indinavir-sulfate and Papillomavirus-Infections

It has been shown that the HIV protease inhibitors indinavir and lopinavir may have activity against the human papilloma virus (HPV) type 16 inhibiting HPV E6-mediated proteasomal degradation of p53 in cultured cervical carcinoma cells. However, their mode and site of action is unknown. HPV-negative C33A cervical carcinoma cells and the same cells stably transfected with E6 (C33AE6) were exposed to indinavir and lopinavir at concentrations of 1 mM and 30 μM, respectively. The intracellular distribution of metabolites and metabolic changes induced by these treatments were investigated by Raman microspectroscopic imaging combined with the analysis of cell fractionation products by liquid chromatography-mass spectrometry (LC-MS). A uniform cellular distribution of proteins was found in drug-treated cells irrespective of cell type. Indinavir was observed to co-localise with nucleic acid in the nucleus, but only in E6 expressing cells. Principal components analysis (PCA) score maps generated on the full Raman hypercube and the corresponding PCA loadings plots revealed that the majority of metabolic variations influenced by the drug exposure within the cells were associated with changes in nucleic acids. Analysis of cell fractionation products by LC-MS confirmed that the level of indinavir in nuclear extracts was approximately eight-fold greater than in the cytoplasm. These data demonstrate that indinavir undergoes enhanced nuclear accumulation in E6-expressing cells, which suggests that this is the most likely site of action for this compound against HPV.

Topics: Cell Fractionation; Cell Line, Tumor; Chromatography, Liquid; Female; HIV Protease Inhibitors; Human papillomavirus 16; Humans; Indinavir; Lopinavir; Oncogene Proteins, Viral; Papillomavirus Infections; Principal Component Analysis; Pyrimidinones; Repressor Proteins; Spectrometry, Mass, Electrospray Ionization; Spectrum Analysis, Raman; Transfection; Tumor Suppressor Protein p53; Uterine Cervical Neoplasms

Human papilloma virus (HPV)-related cutaneous manifestations occur with increased frequency and severity among HIV-infected persons. In this report, we describe an HIV-infected man with persistent, severe cutaneous hand warts that did not respond to multiple therapies, including liquid nitrogen cryotherapy, topical dinitrochlorobenzene, topical podophyllin, and intralesional interferon-alfa injections. Approximately 1 year after starting a potent protease inhibitor-containing antiretroviral regimen, the patient's recalcitrant cutaneous warts markedly diminished in size, even though the patient did not receive any specific therapy for the warts after starting aggressive antiretroviral therapy. The patient continued on a potent protease inhibitor-containing antiretroviral regimen and, approximately 2 years later, the warts completely resolved. Our patient's dramatic clinical improvement of cutaneous HPV infection that followed protease inhibitor-containing antiretroviral therapy provides a clear-cut example that protease inhibitor-containing combination antiretroviral therapy can produce significant clinical benefit.

Topics: Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antiviral Agents; Cryosurgery; Dinitrochlorobenzene; Hand Dermatoses; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Interferon-alpha; Keratolytic Agents; Male; Papillomaviridae; Papillomavirus Infections; Podophyllin; Treatment Outcome; Tumor Virus Infections; Warts

Many sessions at the 5th Conference on Retroviruses and Opportunistic Infections dealt specifically with HIV infection and treatment in women. Highlights are presented from several sessions, including indinavir blood levels at various points in the menstrual cycle, abnormal kidney function associated with women taking indinavir, abnormal pap smears in women with high viral load, the relationship between viral load and the increased risk of death in women, and the impact of ddI crossing the placenta in pregnant women. Information is given on each presentation, including clinical trial results, side effects, and impacts on disease progression.

Topics: Anti-HIV Agents; Cervix Uteri; Chicago; Clinical Trials as Topic; Congresses as Topic; Didanosine; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Kidney Diseases; Male; Maternal-Fetal Exchange; Menstrual Cycle; Papanicolaou Test; Papillomavirus Infections; Pregnancy; Risk Factors; RNA, Viral; Tumor Virus Infections; Vaginal Smears; Viral Load