Kaposi's sarcoma (KS) occurs more often in men than in women and HIV-1-associated KS has a high occurrence in homosexual men (over 30%). Most cultures of KS tumours yield cells with properties of hyperplastic (not malignant) endothelial cells under the control of several cytokines. The role of HIV-1 may be in promoting high levels of some cytokines and providing stimulation to angiogenesis by the HIV-1 Tat protein, which synergizes with basic fibroblast growth factor in promoting these effects. Here we describe an immortalized AIDS-KS cell line (KS Y-1) and show that these cells produce malignant metastatic tumours in nude mice and are killed in vitro and in vivo (apparently by apoptosis) by a pregnancy hormone, the beta-chain of human chorionic gonadotropin. Similarly, chorionic gonadotropin kills KS SLK, cells from another neoplastic cell line (established from a non-HIV-associated KS), as well as the hyperplastic KS cells from clinical specimens grown in short-term culture, but does not kill normal endothelial cells. These results provide evidence that KS can evolve into a malignancy and have implications for the hormonal treatment of this tumour.
A human immunodeficiency virus type 1 (HIV-1)-seropositive patient was treated sequentially with the dideoxynucleoside (ddN) analogues zidovudine, didanosine, zalcitabine, stavudine, and lamivudine and the nonnucleoside HIV-1-specific reverse transcriptase inhibitor (NNRTI) loviride (alpha-APA). Accumulation of drug resistance mutations (mainly V75I, F77L, K103N, F116Y, Q151M, and M184V) eventually resulted in a strain that was genotypically and phenotypically resistant to all tested ddNs and the majority of NNRTIs. However, the multidrug-resistant virus retained wild type sensitivities to drugs such as foscarnet, phosphonomethoxyethyl adenine, dextran sulfate, JM3100, saquinavir, and NNRTI TSAO-m3T. Drug-resistant isolates showed replication kinetics and infectivity in an in vitro peripheral blood mononuclear cell system similar to those of the wild type isolate from the same patient. The multi-ddN-resistant isolate was not eliminated in a competition culture with the wild type isolate. Sequential therapy did not prevent the appearance of multidrug-resistant virus with a conserved replication rate.
The risk of clinical progression for human immunodeficiency virus (HIV)-infected persons receiving treatment with highly active antiretroviral therapy (HAART) is poorly defined. From an inception cohort of 8457 HIV-infected persons, 2027 patients who started HAART during prospective follow-up were examined. Results were validated in another 2 groups of patients (n=1946 and n=1442). In total, 200 patients (9.9%) experienced clinical progression during 5177 person-years (incidence, 3.9/100 years). The most recently measured CD4 cell count, virus load, and hemoglobin level all were independently related to the risk of clinical progression, as was a diagnosis of severe AIDS before the start of HAART. On the basis of these findings, a scoring system was derived (range, 0-17). A single unit increase in the score was associated with a 38% increased risk of clinical progression (relative hazard, 1.38; 95% confidence interval, 1.33-1.43; P<.0001). The scoring system was validated with remarkably good agreement in the 2 other cohorts. This system can be used in patient and resource management.
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.
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.
MddNR resistant HIV-1 can be found in European patients. MddNR is characterized by a specific set of drug resistance mutations, cross-resistance to most ddN analogues and a fast clinical progression. MddNR can be associated with protease inhibitor or NNRTI resistance.
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.
The intralesional injection of hCG induces the regression of AIDS-related Kaposi's sarcoma lesions in a dose-dependent manner. The response of these tumors appears to be mediated by the induction of apoptosis.
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