Genomic variation of human papillomavirus type 16 in relation to risk for high grade cervical and anal intraepithelial neoplasia

Abstract

Prospective studies were conducted among women attending a University and women presenting to a STD clinic to evaluate an association between risk of cervical intraepithelial neoplasia grade 2-3 (CIN 2-3) and human papillomavirus type 16 (HPV16) variants. CIN 2-3 was histologically confirmed in 9 of 57 HPV16 positive women attending the University and in 10 of 66 HPV16 positive women presenting to the STD clinic. Among university students, those with HPV16 non-prototype-like (NPL) variants were 6.5 (95% CI, 1.6-27.2) times more likely to develop CIN 2-3 than those with prototype-like (PL) variants. A similar association was observed among women presenting to the STD clinic (RR = 4.5; 95% CI, 0.9-23.8).An association between risk of anal intraepithelial neoplasia grade 3 or carcinoma in situ (AIN3/CIS) and HPV16 variants was examined in a cohort of bisexual or homosexual men. Of 589 men, 37% were positive for HPV16, including 33% with PL variants and 4% with NPL variants. AIN3/CIS was histologically confirmed in 22 cases. Among men with HPV16 infection, those with NPL variants were 4.3 times (95% CI = 1.6-11.6) more likely to develop AIN3/CIS than those with PL variants. Additional adjustments for HIV status and CD4 count or the level of HPV16 DNA did not alter risk estimates substantially. Neither a high level of viral DNA nor a prolonged period of DNA detection was associated with HPV16 NPL variants.To verify whether HPV16 variants change over time, sequence variation of variants was examined in consecutive specimens from individuals. Seventy subjects who were repeatedly HPV16 DNA positive, over 2-8 four-monthly visits, showed an identical polymorphism at every visit. Sequencing many clones from each specimen confirmed that one major variant seemed to predominate over time, whereas minor variants appeared more transient.While the data suggest that HPV16 NPL as compared to PL variants are associated with an increased risk of high grade lesions, the biological mechanism relating to this excess risk remains undetermined. In view of the relatively short time followed, it would not be appropriate to generalize our data beyond the observed time period nor to the risk of invasive cancer.