This is a competitive renewal for our """"""""Natural history of HPV;infection to neoplasia"""""""" grant. The natural history of HPV is most likely influenced by both innate and adaptive mucosal immunity. More specifically, we hypothesize that Tolllike receptors (TLRs) play an important role in cervical innate immunity to HPV through secretions of proinflammatory, chemotactic and anti-viral cytokines. Up-regulated TLR expression will also result in activation of dendritic cells and T cells that in turn will promote a Thl like response through secretion of several cytokines and consequently, the induction of a successful cell mediated immune (CMI) response. We propose to: 1) examine, in cervical cell samples, the association among TRL expression,TRL-associated cytokines that mediate innate immunity ( IFN alpha, TNF, IL-6 and IL-8) and clearance of incident HPV infection;2) examine, in cervical cell samples, the association among TRL expression, TRL-associated cytokines that induce and mediate adaptive immunity (IFN-gamma, ILs- 12, 23, and 27) and HPV clearance;and 3) examine the association among TLR induced Th-1 responses measured in cervical cell samples, HPV specific CMI responses detected in peripheral blood (PB) and HPV clearance. Adolescent and young women who were a) entered into the cohort during the initial 1990-1995 period and have continued to be followed and b) entered into the cohort during the last recruitment wave (2000-2005) will be asked to continue follow-up for an additional five years (2005-2010). These women will have been well characterized at the time of the initiation of this study with HPV at their entry visit and 4-month interval sampling for HPV DNA, cytology, bacterial vaginosis, colpophotographs (assessment of cervical maturation), C. trachomatis and N. gonorrohea testing, cervical cell cytokines by RT-PCR (IFN-gamma, ILs 4,10 and 12) and PB CMI for HPV 16 positive women. Women will be continued to be characterized for the above at the same intervals through-out the follow-up. Measures of innate and adaptive immunity (TLRs, ILs-6, 8, 5, 13, 23, and 27, TNF, IFN alpha) by RT PCR using cervical cells and by Luminex technology using cervical mucous will be added to the same 4 month interval testing as HPV DNA, cytology and other cervical cytokines described. Women positive for HPV 16 will get additional blood for CMI using IFN-gamma EliSpot technique for detection of anti-E6 and E7 responses. We acknowledge that this design simplifies the pleiotropic nature of cytokines. However, we feel that this model reflects plausible mechanisms involved in HPV control and is feasible to test in our cohort. Information garnered from this type of study will be critical in developing vaccine strategies and therapies as well as illuminating immune responses developed in the mucosal epithelium.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37CA051323-21
Application #
7784208
Study Section
Special Emphasis Panel (NSS)
Program Officer
Starks, Vaurice
Project Start
1990-07-01
Project End
2015-06-30
Budget Start
2010-07-08
Budget End
2011-06-30
Support Year
21
Fiscal Year
2010
Total Cost
$1,638,032
Indirect Cost
Name
University of California San Francisco
Department
Pediatrics
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Kyrgiou, Maria; Mitra, Anita; Moscicki, Anna-Barbara (2017) Does the vaginal microbiota play a role in the development of cervical cancer? Transl Res 179:168-182
Moscicki, Anna-Barbara; Ma, Yifei; Gheit, Tarik et al. (2017) Prevalence and Transmission of Beta and Gamma Human Papillomavirus in Heterosexual Couples. Open Forum Infect Dis 4:ofw216
Averbach, Sarah H; Ma, Yifei; Smith-McCune, Karen et al. (2017) The effect of intrauterine devices on acquisition and clearance of human papillomavirus. Am J Obstet Gynecol 216:386.e1-386.e5
Scott, Mark E; Ma, Yifei; Farhat, Sepideh et al. (2015) Expression of nucleic acid-sensing Toll-like receptors predicts HPV16 clearance associated with an E6-directed cell-mediated response. Int J Cancer 136:2402-8
Hwang, Loris Y; Scott, Mark E; Ma, Yifei et al. (2015) Diversity of Cervicovaginal Cytokine Response to Incident Chlamydia trachomatis Infection Among a Prospective Cohort of Young Women. Am J Reprod Immunol 74:228-36
Moscicki, Anna-Barbara; Darragh, Teresa M; Berry-Lawhorn, J Michael et al. (2015) Screening for Anal Cancer in Women. J Low Genit Tract Dis 19:S27-42
Farhat, Sepideh; Scott, Mark E; Ma, Yifei et al. (2015) Development of a novel liquid bead array human papillomavirus genotyping assay (PGMY-LX) and comparison with linear array for continuity in longitudinal cohort studies. J Clin Microbiol 53:1270-6
Zhang, Chuqing; Park, Jong-Sup; Grce, Magdalena et al. (2014) Geographical distribution and risk association of human papillomavirus genotype 52-variant lineages. J Infect Dis 210:1600-4
Moscicki, Anna-Barbara; Ma, Yifei; Farhat, Sepideh et al. (2014) Natural history of anal human papillomavirus infection in heterosexual women and risks associated with persistence. Clin Infect Dis 58:804-11
Moscicki, Anna-Barbara; Puga, Ana; Farhat, Sepideh et al. (2014) Human papillomavirus infections in nonsexually active perinatally HIV infected children. AIDS Patient Care STDS 28:66-70

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