Insulin-like growth factor axis influence on HIV and HPV pathogenesis in women

This epidemiologic study will examine the influence of the insulin-like growth factor (IGF)-axis on the pathogenesis of HIV and human papillomavirus (HPV), two sexually transmitted viruses. Recent data suggest that the IGF-axis plays a role in host immunity through its effects on cell proliferation and survival, prompting speculation that it might also affect the rate of HIV disease progression. IGF-I, a hormone with mitogenic/antiapoptotic activity can, in animal models, increase lymphocyte count, and even induce thymic regeneration in FIV infected cats. In contrast, the major IGF binding protein (IGFBP), IGFBP-3, has both indirect (sequestering IGF-I) and direct (IGF-I independent) anti-mitotic/pro-apoptotic activity, and is hypothesized to accelerate HIV disease. However, there is little human data. We conducted a pilot investigation using only baseline specimens from the Women[unreadable]s Interagency HIV Study (WIHS), an ongoing cohort of HIV-positive (N=2,793) and HIVnegative (N=975) women, initiated in 1994. Incident clinical AIDS (N=101 cases) was associated with ? IGFBP- 3 (HR=2.7;1.3-5.4) in data/specimens obtained prior to the widespread use of HAART (pre-HAART) [reprint 1] - consistent with IGFBP-3[unreadable]s proposed anti-mitotic/pro-apoptotic effects on the immune system. The association of IGF-I with AIDS was also in the expected direction, albeit, non-significant (HR=0.64;0.35-1.18), and both ? IGFBP-3 (Ptrend=0.02) and ? IGF-I (Ptrend=0.02) were associated with rapid CD4+ T-cell decline. The role of the IGF-axis in HPV natural history was studied in 137 HIV-negative women. Persistence of oncogenic HPV was associated with ? IGF-I/IGFBP-3 ratio (HR=7.1;1.8-25), while ? IGFBP-3 was associated with very low risk of oncogenic HPV-positive cervical neoplasia (HR= 0.07; 0.01-0.66); most other results were non-significant but in the expected direction - consistent with the IGF-axis[unreadable]s effects on other tumors and recent cross-sectional studies of cervical neoplasia. These prospective pilot data have clear clinical implications. For HIV, they imply that the IGF-axis might be exploited as a target for therapies to slow HIV disease (lengthening the time until HAART use becomes needed). If in the current study we find similar results in women using HAART, it could suggest also targeting the IGF-axis during HAART. Similarly, for HPV, our data suggest that the IGF-axis may have untapped potential to treat/prevent disease. The project is notable, therefore, for having potential to open several new areas of epidemiologic and clinical investigation. Under this grant we will for the first time study women using HAART; conduct repeated testing of IGF-I and IGFBP-3 at sequential study visits to carefully characterize IGF-I and IGFBP-3 exposure; study additional IGF-axis related components, including IGF-II, free (bioactive) IGF-I, and C-peptide. This grant will also greatly increase the number of cases for each endpoint. The Specific Aims are to study the role of the IGF-axis in: (1) HIV disease progression in women not using HAART (based on specimens/data obtained prior to the HAART era); (2) The risk of AIDS related death in women using HAART; and (3) The natural history of oncogenic HPV in HIV-positive and -negative women.