, and outcome of HIV are associated with genetic variations in the defensin gene cluster. This same variation also may be associated with the development of oral complications following HIV infection

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Program Projects (P01)
Project #
5P01DE019759-05
Application #
8462471
Study Section
Special Emphasis Panel (ZDE1-JH)
Project Start
2013-05-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$294,827
Indirect Cost
$107,057
Name
Case Western Reserve University
Department
Type
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Dazard, Jean-Eudes; Ishwaran, Hemant; Mehlotra, Rajeev et al. (2018) Ensemble survival tree models to reveal pairwise interactions of variables with time-to-events outcomes in low-dimensional setting. Stat Appl Genet Mol Biol 17:
DasGupta, Twishasri; Nweze, Emeka I; Yue, Hong et al. (2016) Human papillomavirus oncogenic E6 protein regulates human ?-defensin 3 (hBD3) expression via the tumor suppressor protein p53. Oncotarget 7:27430-44
Mehlotra, Rajeev K; Zimmerman, Peter A; Weinberg, Aaron (2016) Defensin gene variation and HIV/AIDS: a comprehensive perspective needed. J Leukoc Biol 99:687-92
Zapata, Wildeman; Aguilar-Jiménez, Wbeimar; Feng, Zhimin et al. (2016) Identification of innate immune antiretroviral factors during in vivo and in vitro exposure to HIV-1. Microbes Infect 18:211-9
Judge, Chelsey J; Reyes-Aviles, Elane; Conry, Sara J et al. (2015) HBD-3 induces NK cell activation, IFN-? secretion and mDC dependent cytolytic function. Cell Immunol 297:61-8
Feng, Zhimin; Jia, Xun; Adams, Mark D et al. (2014) Epithelial innate immune response to Acinetobacter baumannii challenge. Infect Immun 82:4458-65
Chung, Charlotte Y; Alden, Stephanie L; Funderburg, Nicholas T et al. (2014) Progressive proximal-to-distal reduction in expression of the tight junction complex in colonic epithelium of virally-suppressed HIV+ individuals. PLoS Pathog 10:e1004198
Willie, B; Hall, N B; Stein, C M et al. (2014) Association of Toll-like receptor polymorphisms with HIV status in North Americans. Genes Immun 15:569-77
Cheruvu, Vinay K; Igo Jr, Robert P; Jurevic, Richard J et al. (2014) African ancestry influences CCR5 -2459G>A genotype-associated virologic success of highly active antiretroviral therapy. J Acquir Immune Defic Syndr 66:102-7
Mehlotra, R K; Zimmerman, P A; Weinberg, A et al. (2013) Variation in human ?-defensin genes: new insights from a multi-population study. Int J Immunogenet 40:261-9

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