Insulin-like Growth Factor Axis Influence On HIV And HPV Pathogenesis In Women
Howard D Strickler, Associate Professor
Epidemiology & Population Healthyeshiva University
Grant 1R56AI076166-01A2 from National Institute Of Allergy And Infectious Diseases, IRG: ACE
Project start date: 2008-08-01
Project end date: 2009-07-31
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Grants awarded to Howard D Strickler
HPV & Cervix Neoplasia In A Large, Long-term HIV+ Cohort
Howard D Strickler, Associate Professor
Yeshiva University 500 W 185th St New York, Ny 10033
Grant 5R01CA085178-08 from National Cancer Institute, IRG: ACE
Abstract: Women with HIV/AIDS are at high risk of cervical cancer, and have high rates of infection with human papillomavirus (HPV), the viral cause of cervical cancer. Through the semiannual evaluation of 2,793 HIV+and 975 HIV- women enrolled in the Women s Interagency HIV Study (WIHS), a multicenter cohort, the "WIHS HPV Investigation" is intended to be the definitive study of the effects of HIV coinfection on HPV and cervical dysplasia. This application seeks support for continuation of HPV research in the WIHS. The proposed project will be the first systematic effort to study type-specific differences in the effects of host immune status on HPV natural history in HIV+ women. Our recent results showed that HPV 16, the type that accounts for half of all cervical cancers, was the least affected by immune status (CD4+ count) of any HPV type. Two HPV types related to HPV 16 were also weakly associated with CD4+. Other HPVs, however, have not been adequately characterized, nor could we previously address the strong interaction between the effects of plasma HIV RNA and CD4+ count. Continuation of the WIHS HPV Investigation will provide the needed statistical power to examine HPV type-specific results by combined plasma HIV RNA/CD4+ strata, and it will generate the only truly long term prospective data regarding HPV infection in HIV+ women -valuable data in an era in which women can live for years with HIV. This application also represents an important opportunity to study local cervical HIV levels and their effects on HPV infection. It is known that there is substantial compartmentalization of HIV in the genital tract, but whether cervical HIV RNA levels are independently or, compared with plasma levels, more strongly associated with HPV has not been determined. Finally, once infection with an oncogenic HPV is established it remains unclear what role immune status plays in progression to severe cervical dysplasia. Continued follow-up in the WIHS will, for the first time, make it possible to prospectively study the risk factors for severe cervical dysplasia (a true cancer precursor) in HIV+ women. In summary, the aims are to study (i) type-specific differences in the effects of host immune status on HPV natural history; (ii) the relationship between cervical HIV RNA levels and HPV infection; (iii) risk factors for progression to severe cervical dysplasia in HIV+ women.
Keywords: RNA, cervix, infection, plasma, AIDS, HIV infection, age group, base, behavior, cell sorting, cervix neoplasm, contraceptive, emotion, estradiol, genotype, health /scientific organization, hormone, human papillomavirus, immunity, menopause, menstrual cycle, motivation, neoplasm /cancer, play, progesterone, role, serology /serodiagnosis, serum, smoking, therapy, clinical research
Project start date: 2000-01-15
Project end date: 2010-04-30
5R01CA085178-08 (2007): $722808
5R01CA085178-07 (2006): $723725
2R01CA085178-06A1 (2005): $752144
HPV & Cervix Neoplasia In A Large, Long-term HIV+ Cohort
Howard D Strickler, Associate Professor
Epidemiology & Population Healthyeshiva University
Grant 5R01CA085178-09 from National Cancer Institute, IRG: ACE
Abstract: Women with HIV/AIDS are at high risk of cervical cancer, and have high rates of infection with human papillomavirus (HPV), the viral cause of cervical cancer. Through the semiannual evaluation of 2,793 HIV+and 975 HIV- women enrolled in the Women´s Interagency HIV Study (WIHS), a multicenter cohort, the "WIHS HPV Investigation" is intended to be the definitive study of the effects of HIV coinfection on HPV and cervical dysplasia. This application seeks support for continuation of HPV research in the WIHS. The proposed project will be the first systematic effort to study type-specific differences in the effects of host immune status on HPV natural history in HIV+ women. Our recent results showed that HPV 16, the type that accounts for half of all cervical cancers, was the least affected by immune status (CD4+ count) of any HPV type. Two HPV types related to HPV 16 were also weakly associated with CD4+. Other HPVs, however, have not been adequately characterized, nor could we previously address the strong interaction between the effects of plasma HIV RNA and CD4+ count. Continuation of the WIHS HPV Investigation will provide the needed statistical power to examine HPV type-specific results by combined plasma HIV RNA/CD4+ strata, and it will generate the only truly long term prospective data regarding HPV infection in HIV+ women -valuable data in an era in which women can live for years with HIV. This application also represents an important opportunity to study local cervical HIV levels and their effects on HPV infection. It is known that there is substantial compartmentalization of HIV in the genital tract, but whether cervical HIV RNA levels are independently or, compared with plasma levels, more strongly associated with HPV has not been determined. Finally, once infection with an oncogenic HPV is established it remains unclear what role immune status plays in progression to severe cervical dysplasia. Continued follow-up in the WIHS will, for the first time, make it possible to prospectively study the risk factors for severe cervical dysplasia (a true cancer precursor) in HIV+ women. In summary, the aims are to study (i) type-specific differences in the effects of host immune status on HPV natural history; (ii) the relationship between cervical HIV RNA levels and HPV infection; (iii) risk factors for progression to severe cervical dysplasia in HIV+ women
Keywords: RNA, cervix, infection, plasma AIDS, HIV infection, age group, base, behavior, cell sorting, cervix neoplasm, contraceptive, emotion, estradiol, genotype, health /scientific organization, hormone, human papillomavirus, immunity, menopause, menstrual cycle, motivation, neoplasm /cancer, play, progesterone, role, serology /serodiagnosis, serum, smoking, therapy clinical research
Project start date: 2000-01-15
Project end date: 2010-04-30
Effects Of HLA And KIR Genotype On HIV And HCV
Howard D Strickler, Associate Professor
Yeshiva University 500 W 185th St New York, Ny 10033
Grant 1R01AI057006-01 from National Institute Of Allergy And Infectious Diseases, IRG: AARR
Abstract: This application is to study the effects of human leukocyte antigen (HLA) and killer immunoglobulin-like receptor (KIR) polymorphisms in women on (i) risk of infection by HIV, (ii) risk of infection by HCV, and (iii/iv) the course of HIV and HCV infections. HLA molecules are polymorphic proteins that play a central role in the immune response to viruses through the presentation of antigens to T-cells, and act as ligand for KIR (polymorphic molecules that help regulate natural killer cell function). Due to shared risk factors, HIV and HCV affect similar populations, and coinfection is common. For both HIV and HCV, previous epidemiologic studies have indicated that HLA type is related to course of infection. However, the known biologic interaction of HLA and KIR has only recently been taken into consideration. A large study in men conducted by our group found strong significant interactions between HLA and KIR associated with HIV/AIDS progression. HLA/KIR interactions have also been observed in other immune-related diseases. Thus, it is important to know both HLA and KIR to fully interpret the data for either; data that were incomplete in prior studies of HIV and HCV. Critical gaps in our knowledge regarding the effects of HLA type go substantially beyond the need to consider KIR, To date, there is a paucity of HLA data in women despite gender differences in HIV natural history and, surprisingly, little is also known regarding the HLA alleles associated with response to HAART, or even risk of becoming HIV infected. Our understanding of HCV and HLA type is even more incomplete. Studies of HCV clearance have focused almost entirely on HLA class II, but it is HLA class Ia that plays a central role in the cytotoxic T-cell response to HCV. Risk of becoming HCV infected has never been carefully studied. The planned study will be the first to carefully assess the independent effects and interactions of HLA and KIR on HIV/AIDS progression among women, response to HAART, risk of HIV infection, HCV viremia, and risk of HCV infection. To address these issues, we will conduct high resolution HLA and KIR genotyping in the Women s Interagency HIV Study (WIHS). WlHS is a large, racially and geographically diverse cohort of HIV(+) (n=2761 with - 40% HCV(+)), and HIV(-) women who share similar risk factors (n=942 with - 25%HCV(+)).
Keywords: HIV infection, MHC class I antigen, MHC class II antigen, disease /disorder proneness /risk, genetic polymorphism, genotype, hepatitis C virus, immunogenetics, immunologic receptor, pathologic process, AIDS, communicable disease transmission, gene interaction, helper T lymphocyte, intravenous drug abuse, longitudinal human study, viremia, virus RNA, women s health, clinical research, genetic registry /resource /referral center, human genetic material tag, human subject
Project start date: 2003-07-01
Project end date: 2006-12-31
1R01AI057006-01 (2003): $306795
Insulin And IGF In Female Colon, Breast, Uterine Cancer
Howard D Strickler, Associate Professor
Yeshiva University 500 W 185th St New York, Ny 10033
Grant 5R01CA093881-04 from National Cancer Institute, IRG: EDC
Abstract: Increasing evidence indicates that high serum insulin-like growth factor-1 (IGF-1) is associated with elevated risk of colorectal, breast, and endometrial cancer. Three Insulin Resistance Syndrome-related conditions, type 2 diabetes, obesity, and sedentary lifestyle, are also associated with greater risk of these cancers, and hyperinsulinemia is hypothesized to drive these relationships, at least in part. Insulin shares 40 percent homology with IGF-1, and biologic studies suggest both are mitogens. However, few epidemiologic studies have evaluated cancer risk based on insulin levels, and none have been prospective with sufficient sample size or adequate control for confounders. Similarly, there are sparse epidemiologic data regarding free IGF-1 and cancer, even though the unbound form is the main bioactive component. A cross-sectional study by our group found free IGF-I more strongly associated with breast cancer than total IGF-1. To provide definitive evidence of their associations with cancer, a prospective study of insulin and free IGF-1 is necessary. Therefore, the purpose of this application is to determine the effects of high serum insulin and free IGF-1 on risk of incident colorectal, breast and endometrial cancer in postmenopausal women. Specimens and data will be obtained from the Observational Study of the Women s Health Initiative (WHI), a large (n=93,725), ethnically and geographically diverse cohort of postmenopausal women aged 50-79. We propose conducting a case-cohort study, testing baseline serum for fasting glucose, insulin, total and free IGF-1, IGF binding protein-3 (IGFBP-3), and total estradiol. Follow-up will average 7 years, with cases excluded if diagnosed in the first 18 months. Our specific aims are to study (1) The independent effects of high serum insulin and free IGF-1 on risk of colorectal (n=500), breast (n=900) and endometrial cancers (n=300); (2) Among the subcohort (controls; n=900), the factors related to levels of total IGF-1, free IGF-1, and IGFBP-3; (3) Whether type 2 diabetes is an independent risk factor for colorectal, breast and endometrial cancers, controlling for insulin resistance, IGF-1 and IGFBP-3.
Keywords: breast neoplasm, colon neoplasm, hormone related neoplasm /cancer, neoplasm /cancer epidemiology, uterus neoplasm, binding protein, hormone regulation /control mechanism, insulin, insulinlike growth factor, noninsulin dependent diabetes mellitus, clinical research, female, human middle age (35-64), human old age (65+), human subject, women s health
Project start date: 2002-01-15
Project end date: 2007-12-31
5R01CA093881-04 (2005): $480595
5R01CA093881-03 (2004): $572830
5R01CA093881-02 (2003): $560767
HPV & CERVIX NEOPLASIA IN A LARGE, LONG TERM HIV+ COHORT
Howard D Strickler, Associate Professor
Yeshiva University 500 W 185th St New York, Ny 10033
Grant 5R01CA085178-05 from National Cancer Institute, IRG: ZRG1
Abstract: Human papillomavirus (HPV) is the central etiologic agent in the development of most cervical neoplasms, including invasive cervical cancer. HIV-positive women are at substantially elevated risk for HPV infection as well as cervical disease, and this risk increases with diminished CD4+ T-cell and/or higher HIV RNA levels. Surprisingly few studies, however, have assessed the natural history of HPV infection in HIV-positive women. Gaps in our knowledge include the persistence of HPV DNA in HIV-positive women and its relation with risk of cervical neoplasms. Reactivation of latent HPV infections has been suggested to be important in immune compromised individuals, but clear evidence that this occurs is lacking. The effects of highly active anti- retroviral therapy (HAART) on HPV natural history are unknown. The purpose of this application is to study the long term effects of HIV on the natural history of HPV infection and the development of cervical neoplasms, using specimens obtained from the Women s Interagency HIV Study (WIHS). The WIHS cohort is a large, geographically and ethnically diverse population of HIV- positive (n=2056), and risk-matched HIV-negative women (n=569). Since enrollment (October, 1994 - November 1995) WIHS subjects have been followed at 6 month intervals, and follow-up is funded through 2002. We have analyzed HPV and cytologic results at enrollment, but HPV DNA testing for most planned visits (years 2- 7 of follow-up) has not been arranged. Under this application we will test all untested cervical specimens for HPV DNA, and specimens positive for HPV 16, 18 and/or 31 will be further tested to identify the type-specific variant. Serum antibodies to papillomavirus antigens, including a panel of virus-like particles, will be measured. Our specific aims include (1) To study the relation of HIV serostatus, CD4+ T-cell, HIV RNA levels, and use of HAART with risk of 3 outcomes, namely, incident type-specific HPV DNA detection, persistence of HPV DNA, and incident cervical neoplasms; (2) To determine whether HPV can become latent and then be reactivated; and (3) To study humoral immune responses to HPV and their relation with HPV natural history in HIV-positive and -negative women.
Keywords: HIV infection, cancer risk, cervix neoplasm, human papillomavirus, viral carcinogenesis, virus disease, women s health, AIDS therapy, combination chemotherapy, helper T lymphocyte, humoral immunity, latent virus infection, longitudinal human study, virus DNA, clinical research, female, human subject
Project start date: 2000-01-15
Project end date: 2005-04-30
5R01CA085178-05 (2004): $1309031
5R01CA085178-04 (2003): $1271722
HPV & CERVIX NEOPLASIA IN A LARGE, LONG TERM HIV+ COHORT
Howard D Strickler, Associate Professor
Epidemiology & Population Healthyeshiva University
500 W 185th St
new York, Ny 10033
Grant 5R01CA085178-02 from National Cancer Institute, IRG: ZRG1
Abstract: Human papillomavirus (HPV) is the central etiologic agent in the development of most cervical neoplasms, including invasive cervical cancer. HIV-positive women are at substantially elevated risk for HPV infection as well as cervical disease, and this risk increases with diminished CD4+ T-cell and/or higher HIV RNA levels. Surprisingly few studies, however, have assessed the natural history of HPV infection in HIV-positive women. Gaps in our knowledge include the persistence of HPV DNA in HIV-positive women and its relation with risk of cervical neoplasms. Reactivation of latent HPV infections has been suggested to be important in immune compromised individuals, but clear evidence that this occurs is lacking. The effects of highly active anti- retroviral therapy (HAART) on HPV natural history are unknown. The purpose of this application is to study the long term effects of HIV on the natural history of HPV infection and the development of cervical neoplasms, using specimens obtained from the Women´s Interagency HIV Study (WIHS). The WIHS cohort is a large, geographically and ethnically diverse population of HIV- positive (n=2056), and risk-matched HIV-negative women (n=569). Since enrollment (October, 1994 - November 1995) WIHS subjects have been followed at 6 month intervals, and follow-up is funded through 2002. We have analyzed HPV and cytologic results at enrollment, but HPV DNA testing for most planned visits (years 2- 7 of follow-up) has not been arranged. Under this application we will test all untested cervical specimens for HPV DNA, and specimens positive for HPV 16, 18 and/or 31 will be further tested to identify the type-specific variant. Serum antibodies to papillomavirus antigens, including a panel of virus-like particles, will be measured. Our specific aims include (1) To study the relation of HIV serostatus, CD4+ T-cell, HIV RNA levels, and use of HAART with risk of 3 outcomes, namely, incident type-specific HPV DNA detection, persistence of HPV DNA, and incident cervical neoplasms; (2) To determine whether HPV can become latent and then be reactivated; and (3) To study humoral immune responses to HPV and their relation with HPV natural history in HIV-positive and -negative women
Keywords: HIV infection, cancer risk, cervix neoplasm, human papillomavirus, viral carcinogenesis, virus disease, women`s health AIDS therapy, combination chemotherapy, helper T lymphocyte, humoral immunity, latent virus infection, longitudinal human study, virus DNA clinical research, female, human subject
Project start date: 2000-01-15
Project end date: 2004-12-31
5R01CA085178-02 (2001): $681365
1R01CA085178-01 (2000): $733167
Insulin-like Growth Factor Axis Influence On HIV And HPV Pathogenesis In Women
Howard D Strickler, Associate Professor
Epidemiology & Population Healthyeshiva University
Grant 1R56AI076166-01A2 from National Institute Of Allergy And Infectious Diseases, IRG: ACE
Project start date: 2008-08-01
Project end date: 2009-07-31
Effects Of HLA And KIR Genotype On HIV And HCV
Howard D Strickler, Associate Professor
Epidemiology & Population Healthyeshiva University
500 W 185th St
new York, Ny 10033
Grant 5R01AI057006-04 from National Institute Of Allergy And Infectious Diseases, IRG: AARR
Project start date: 2003-07-01
Project end date: 2008-12-31
5R01AI057006-04 (2006): $489857
5R01AI057006-03 (2005): $614374
5R01AI057006-02 (2004): $588021
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