MERIT Award Recipient: Anna-Barbara Moscicki, M.D.
Natural History of HPV Infection to Neoplasia
Dr. Moscicki and her staff focus on the natural history of human papillomavirus (HPV) from initial infection to the development of the significant precancer, high-grade squamous intraepithelial lesion (HSIL). To understand the relationship between HPV infection and development of cervical cancer, they have been detailing HPV testing, systemic and local immune responses to HPV, reproductive behaviors and co-infections. Data from their ongoing cohort study of HPV infection in the San Francisco area demonstrates that HPV persistence, beginning with infections obtained during adolescence is key to the development of HSIL and that cell-mediated immune responses are key for the control of HPV.
Focusing on young women under the age of 22 years, their group was one of the first to show that exposure and acquisition of this virus begins shortly after the onset of sexual activity with over 50% acquiring HPV within 4-5 years after starting sexual intercourse. The strongest risk shown for acquiring HPV was a recent new sexual partner, underscoring the ease of sexual transmission. Oral contraceptives were found to be protective, showing the positive effect of hormonal contraceptives. The group also demonstrated that the majority of HPV infections were transient. Unfortunately, in the few infections that result in persistent infection, the risk of developing significant precancerous lesions began to rise exponentially. Persistent infections were shown to occur in the face of normal cytology, making detection of persistent infections difficult unless the presence of viral DNA is assessed. However, in parallel with HPV elimination, the common HPV-induced low grade SIL found in adolescents was also shown to regress in almost all subjects. These important findings have influenced the development of new guidelines for Pap smear screening in adolescents. The new guidelines will reduce the number of "over-treatments" common in this age group.
Much of Dr. Moscicki's research has focused on young women because of their apparent vulnerability to HPV acquisition. One factor that may play a role in adolescent vulnerability is the presence of immature epithelium on the adolescent cervix. Using photographs of the cervix obtained during colposcopic examination, the team devised a method to carefully measure the amount of immature cervical tissue on computerized images of the photographs. Their work shows that a process involving cervical maturation promotes the development of low-grade squamous intraepithelial lesions (LSIL) by supporting viral replication which in turn results in viral transcription of proteins important in cellular proliferation and the cytoskeletal changes associated with SIL. This may explain why LSIL are found predominantly in adolescents and young women.
The natural history observed in immunosuppressed cohorts began to illuminate mechanisms of HPV control. As HPV is a localized infection, the study of immune responses would be a challenge. As in other intracellular infections, it was hypothesized that Th1 cytokine responses are essential for HPV control. In Dr. Moscicki's laboratory, a sensitive test to assess cytokine expression at the mRNA level developed using samples from a cervical cytobrush. Preliminary studies demonstrate that, in women with HPV clearance, Th1 patterns are present, whereas among women with unknown histories or persistence, the patterns are variable. To examine these associations further, two assays have been adopted to the study of immune responses. The expansion of the two assays will allow detection of over 10 cytokines in a single sample.
Although the cervix sample cytokine assays are informative, none are specific to HPV. Despite the localized nature of HPV infection, the laboratory staff developed cell-mediated assays that are sensitive enough to detect circulating cells capable of recognizing HPV. Using standard cytotoxic T lymphocytes (CTL) expressing the HPV early proteins E6 and E7, the team found that CTL responses to HPV 16 E6 appear important in maintaining viral clearance, underscoring the importance of E6 in therapeutic vaccines. The team continues to study new measures of both innate and adaptive immunity with the hope of guiding the development of novel therapeutic therapies for HPV persistence and disease.