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Grant Details

Grant Number: 5R01CA085178-13 Interpret this number
Primary Investigator: Strickler, Howard
Organization: Albert Einstein College Of Medicine
Project Title: HPV & Cervix Neoplasia in a Large, Long Term HIV + Cohort
Fiscal Year: 2012
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Abstract

DESCRIPTION (provided by applicant): Women with HIV/AIDS are at high risk for cervical cancer, and have high rates of infection with human papillomavirus (HPV), the viral cause of cervical cancer. Through semiannual evaluations of 2,793 HIV+ and 975 HIV- women enrolled in the Women's Interagency HIV Study (WIHS), a multicenter cohort, the "WIHS HPV Study" is intended to be the authoritative investigation of the effects of HIV coinfection on HPV and cervical dysplasia. This application seeks support for continuation of HPV research in the WIHS. A major demographic change that must be addressed under the new grant is the aging of the HIV+ population. Many are now middle-aged. In particular, a large number of HIV+ women have undergone menopause. Menopause has been associated with diminished immune response, as well as cervicovaginal atrophy (weakening the epithelial barrier). A recent study reported high HPV prevalence in peri-/post- vs pre-menopausal HIV- women. Amongst HIV+ women, however, the impact of menopause on HPV natural history / dysplasia is unknown. Furthermore, beyond total CD4+ T-cell count, the nature of the immune deficits in HIV+ women which effect HPV are poorly understood. Recent analyses in the WIHS have shown that there is a strong relation of high (not low) total CD8+ T-cell count with HPV/dysplasia. High CD8+ activation may cause accelerated T-cell aging / differentiation, and is reported to increase the number of terminally differentiated T-cells with diminished functional capacity. CD4+ show similar changes. Age-related changes in these immune cells may be superimposed. We hypothesize that T- cell differentiation is an important factor in middle-aged HIV+ patients. Under this grant, we will quantify CD8+ and CD4+ T-cells by stage of differentiation, and study their relation with HPV/dysplasia. CD4+ and CD8+ T- cells, as well as other infiltrating immune cells, will additionally be studied as part of the local immune response to dysplasia (i.e., cervical intraepithelial neoplasia; CIN). Specifically, using immunohistochemistry we will conduct one of the few prospective studies of the immune infiltrates that distinguish (a) CIN-1 that regress vs progress to CIN-2+, and (b) CIN recurrence after treatment. Lastly, we will build upon our recent study of HLA class I/II genotype and risk of cervical dysplasia by examining additional informative immune gene variants. We found that HLA alleles which act as ligand for KIR (receptors on natural killer (NK) cells) are significantly related to oncogenic HPV. To better understand the genetic factors that affect the NK cell-HPV relationship, we will now study polymorphisms in KIR and IL28B (which codes for IFN-;3, an NK cell activator). In summary, this grant will address three aims: First, to study the associations of cervical HPV/dysplasia natural history with (ia) menopausal status and (ib) the number of CD8+ and CD4+ T-cells that are naove T-cells, central memory T- cells, effector memory, or terminally differentiated T-cells; Second, to study the relation of local cervical immune cells with (iia) CIN-1 regression vs progression to CIN-2+ and (iib) CIN recurrence after treatment; Third, to study polymorphisms in KIR and IL28B and their relation with cervical precancer. PUBLIC HEALTH RELEVANCE: Women with HIV/AIDS are at high risk for cervical cancer. Through the use of highly active antiretroviral therapy (HAART), an increasing number of HIV+ women with varied immune status are now entering the age groups in which cervical cancer rates reach their peak. Understanding the biologic risk factors for cervical disease and human papillomavirus (HPV), the viral cause of cervical cancer, in middle-aged HIV+ women is a priority. This application seeks support to continue our studies of cervical HPV/dysplasia in a large, long term HIV+ cohort. The planned studies will address several important issues regarding aging and immune function that are likely to have a major impact on the control of HPV/dysplasia in HIV+ women: (i) the effects of menopause and accelerated immune aging (caused by HIV) on the type-specific natural history of HPV and cervical dysplasia; (ii) the local cervical immune infiltrates that distinguish cervical intraepithelial neoplasia (CIN)-1 that regress vs progress to CIN-2+ and, secondly, those CIN that are treated but recur within 1 year; and lastly (iii) the polymorphisms in KIR and IL28B genes (which are involved in natural killer (NK) cell activation) that affect the NK cell - HPV/dysplasia relationship.

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Publications

A new method to address verification bias in studies of clinical screening tests: cervical cancer screening assays as an example.
Authors: Xue X, Kim MY, Castle PE, Strickler HD
Source: J Clin Epidemiol, 2014 Mar;67(3), p. 343-53.
EPub date: 2013 Dec 12.
PMID: 24332397
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Changes in knowledge of cervical cancer prevention and human papillomavirus among women with human immunodeficiency virus.
Authors: Massad LS, Evans CT, Weber KM, Goderre JL, Hessol NA, Henry D, Colie C, Strickler HD, Watts DH, Wilson TE
Source: Obstet Gynecol, 2010 Oct;116(4), p. 941-7.
PMID: 20859159
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Knowledge of cervical cancer prevention and human papillomavirus among women with HIV.
Authors: Massad LS, Evans CT, Wilson TE, Goderre JL, Hessol NA, Henry D, Colie C, Strickler HD, Levine AM, Watts DH, Weber KM
Source: Gynecol Oncol, 2010 Apr;117(1), p. 70-6.
EPub date: 2010 Jan 27.
PMID: 20106513
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The relationship between cocaine use and human papillomavirus infections in HIV-seropositive and HIV-seronegative women.
Authors: Minkoff H, Zhong Y, Strickler HD, Watts DH, Palefsky JM, Levine AM, D'Souza G, Howard AA, Plankey M, Massad LS, Burk R
Source: Infect Dis Obstet Gynecol, 2008;2008, p. 587082.
PMID: 18437233
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Contraceptive use among U.S. women with HIV.
Authors: Massad LS, Evans CT, Wilson TE, Golub ET, Sanchez-Keeland L, Minkoff H, Weber K, Watts DH
Source: J Womens Health (Larchmt), 2007 Jun;16(5), p. 657-66.
PMID: 17627401
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Outcomes after treatment of cervical intraepithelial neoplasia among women with HIV.
Authors: Massad LS, Fazzari MJ, Anastos K, Klein RS, Minkoff H, Jamieson DJ, Duerr A, Celentano D, Gange S, Cu-Uvin S, Young M, Watts DH, Levine AM, Schuman P, Harris TG, Strickler HD
Source: J Low Genit Tract Dis, 2007 Apr;11(2), p. 90-7.
PMID: 17415113
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Relationship of pregnancy to human papillomavirus among human immunodeficiency virus-infected women.
Authors: Minkoff H, Shen X, Watts DH, Leighty R, Hershow R, Palefsky J, Tuomala R, Neu N, Zorrilla CD, Paul M, Strickler H
Source: Obstet Gynecol, 2006 Oct;108(4), p. 953-60.
PMID: 17012459
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The occurrence of vaginal infections among HIV-infected and high-risk HIV-uninfected women: longitudinal findings of the women's interagency HIV study.
Authors: Watts DH, Springer G, Minkoff H, Hillier SL, Jacobson L, Moxley M, Justman J, Cejtin H, O'Connell C, Greenblatt RM
Source: J Acquir Immune Defic Syndr, 2006 Oct 1;43(2), p. 161-8.
PMID: 16951644
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Serological detection of human papillomavirus type 16 infection in human immunodeficiency virus (HIV)-positive and high-risk HIV-negative women.
Authors: Silverberg MJ, Schneider MF, Silver B, Anastos KM, Burk RD, Minkoff H, Palefsky J, Levine AM, Viscidi RP
Source: Clin Vaccine Immunol, 2006 Apr;13(4), p. 511-9.
PMID: 16603621
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Outcome after negative colposcopy among human immunodeficiency virus-infected women with borderline cytologic abnormalities.
Authors: Massad LS, Evans CT, Strickler HD, Burk RD, Watts DH, Cashin L, Darragh T, Gange S, Lee YC, Moxley M, Levine A, Passaro DJ
Source: Obstet Gynecol, 2005 Sep;106(3), p. 525-32.
PMID: 16135582
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Diversifying selection in human papillomavirus type 16 lineages based on complete genome analyses.
Authors: Chen Z, Terai M, Fu L, Herrero R, DeSalle R, Burk RD
Source: J Virol, 2005 Jun;79(11), p. 7014-23.
PMID: 15890941
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Natural history and possible reactivation of human papillomavirus in human immunodeficiency virus-positive women.
Authors: Strickler HD, Burk RD, Fazzari M, Anastos K, Minkoff H, Massad LS, Hall C, Bacon M, Levine AM, Watts DH, Silverberg MJ, Xue X, Schlecht NF, Melnick S, Palefsky JM
Source: J Natl Cancer Inst, 2005 Apr 20;97(8), p. 577-86.
PMID: 15840880
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Effects of bacterial vaginosis and other genital infections on the natural history of human papillomavirus infection in HIV-1-infected and high-risk HIV-1-uninfected women.
Authors: Watts DH, Fazzari M, Minkoff H, Hillier SL, Sha B, Glesby M, Levine AM, Burk R, Palefsky JM, Moxley M, Ahdieh-Grant L, Strickler HD
Source: J Infect Dis, 2005 Apr 1;191(7), p. 1129-39.
EPub date: 2005 Feb 21.
PMID: 15747249
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Natural history of grade 1 cervical intraepithelial neoplasia in women with human immunodeficiency virus.
Authors: Massad LS, Evans CT, Minkoff H, Watts DH, Strickler HD, Darragh T, Levine A, Anastos K, Moxley M, Passaro DJ
Source: Obstet Gynecol, 2004 Nov;104(5 Pt 1), p. 1077-85.
PMID: 15516404
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Effect of antiretroviral therapy on the incidence of genital warts and vulvar neoplasia among women with the human immunodeficiency virus.
Authors: Massad LS, Silverberg MJ, Springer G, Minkoff H, Hessol N, Palefsky JM, Strickler HD, Levine AM, Sacks HS, Moxley M, Heather Watts D
Source: Am J Obstet Gynecol, 2004 May;190(5), p. 1241-8.
PMID: 15167825
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Relationship between smoking and human papillomavirus infections in HIV-infected and -uninfected women.
Authors: Minkoff H, Feldman JG, Strickler HD, Watts DH, Bacon MC, Levine A, Palefsky JM, Burk R, Cohen MH, Anastos K
Source: J Infect Dis, 2004 May 15;189(10), p. 1821-8.
EPub date: 2004 Apr 27.
PMID: 15122518
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Serum immunoglobulin A response to human papillomavirus type 16 virus-like particles in human immunodeficiency virus (HIV)-positive and high-risk HIV-negative women.
Authors: Viscidi RP, Ahdieh-Grant L, Schneider MF, Clayman B, Massad LS, Anastos KM, Burk RD, Minkoff H, Palefsky J, Levine A, Strickler H
Source: J Infect Dis, 2003 Dec 15;188(12), p. 1834-44.
EPub date: 2003 Dec 5.
PMID: 14673762
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Human papillomavirus type 16 and immune status in human immunodeficiency virus-seropositive women.
Authors: Strickler HD, Palefsky JM, Shah KV, Anastos K, Klein RS, Minkoff H, Duerr A, Massad LS, Celentano DD, Hall C, Fazzari M, Cu-Uvin S, Bacon M, Schuman P, Levine AM, Durante AJ, Gange S, Melnick S, Burk RD
Source: J Natl Cancer Inst, 2003 Jul 16;95(14), p. 1062-71.
PMID: 12865452
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