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

Abstract

Purpose: Increasing risk of squamous cervical intraepithelial neoplasia (CIN) exits in HIVinfected 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 nickend 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 = À0.88, 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.

A robust ex vivo model for evaluation of induction of apoptosis by rhTRAIL in combination with proteasome inhibitor MG132 in human premalignant cervical explants

“…8 Apoptosis percentages were between 0 and 2% in CIN and were quite comparable to our data in the ex vivo cervical explants as obtained in the current study, pointing again to the representability of our ex vivo model. Other studies, [34][35][36] using different methods to determine apoptosis percentages in cervical neoplasia also showed comparable percentages of apoptosis, as described in our previous and present work. The proportion of epithelial cells undergoing apoptotic cell death increased with increasing severity of neoplasia, which has also been previously described in sections from cervical epithelium and from epithelium of other origin.…”

“…The proportion of epithelial cells undergoing apoptotic cell death increased with increasing severity of neoplasia, which has also been previously described in sections from cervical epithelium and from epithelium of other origin. [34][35][36][37] Determination of apoptosis by immunostaining of cleaved caspase-3 in a limited number of paired samples also indicated an enhancement of apoptosis by TRAIL in combination with MG132. However, from the present and previous work from our group and others it appears that determination of apoptosis by immunostaining of cleaved caspase-3 is less sensitive than by scoring of morphology, which is probably due to the fact that by immunostaining of cleaved caspase-3 only early apoptotic cells are visualized.…”

Direct activation of caspase 8 by the proapoptotic E2 protein of HPV18 independent of adaptor proteins

“…In contrast, the apoptotic index was only slightly increased in LR-HPVassociated condyloma accuminata lesions of HIV-infected women, corroborating the link between HR-HPV-associated lesion and apoptotic induction. 20 These data point to a potential involvement of apoptosis in the natural course of infection with HR-HPV. In addition, such apoptotic activity may stimulate the cellular immune response, and therefore account for the relatively high rate of spontaneous regression of HPV-associated lesions.…”

The effects of HIV-1 Tat protein on cell cycle during cervical carcinogenesis

“…For this reason, the CDC declared invasive cervical cancer an AIDS-defining neoplasm in 1993. However, cervical cancer differs from other HIV-1 related malignancies because its occurrence is probably independent of immune suppression, and the diagnosis is believed to precede that of HIV-1 in approximately 70% of cases, according to Walker et al 14 Although the oncogenic role of HIV-1 in cervical carcinoma is still controversial, it is known that HIV-1 infection correlates with a more aggressive and less therapy-responsive phenotype, as noted by DeFilippis et al 15 Buonaguro et al 16 have postulated an upregulation of HPV E6 and E7 gene expression by HIV-1 proteins such as Tat. In addition, recent evidence underlines the implication of Tat in the pathogenesis of AIDS-related malignancies by interfering with cellular functions (reviewed in ref.…”