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P Hermans

Publications and source records attributed to P Hermans.

At least 37 records · Page 2Linked to original sources
PubMed2000

HIV-associated multinucleated giant cells in lymphoid tissue of the Waldeyer's ring: a detailed study.

Hyperplastic lymphoid tissues of the Waldeyer's ring in human immunodeficiency virus (HIV)-infected patients may occasionally contain multinucleated giant cells (MGCs). These cells, which are unrelated to any opportunistic infection, previously have been demonstrated to harbor significant amounts of HIV. Studies undertaken to characterize these MGCs have generated conflicting results: some reports suggested a macrophage origin, whereas others supported a dendritic cell lineage. This study was performed to determine the occurrence of MGCs in a series of adenoid/tonsil specimens from HIV-seropositive patients showing no histological evidence of opportunistic infection in order to further characterize the phenotype of these cells and to investigate the role of a viral infection in their pathogenesis. Adenoid/tonsil tissue specimens from 21 HIV-seropositive patients with no documented opportunistic infection were scrutinized for the presence of MGCs and evaluated immunohistochemically on paraffin sections by antibodies directed against various macrophage and DC antigens. These antigens included CD68, the macrophage marker 3A5, major histocompatibility complex Class II, S-100 protein, CD1a, and CD83. Additional immunostainings directed at CD21 and CD35 as well as at the HIV-associated p24 antigen were also performed. Finally, the presence of Epstein-Barr virus and human herpesvirus 8 viral sequences was investigated by in situ hybridization and by polymerase chain reaction analysis, respectively. MGCs were found in 14 patients (66.7%), regardless of gender, age, method of viral transmission, CD4 cell count, viral load, or ethnic group. These cells were mostly localized at the lymphoepithelium layer of the tonsillar crypts and, to a lesser extent, in the interfollicular areas of the underlying lymphoid tissue, which consistently exhibited features of follicular hyperplasia. Phenotypically, MGCs were found to be CD68+, 3A5+, major histocompatibility complex Class II+, S-100 protein+/-, CD1a-, CD21-, CD35-, and CD83-. Although the HIV-associated p24 protein was consistently present in the cytoplasm of these cells, no sign of Epstein-Barr virus or human herpesvirus 8 infection could be demonstrated. Consequently, our study didn't show any conclusive evidence to support that MGCs in hyperplastic lymphoid tissues of the Waldeyer's ring from HIV-seropositive patients originated from dendritic cells. The definite nature of these cells has yet to be elucidated, but it is plausible that they simply represent activated macrophages that are infected with HIV present in the oropharyngeal secretions during the circulation of their precursor through the lymphoepithelium area of adenoids and tonsils.

Adenoids↗
PubMed2000

Kaposi's sarcoma in HIV-infected patients: treatment options.

Kaposi's sarcoma (KS) is the most prevalent AIDS-associated tumour, occurring in 20-30% of HIV-1-infected individuals in the early 1980s. The introduction of highly active antiretroviral therapy (HAART) has dramatically reduced the incidence of the disease and might therefore support the concept of 'opportunistic malignancies' requiring immune impairments to occur. The relationship between the immune system and the epidemiology of this virus-induced tumour is of importance in order to identify new therapeutic approaches for treating or preventing its occurrence. As a model of impaired angiogenesis, therapeutic options for treating AIDS patients with KS should therefore target cell division, anti-angiogenic processes, immune modulators, cytokines and potentially antiviral drugs.

AIDS-Related Opportunistic Infections↗
PubMed2000

Iron chelators inhibit the growth and induce the apoptosis of Kaposi's sarcoma cells and of their putative endothelial precursors.

Iron is suspected to be involved in the induction and/or progression of various human tumors. More particularly, iron may be involved in the pathogenesis of Kaposi's sarcoma, a tumor of probable vascular origin. This study was designed to investigate the effect of iron deprivation on Kaposi's sarcoma. The effects of iron chelators and iron deprivation associated with serum withdrawal were investigated on Kaposi's sarcoma-derived spindle cells, on a transformed Kaposi's sarcoma cell line (Kaposi's sarcoma Y-1) and on endothelial cells, which are the probable progenitors of Kaposi's sarcoma cells. Desferrioxamine and deferiprone, two chemically unrelated iron chelators, induced a time- and concentration-dependent inhibition of endothelial and Kaposi's sarcoma cell growth. The inhibition of cell growth was associated with a decrease in Ki-67 and in both stable and total proliferating cell nuclear antigen expression. Inhibition of the progression through the G1-phase of the cell cycle was further evidenced by decreased expression of cyclin D1 and of p34 cyclin-dependent kinase 4. Terminal deoxynucleotidyl transferase-mediated desoxyuridinetriphosphate nick end labeling assay, flow cytometry with annexin-V-fluorescein and morphologic analysis indicated that iron chelation also induced a time- and concentration-dependent apoptosis. This apoptotic effect was prevented by the addition of exogenous iron. Induction of iron deprivation in the culture medium by serum withdrawal led to similar cell cycle effects, which, however, could only be partly reverted by the addition of exogenous iron. In conclusion, these results show that iron deprivation inhibits the growth and induces the apoptosis of Kaposi's sarcoma cells and of their putative endothelial precursors. This suggests that iron chelators may represent a potential therapeutic approach for the treatment of Kaposi's sarcoma.

Apoptosis↗
PubMed2000

Phenotypic characteristics of Kaposi's sarcoma tumour cells derived from patch-, plaque- and nodular-stage lesions: analysis of cell cultures isolated from AIDS and non-AIDS patients and review of the literature.

BACKGROUND: Kaposi's sarcoma (KS) is commonly thought to be derived from endothelial cells because of the predominant expression of endothelial markers in KS lesions. However, the heterogeneity of the spindle-cell compartment makes the precise lineage relationship of KS tumour cells unclear. Cultured KS-derived spindle cells constitutively overexpress antiapoptotic proteins and exhibit invasive properties, which suggests that they may adequately represent the tumour cells of KS. OBJECTIVES: We aimed to investigate the expression of a wide variety of immunohistochemical markers by spindle cells derived from patch-, plaque- and nodular-stage lesions from patients with iatrogenic, sporadic and acquired immune deficiency syndrome-related KS, and to review the data reported by other laboratories. METHODS: Cells from six KS cell cultures derived from four subjects were examined by immunostaining. RESULTS: Comparison of these data indicates that KS-derived spindle cells generally express myofibroblast antigens but lack endothelial and/or leucocyte markers. CONCLUSIONS: As the myofibroblast phenotype is not the predominant feature of KS tissues, our findings further substantiate the view that the in vivo dominant endothelial population represents a reactive hyperplasia rather than the true KS tumour process.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Insight into odorant perception: the crystal structure and binding characteristics of antibody fragments directed against the musk odorant traseolide.

Monoclonal antibodies were elicited against the small hydrophobic hapten traseolide, a commercially available musk fragrance. Antibody variable region sequences were found to belong to different sequence groups, and the binding characteristics of the corresponding antibody fragments were investigated. The antibodies M02/01/01 and M02/05/01 are highly homologous and differ in the binding pocket only at position H93. M02/05/01 (H93 Val) binds the hapten traseolide about 75-fold better than M02/01/01 (H93 Ala). A traseolide analog, missing only one methyl group, does not have the characteristic musk odorant fragrance. The antibody M02/05/01 binds this hapten analog about tenfold less tightly than the original traseolide hapten, and mimics the odorant receptor in this respect, while the antibody M02/01/01 does not distinguish between the analog and traseolide. To elucidate the structural basis for the fine specificity of binding, we determined the crystal structure of the Fab fragment of M02/05/01 complexed with the hapten at 2.6 A resolution. The crystal structure showed that only van der Waals interactions are involved in binding. The somatic Ala H93 Val mutation in M02/05/01 fills up an empty cavity in the binding pocket. This leads to an increase in binding energy and to the ability to discriminate between the hapten traseolide and its derivatives. The structural understanding of odorant specificity in an antibody gives insight in the physical principles on how specificity for such hydrophobic molecules may be achieved.

Amino Acid Sequence↗
PubMed1999

Phenotypic assays and sequencing are less sensitive than point mutation assays for detection of resistance in mixed HIV-1 genotypic populations.

The sensitivity and discriminatory power of the 151 and 215 amplification refractory mutation system (ARMS) were evaluated, and their performance for the detection of drug resistance in mixed genotypic populations of the reverse transcription (RT) gene of HIV-1 were compared with T7 sequencing, cycle sequencing, the line probe assay (LiPA) HIV-1 RT test, and the recombinant virus assay (RVA). ARMS and the LiPA HIV-1 RT test were shown to be able to detect minor variants that in particular cases comprised only 1%. T7 sequencing on an ALF semiautomated sequencer could correctly score mixtures only when variants were present at 50%. Cycle sequencing on an ABI PRISM 310 improved the sensitivity for mixtures to about 25%. Using RVA, it was shown that at least 50% of the virus population needed to carry the resistance mutation at codon 184 to afford phenotypic resistance against lamivudine. The two point mutation assays therefore proved to be more sensitive methods than sequencing and RVA to reliably determine a gradual shift in HIV-1 drug resistance mutations in follow-up of patients infected with HIV-1. In 4 of 5 treated patients who were followed by ARMS, a gradual shift in resistant genotypic populations was observed during a period of 6 to 19 months. For 1 patient, a shift from wild to mutant type at position 151 occurred within 2 months, without mixed genotypic intermediate type's being detected.

DNA Mutational Analysis↗
PubMed1999

Active anti-interferon-alpha immunization: a European-Israeli, randomized, double-blind, placebo-controlled clinical trial in 242 HIV-1--infected patients (the EURIS study).

This randomized, double-blind, placebo-controlled, phase II/III study was designed to evaluate safety, immunogenicity, and efficacy of an active anti-interferon-alpha (anti-IFN-alpha) vaccine in asymptomatic HIV-1-infected patients. The active immunization was aimed at inducing anti-IFN-alpha antibodies to counteract IFN-alpha overproduction. In all, 242 patients, recruited between December 1995 and July 1996 in eight centers in Europe and Israel, with CD4+ counts from 100 to 634 cells/mm3 who were receiving or not receiving antiretroviral therapy (including protease inhibitors) were randomized to receive either anti-IFN-alpha vaccine or placebo. The anti-IFN-alpha immunization regimen consisted of three priming injections delivered intramuscularly at 1-month intervals in a water-in-oil emulsion of inactivated recombinant IFN-alpha-2b (i-IFN-alpha) followed by intramuscular booster injections of i-IFN-alpha adsorbed onto calcium phosphate every 3 months. Immunogenicity to vaccine was defined as an increase of anti-IFN-alpha antibody level of more than twofold the preimmunization value. Clinical progression, changes in antiretroviral treatment, and decrease of CD4+ counts to <200 cells/mm3 were considered endpoints for efficacy evaluation. Contrary to our previous experience, in which six to seven oil priming injections induced a >90% response rate, the three oil-adjuvanted injections in this trial were suboptimal because only 40 of 122 vaccinees (33%) had raised anti-IFN-alpha antibody following immunization. In vaccinees, both antibody responders (AbRV) and nonresponders (AbNRV), the tolerance to the vaccine was good and was without evidence of significant safety concerns. During the course of the trial, 62% of vaccine responders, 64% of nonresponders, and 63% of placebo patients elected to add protease inhibitor-containing regimens as new treatment guidelines were established, resulting in a marked decrease in clinical and laboratory progression such that the expected endpoints of the study could not be achieved and further follow-up was halted. Despite the unexpectedly low immunogenicity and fewer than expected endpoints, anti-IFN-alpha vaccine recipients, in comparison with placebo recipients, showed a lower rate of disease progression, nonelective treatment changes, and/or CD4+ count decrease to <200 cells/mm3, but the difference was not statistically significant. Nevertheless, the subgroup of patients immunized to IFN-alpha who experienced a rise in anti-IFN-alpha antibodies had a significantly lower rate of occurrence of HIV-1-related events and of any combination of the endpoints compared with those of either placebo patients or vaccinees who failed to develop anti-IFN-alpha antibodies, the latter two groups behaving similarly. Further studies of this approach are warranted because these data suggest a beneficial effect of this adjuvant approach.

AIDS Vaccines↗
PubMed1999

Anti-IFN alpha immunization raises the IFN alpha-neutralizing capacity of serum--an adjuvant to antiretroviral tritherapy.

HAART (highly active antiretroviral therapy) suppresses but does not eradicate HIV-1 infection. However, since the antiretroviral agents used in HAART may also be toxic in the long-term, immunotherapies which correct HIV-1 immunosuppression or the cytokine dysregulation associated with it may be beneficial. In this respect, a double blind multicentric placebo-controlled phase II/III anti-IFN alpha vaccine trial has been carried out on 242 HIV-1 patients, the majority of whom were undergoing HAART treatment. In vaccinated patients (vaccinees) who responded to immunization by increased levels of IFN alpha Abs (whether under HAART or not) when compared to placebo or non-responder vaccinees, a strong correlation was found between an increased IFN alpha neutralizing capacity and the reduction of clinical manifestations.

AIDS Vaccines↗
PubMed1999

Neutropenia in patients with HIV infection: a case control study in a cohort of 1403 patients between 1982 and 1993.

The relationship between neutropenia and increased risks of severe infections in patients with HIV infection and the factors associated with neutropenia-induced infections was studied by a retrospective comparative study using matched case-control analysis. A database (1982-1993) of 1870 patients with HIV infection was searched, and from 484 patients with neutropenia, 177 patients were paired with 177 nonneutropenic control subjects. Descriptive analysis and development of logistic models were used to determine factors associated with the risk of developing bacterial infections and major fungal infections. The occurrence of severe bacterial and fungal infections was significantly higher in neutropenic patients (p < or = 0.001). Bacteremia was more common in neutropenic patients than in nonneutropenic patients (p < or = 0.02) in the matched case-control analysis. Risk of severe infections was strongly associated with the neutrophil count (p < or = 0.05), clinical stage, and hemoglobin level (p < 0.005) when paired patients were compared. More neutropenic episodes occurred between 1991 to 1993, possibly due to prolonged survival and the increasing use of concomitant myelosuppressive therapies. Neutropenic HIV-infected patients are significantly at risk of developing severe infections at the end-stage of HIV disease, and this may have a major impact on hospitalization and death. Preventing neutropenia could dramatically improve the quality of life of these patients.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Early- and late-stage Kaposi's sarcoma lesions exhibit similar proliferation fraction.

There are few studies on the proliferative activity of cells in Kaposi's sarcoma. It remains unclear whether the different progressive histologic stages of Kaposi's sarcoma correlate with the proliferative activity of the tumor. To clarify this issue, we studied the Ki-67 proliferation index in 40 specimens of acquired immune deficiency syndrome-related Kaposi's sarcoma in correlation with the histologic stage of the lesions. The mean proliferation index in our combined material was rather low (8%, range 1-20%) and there was no significant difference among the different stages of the disease. Contrary to a common and probably misleading concept, our results suggest that the histologic progression of the Kaposi's sarcoma is not related to an increase of the proliferative compartment.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Penile intraepithelial neoplasia overlying Kaposi's sarcoma lesions: role of viral synergy?

Several viral agents have been detected in the lesional tissue of Kaposi's sarcoma (KS). Their precise oncogenic role remains to be determined. A 32-year-old heterosexual man with acquired immunodeficiency syndrome (AIDS) who had penile lesions of KS with overlying epithelial changes characteristic of intraepithelial neoplasia associated with concurrent infection by human papillomavirus (HPV) and human herpesvirus 8 (HHV-8) is reported. The absence of viral DNA from uninvolved skin suggests that this coinfection is more than coincidental and may involve synergy between these viruses, as has already been suggested for HPV and herpes simplex 2 virus.

Acquired Immunodeficiency Syndrome↗
PubMed1999

HIV disease-related neutropenia: an independent risk factor for severe infections.

An increasing number of clinical studies have been reported in which neutropenia has been identified as an important independent risk factor in the development of infectious complications in patients with HIV and AIDS. Information on the clinical significance of infecting pathogens and the causes of neutropenia within different patient groups will be discussed, and may have clinical implications in subsequent disease management in these groups. Although the use of highly active antiretroviral therapy has shown some promise in the treatment of HIV-associated hematologic disturbances and immune dysfunction, the rate of virological failure with this treatment over time suggests that these disturbances could reappear in the near future, as well as their associated infectious complications.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Use of hydroxyurea in heavily pretreated patients with HIV infection.

This study was designed to assess the potential benefit of hydroxyurea (HU) on virological and immunological markers in heavily pretreated human immunodeficiency virus (HIV)-infected patients. A total of 118 patients received hydroxyurea as treatment added to their current antiviral therapy ('add' group), or as treatment added together with a switched nucleoside reverse transcriptase inhibitor or protease inhibitor or with the introduction of an additional antiviral agent ('add and switch' group). Efficacy of HU was also compared among patients receiving didanosine- and non-didanosine-containing regimens. Results showed that HU was not associated with a significant decline in plasma HIV-1 RNA, and no significant difference in plasma HIV-1 RNA changes was noted between patients who did and did not receive didanosine. The absolute number of CD4 cells, but not the CD4 percentage, declined significantly from baseline. Significantly more grade 3-4 neutropenia occurred among patients receiving HU combined with zidovudine, although the discontinuation rate for haematological toxicity was similar in zidovudine- and non-zidovudine-treated patients.

Adult↗
PubMed1998

Iron as a potential co-factor in the pathogenesis of Kaposi's sarcoma?

The role of iron in the pathogenesis of several tumours is being increasingly investigated. In particular, its involvement in the pathogenesis of Kaposi's sarcoma (KS) is suggested by the distribution of the endemic form of KS corresponding to continental rifts and associated iron-oxide-rich volcanic clays. We investigated in vitro to what extent iron supplementation or withdrawal could affect the growth of KS-derived cells, by analysing the effects of adding iron salts (iron chloride and ferric nitrilotriacetate) and/or reducing iron by iron chelators (desferrioxamine) on KS-derived cell cultures. The addition of iron salts strongly stimulated the growth of KS cells, as reflected by increase in thymidine incorporation and cell number. Conversely, desferrioxamine and deferiprone inhibited cell growth. The inhibitory effect of iron chelation was more pronounced on rapidly dividing basic fibroblast-growth-factor-stimulated cells. These results may point to a novel therapeutic approach to KS.

Carcinogens↗