Oncogenic HPV, mucosal immune response and risk of HIV acquisition. Approximately 33 million people are infected with HIV worldwide, with 2.7 million new infections in 2008 alone. The infection disproportionately affects sub-Saharan Africa with 67% of all HIV infections and 75% of all HIV/AIDS deaths. High-risk human papillomavirus (HR-HPV) infection leads to anogenital cancers, including cervical cancer (the third leading cause of cancer mortality in women worldwide). HR-HPV may also be a risk factor for HIV acquisition, presumably due to recruitment of HIV target cells into the mucosa. However, the genital mucosal immunologic microenvironment and HIV/HR-HPV interactions are poorly understood. Male circumcision reduces the risk of HIV and HR-HPV, demonstrating the critical role of the foreskin in acquisition and transmission of these viral infections. Foreskin tissue, genital swabs of men and their female partners, and epidemiologic data from male circumcisions in Rakai, Uganda, provide biological samples to assess HIV and HR-HPV mucosal immunologic interactions. We hypothesize that HR-HPV clearance induces a distinct proinflammatory cytokine/chemokine profile and increased foreskin mucosal T-cell densities which are associated with increased risk of HIV acquisition. We propose the following aims. 1) Assess whether clearance of pre-existing HR-HPV infection and/or acquisition of a new HR-HPV genotype are associated with an increased risk of HIV acquisition in men and women using a case-control design in which cases will be HIV seroconverters and controls will be persistently HIV-negative individuals. 2) Characterize the foreskin cellular mucosal immunologic response associated with HR-HPV in HIV+ and HIV-negative men. 3) Compare cytokine/chemokine concentrations in penile swabs associated with HR-HPV and HIV infection status. <4) Determine whether increased foreskin immunologic cell densities and penile proinflammatory cytokines/chemokines are associated with HR-HPV clearance.>The foreskin mucosa, genital swabs and epidemiologic data provide a unique opportunity to study HIV and HR-HPV infection and could potentially inform the development of HIV preventive measures. This K23 grant will contribute to the professional and scientific development of a physician scientist. The applicant has completed an NIH-funded MD/PhD program and a clinical pathology residency. This grant will enable the applicant to develop proficiency in epidemiology and biostatistics and, building on the proposed research program, to design and manage an independent RO1-level research program in molecular/clinical epidemiology. The applicant will utilize the strengths of his mentors and the Rakai Health Science Program in Uganda (one of the largest and longest-running population-based HIV and infectious diseases cohorts in sub- Saharan Africa) to learn how to design, implement, manage and analyze international HIV research studies.

Public Health Relevance

High-risk human papillomavirus (HR-HPV) infection may be a risk for HIV acquisition by recruiting T cells to the genital mucosa. However, little is known about the genital mucosal immune response to HR-HPV and HIV infection, especially in men. Male circumcision trials provide access to foreskin genital mucosa and genital swabs permit cytokine/chemokine measurements. An improved understanding of the mucosal immune milieu associated with HIV and HR-HPV infection could have an impact on future HIV prevention. If our hypothesis is supported by this study, it will provide the rationale for future HIV prevention trials, potentially employing HR-HPV vaccines.

Agency
National Institute of Health (NIH)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23AI093152-04
Application #
8683087
Study Section
Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
Program Officer
Stansell, Elizabeth H
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
None
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Savage, William J; Tobian, Aaron A R; Savage, Jessica H et al. (2015) Transfusion and component characteristics are not associated with allergic transfusion reactions to apheresis platelets. Transfusion 55:296-300
Savage, William J; Hamilton, Robert G; Tobian, Aaron A R et al. (2014) Defining risk factors and presentations of allergic reactions to platelet transfusion. J Allergy Clin Immunol 133:1772-5.e9
Kacker, Seema; Ness, Paul M; Savage, William J et al. (2014) Cost-effectiveness of prospective red blood cell antigen matching to prevent alloimmunization among sickle cell patients. Transfusion 54:86-97
Kacker, Seema; Ness, Paul M; Savage, William J et al. (2014) Economic evaluation of a hypothetical screening assay for alloimmunization risk among transfused patients with sickle cell disease. Transfusion 54:2034-44
Tobian, Aaron A R; Fuller, Alice K; Uglik, Kristin et al. (2014) The impact of platelet additive solution apheresis platelets on allergic transfusion reactions and corrected count increment (CME). Transfusion 54:1523-9; quiz 1522
Tobian, Aaron A R; Gaydos, Charlotte; Gray, Ronald H et al. (2014) Male circumcision and Mycoplasma genitalium infection in female partners: a randomised trial in Rakai, Uganda. Sex Transm Infect 90:150-4
Grabowski, Mary K; Gray, Ronald H; Serwadda, David et al. (2014) High-risk human papillomavirus viral load and persistence among heterosexual HIV-negative and HIV-positive men. Sex Transm Infect 90:337-43
Tobian, Aaron A R; Kacker, Seema; Quinn, Thomas C (2014) Male circumcision: a globally relevant but under-utilized method for the prevention of HIV and other sexually transmitted infections. Annu Rev Med 65:293-306
Kacker, Seema; Tobian, Aaron A R (2013) Male circumcision: integrating tradition and medical evidence. Isr Med Assoc J 15:37-8
Redd, Andrew D; Quinn, Thomas C; Tobian, Aaron A R (2013) Frequency and implications of HIV superinfection. Lancet Infect Dis 13:622-8

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