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.
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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