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Increased Apoptosis in Cervical Intraepithelial Neoplasia Associated with HIV Infection: Implication of Oncogenic Human Papillomavirus, Caspases, and Langerhans Cells

Authors' Affiliations: ¹ Department of Pathology, ² INSERM LL683, IFR2 Physiologie et Pathophysiologie, and ³ Department Gynaecology, Hôpital Bichat-Claude Bernard, Paris, France

Requests for reprints: Francine Walker, Department of Pathology, 46 rue Henri Huchard, BP 416, 75877 Paris Cedex 18, France. Phone: 331-40-25-82-92; Fax: 331-40-25-80-00; E-mail: francine.walker{at}bch.ap-hop-paris.fr..

Purpose: Increasing risk of squamous cervical intraepithelial neoplasia (CIN) exits in HIV-infected women. However, the relatively low incidence of invasive carcinoma in the untreated HIV-infected population suggests an imbalance between cell proliferation and apoptosis. We investigated apoptosis and caspases in cervical samples from this population comparatively to non-HIV-infected and control subjects.

Experimental Design: Apoptotic terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling method, immunohistochemistry for caspase-2, caspase-3, caspase-8, caspase-9, and other apoptosis markers were done on 12 normal cervical samples and 103 low- and high-grade cervical lesions, containing human papillomavirus(es) from 35 HIV-negative and 33 HIV-positive women before tritherapy advent.

Results: (a) The apoptotic index (AI) in epithelial cells did not vary between normal mucosa and condyloma acuminata infected or not with HIV. (b) AI augmented with the CIN severity in HIV-positive and HIV-negative women. (c) AI dramatically increased in oncogenic human papillomavirus-infected CIN of HIV-positive population compared with the CIN of similar grade in HIV-negative one. This was associated with a greater expression of caspase-8, active caspase-9, and active caspase-3 in those samples. Moreover, densities of Langerhans' cells, involved in apoptotic bodies engulfment, were greatly reduced in CIN of HIV-positive women. In samples, these densities were highly inversely correlated with AI (r = –0.88, P < 0.002).

Conclusions: This study provides the first evidence for the strongly enhanced apoptosis levels and caspase expression in CIN of untreated HIV-infected women. We suggest that the reduction in Langerhans' cell number could contribute at least partly to apoptotic cell accumulation.

Key Words: TUNEL method • immunocytochemistry • Langerhans' cells • caspases • cell quantification