Because human papillomavirus (HPV) infections appear to be causally linked to most cervical intraepithelial neoplasia (CIN) and cervical carcinoma, it is important to identify determinants of HPV-associated cervical disease. A growing body of evidence suggests an important role for the major histocompatibility complex (MHC) in the etiology of cervical dysplasia and cancer. Further studies in this area are needed to determine the relationship between host-virus interaction and the risk for cervical disease. In addition to understanding host factors, we also need to understand the population dynamics of HPV infections. Currently, HPV """"""""types"""""""" have been used as the exposure measure for HPV-associated risk for invasive cervical carcinoma. This level of exposure determination has not provided us with useful prognostic markers for determining risk of progression to invasive cervical carcinoma. Virtually no information is available concerning specific HPV sequences within HPV types associated with risk for invasive cervical carcinoma or presumed precursor lesions. Furthermore, sequence diversity of HPVs, the potential significance of HPV variants and subtypes, and relationships between HPV types have been given little consideration as factors important for determining risk for cervical disease. This grant application requests funding for studies that will examine host- and viral-specific risk factors of HPV-associated cervical disease. We have previously identified HPV-specific MHC associations with severe dysplasia/ClS and invasive cervical carcinoma in case-control studies of Hispanic women. We will characterize HLA class l and II loci in case-control studies of in situ and invasive cervical cancer in Hispanic and non-Hispanic white women from the same geographic location. We will also consider HPV sequence-specific risk factors for cervical disease. We have previously observed an amino acid change in the HPV-16 E6 open reading frame that is associated with high grade squamous intraepithelial lesions. We will examine this observation in a blinded investigation using specimens obtained through an ongoing longitudinal cohort study of HPV and cervical disease being conducted by the NCl. The proposed studies will form a basis for elucidating specific mechanisms of HPV-associated cervical cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI032917-07
Application #
2457751
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Project Start
1991-09-30
Project End
2000-07-31
Budget Start
1997-08-01
Budget End
1998-07-31
Support Year
7
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of New Mexico
Department
Physiology
Type
Schools of Medicine
DUNS #
829868723
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Wheeler, Cosette M; Hunt, William C; Joste, Nancy E et al. (2009) Human papillomavirus genotype distributions: implications for vaccination and cancer screening in the United States. J Natl Cancer Inst 101:475-87
Deshpande, Alina; Wheeler, Cosette M; Hunt, William C et al. (2008) Variation in HLA class I antigen-processing genes and susceptibility to human papillomavirus type 16-associated cervical cancer. J Infect Dis 197:371-81
Arias-Pulido, Hugo; Peyton, Cheri L; Joste, Nancy E et al. (2006) Human papillomavirus type 16 integration in cervical carcinoma in situ and in invasive cervical cancer. J Clin Microbiol 44:1755-62
Deshpande, Alina; Nolan, John P; White, P Scott et al. (2005) TNF-alpha promoter polymorphisms and susceptibility to human papillomavirus 16-associated cervical cancer. J Infect Dis 191:969-76
Arias-Pulido, Hugo; Joste, Nancy; Wheeler, Cosette M (2004) Loss of heterozygosity on chromosome 6 in HPV-16 positive cervical carcinomas carrying the DRB1*1501-DQB1*0602 haplotype. Genes Chromosomes Cancer 40:277-84
Clark, Kevin D; Garczynski, Stephen F; Arora, Aditi et al. (2004) Specific residues in plasmatocyte-spreading peptide are required for receptor binding and functional antagonism of insect immune cells. J Biol Chem 279:33246-52
Emeny, Rebecca T; Wheeler, Cosette M; Jansen, Kathrin U et al. (2002) Priming of human papillomavirus type 11-specific humoral and cellular immune responses in college-aged women with a virus-like particle vaccine. J Virol 76:7832-42
Juarez-Figueroa, L A; Wheeler, C M; Uribe-Salas, F J et al. (2001) Human papillomavirus: a highly prevalent sexually transmitted disease agent among female sex workers from Mexico City. Sex Transm Dis 28:125-30
Wang, S S; Wheeler, C M; Hildesheim, A et al. (2001) Human leukocyte antigen class I and II alleles and risk of cervical neoplasia: results from a population-based study in Costa Rica. J Infect Dis 184:1310-4
Peyton, C L; Gravitt, P E; Hunt, W C et al. (2001) Determinants of genital human papillomavirus detection in a US population. J Infect Dis 183:1554-64

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