Cervical cancer is the leading cause of cancer death in HIV infected women in Haiti, (3 deaths/1,000 patient years), and is causally linked to infection with human papillomavirus (HPV) infection. The two hypotheses are: 1) HPV incidence, prevalence, persistence, and number of viral types are increased in HIV infected women who have uncontrolled HIV replication, low nadir CD4 count, and persistent immune dysfunction due to a delay in initiation of antiretroviral therapy (ART). We have a unique opportunity to study the effects of ART on the natural history of cervical HPV infection in a randomized cohort in Haiti. Between 2005 and 2009, HIV infected patients with a CD4 T cell count of 200 - 350 cells/mm3 were randomized to initiate ART immediately or to defer ART until their CD4 T cell count fell below 200 cells/mm3 or they developed an AIDS illness. This trial showed that early ART decreased mortality by 75% (p=.001). All patients in the trial were initiated on ART and continue to be followed. Women in this cohort were screened with an annual Pap test, and cervical samples were frozen. We will study this cohort and banked cervical samples and compare HPV incidence, prevalence, persistence, and diversity between the two study groups. The data will provide insights into the relationship between HIV immune dysfunction, ART immune reconstitution, and HPV infection and may support earlier ART for HIV infected women. 2) HIV infection increases the synthesis of the inflammatory molecule Prostaglandin E2 (PGE2) in cervical cells. PGE2 is an important mediator of oncogenesis, and increased levels may affect HPV oncoprotein production and the risk of developing cervical cancer. We have shown that PGE2 promotes expression of the HPV viral oncoproteins E6 and E7 in cervical cancer cells. In turn, E6 and E7 up-regulate expression of the enzyme COX-2, which is an important enzyme in the synthesis of PGE2, suggesting a positive feedback loop that can be pharmacologically inhibited to reduce the risk of cancer. HIV-1 infection is also associated with increased levels of COX-2 and PGE2 production in several cell types, although the effects in the cervix are unknown. We propose to evaluate the expression of genes involved in PGE2 synthesis, catabolism, and signaling in cervical cells obtained from HIV infected and uninfected women. Results will provide new insights into the effects of HIV on PGE2 biology and could provide a mechanistic platform for future chemoprevention trials with drugs that block the formation of PGE2 such as aspirin or COX-2 inhibitors.

Public Health Relevance

Cervical cancer is the most common cause of cancer death In HIV infected women in Haiti (3 deaths per 1,000 patient-years) and is causally linked to human papillomavirus (HPV) infection. We will determine the effect of antiretroviral therapy and immune reconstitution on the natural history of HPV infection in HIV infected women, and study the effect of HIV/HPV co-infection on prostaglandin E2, an inflammatory molecule that is an important mediator of cancer development. Drugs that decrease synthesis of prostaglandin E2 (e.g. aspirin) could serve as cancer prevention agents for HIV infected women.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA142422-03
Application #
8311699
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Starks, Vaurice
Project Start
2010-09-20
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$340,155
Indirect Cost
$138,880
Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Pape, Jean W; Severe, Patrice D; Fitzgerald, Daniel W et al. (2014) The Haiti research-based model of international public health collaboration: the GHESKIO Centers. J Acquir Immune Defic Syndr 65 Suppl 1:S5-9
Fitzgerald, Daniel W; Bezak, Karl; Ocheretina, Oksana et al. (2012) The effect of HIV and HPV coinfection on cervical COX-2 expression and systemic prostaglandin E2 levels. Cancer Prev Res (Phila) 5:34-40