This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT HIV-infected individuals are living longer, and non-AIDS-defining conditions are likely to affect this population in increasing numbers. HPV infections are more prevalent and persistent in HIV-infected women, with a prevalence of 64% compared to 28% in HIV-negative women. However, in a study of 146 treatment na?ve women initiating HAART, the prevalence of HPV types 16 and 18 was 16% and 11%, respectively, at baseline (personal communication, Kenneth Fife, Indiana University Medical Center, September 2007). Additionally, in the HER study, evaluating 767 HIV-infected and 390 non-infected women, the DNA prevalence of one or more of HPV types 6, 11, 16, and 18 was 15.9%;specifically, type 6 was 3.1%, 11 was 0.9%, 16 was 5.7%, and 18 was 6.1% (6.7% in HIV-negative women). Thus, although HIV-infected women have a much higher prevalence of these four types than HIV-negative women, the majority of them (84-89%) did not have the types contained in the vaccine. Preventing infection of the four vaccine HPV types could decrease the impact of HPV infection among HIV-infected individuals. To date, the immunogenicity and safety of an HPV vaccine in HIV-infected adults has not been studied. This study is an initial step in evaluating an HPV vaccine in adult HIV-infected females. Immunogencity Rationale HIV-infected individuals have been known to have a poor response to standard vaccination series like hepatitis A and B, compared with HIV-uninfected people. Investigators have analyzed patient specific predictors associated with poor response and found that low CD4+ cell count and detectable HIV viral load have been associated with poor response to hepatitis A and B vaccinations in some studies. In this study, we will evaluate the immunogenicity and safety of GARDASIL. Since this is a population analysis, the study is stratified by CD4+ cell count and HIV-1 RNA viral load to assess whether these factors affect the participants ability to generate antibodies. To address the potential effect of HIV serum viral load on the vaccine immunogenicity, there will be an equal number of females in each CD4+ cell count =350 cells/mm? stratum with an HIV-1 RNA viral load = or 10,000 copies/mL. This approach will allow assessing the vaccine immunogenicity among females with different levels of immunosuppression. Immunogenicity will be measured with serological testing for antibodies to HPV types 6, 11, 16, and 18 after the vaccination series. The serological testing will be done by Merck, using an anti-HPV 6, 11, 16, and 18 competitive Luminex Immuno-Assay (HPV-4 cLIA). The scales for these assays are unique to each HPV type, with HPV type-specific lower limit of detection. Comparisons across types and to other assays are not appropriate. Seroconversion is defined as the development of antibody titer levels above a cutoff for each HPV type, as validated by Merck. The methods for determining serostatus cutoffs are described in Dias et al. Immunogenecity will also be measured by assessing cellular immune responses to HPV vaccination and correlations with the development and magnitude of HPV responses. Measuring responses in each CD4+ cell count stratum will allow for more careful comparisons across the strata. Higher viral load levels are associated with higher CD4+ and CD8+ cell count activation markers and may be associated with less immunologic response. Therefore, cellular immune responses will be measured in the subset of U.S. participants defined in the schema. Rationale for collecting data on HPV in the oral cavity The prevalence of HPV-associated OW appears to have increased since the introduction of HAART. However, to date, the correlation between an increased prevalence of OW and increased replication of HPV in squamous epithelium has not been explored. Furthermore, the clinical significance of HPV shedding from the oral epithelium with respect to subsequent development of OW or even squamous cell carcinoma is poorly understood. Therefore, study participants will undergo oral examinations and cytobrush specimens will be collected on OW to explore the baseline prevalence of OW and their development during the study. Furthermore, pilot data will be collected in the subset of U.S. participants defined in the schema to explore the prevalence of HPV in oral cells and fluids prior to and after administration of the vaccine and the effect of the vaccine on cross-strain HPV variation (only some of the HPV types targeted by the vaccine are not the HPV types typically isolated in the oral cavity). Oral and cervical compartmental shedding and strain variation of HPV before and after vaccine administration will be compared. HPV specific oral mucosal antibodies generated in response to the vaccine will be measured as well.
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