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Anti-herpesvirus treatment and risk of Kaposi's sarcoma in HIV infection
Abstract
Objective: With the recent identification of a new herpesvirus in patients with Kaposi's sarcoma (human herpesvirus-8 or Kaposi's sarcoma-associated herpesvirus), there have been several reports on the use of anti-herpesvirus therapy (foscarnet, ganciclovir and aciclovir) and risk of developing Kaposi's sarcoma. We therefore investigated the association between use of anti-herpesvirus drugs and Kaposi's sarcoma in a large unselected group of patients with AIDS.
Patients and methods: We studied a group of HIV-positive patients at the Chelsea and Westminster Hospital, for whom details on all AIDS-defining diagnoses made during follow-up, treatment and regular CD4 counts were available. Cox proportional hazards models with time dependant covariates were used to assess the association between treatment with aciclovir, foscarnet and ganciclovir and risk of Kaposi's sarcoma.
Results: A total of 3688 patients have been followed up for a median period of 4.2 years, during which time 598 patients (16.2%) developed Kaposi's sarcoma. After adjustments for sex, exposure category, age, treatment with antiretrovirals or Pneumocystis carinii pneumonia prophylaxis, the development of AIDS-defining conditions (including separate adjustment for the development of cytomegalovirus and herpes simplex virus) and CD4 count, there was a decreased risk of developing Kaposi's sarcoma with foscarnet (relative hazard (RH), 0.38; 95% confidence interval (CI), 0.15-0.95; P = 0.038) and with ganciclovir (RH, 0.39; 95% CI, 0.19-0.84; P = 0.015), but not with aciclovir (RH, 1.10; 95% CI, 0.88-1.38; P = 0.40).
Conclusions: These results suggest that both foscarnet and ganciclovir may have some activity in preventing the occurrence of Kaposi's sarcoma, but that aciclovir has no benefit. Further studies of the effect of these drugs on the risk of Kaposi's sarcoma is warranted.
(C) Lippincott-Raven Publishers.
... An observational study has also suggested that GCV and PFA, but not acyclovir (ACV), may prevent the development of KS in HIV-infected patients [35]. Another study performed in the United Kingdom where a total of 3688 HIV patients were followed up for a median period of 4.2 years, during which time 598 patients developed KS, also indicated that GCV and PFA may have some activity in preventing the occurrence of KS, but that ACV had no benefit [36]. In a prospective, randomized, double-blind, placebo-controlled study including CMV-infected persons with advanced AIDS stage, prophylactic oral GCV significantly reduced the risk of CMV disease but not significant differences between the placebo and GCV groups were observed in the 12-month Kaplan-Meir estimates of KS (12% in the placebo group and 8% in the GCV group) [37]. ...
... PFA can be considered as a second-line therapy and its use is reserved to HSV, VZV, and HCMV patients that have failed ACV or GCV therapy due to viral resistance or that cannot be treated with GCV due to side effects of the drug [62]. PFA has been used as antiviral for the treatment of KSHV and, despite its lower activity against KSHV replication in vitro compared to GCV and CDV, this drug has shown efficacy in KS patients [35,36]. ...
Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease. Since the discovery of KSHV 20 years ago, there is still no standard treatment and the management of virus-associated malignancies remains toxic and incompletely efficacious. As the majority of tumor cells are latently infected with KSHV, currently marketed antivirals that target the virus lytic cycle have shown inconsistent results in clinic. Nevertheless, lytic replication plays a major role in disease progression and virus dissemination. Case reports and retrospective studies have pointed out the benefit of antiviral therapy in the treatment and prevention of KSHV-associated diseases. As a consequence, potent and selective antivirals are needed. This review focuses on the anti-KSHV activity, mode of action and current status of antiviral drugs targeting KSHV lytic cycle. Among these drugs, different subclasses of viral DNA polymerase inhibitors and compounds that do not target the viral DNA polymerase are being discussed. We also cover molecules that target cellular kinases, as well as the potential of new drug targets and animal models for antiviral testing.
... Fourth, KS lesions show a substantial rate of spontaneous remission, observed after the introduction of HAART (J. Gill et al., 2002; Ledergerber et al., 1999), cessation of immunosuppression (Kondo et al., 2000; Nagy et al., 2000), or treatment with ganciclovir or foscarnet, which selectively inhibits lytic KSHV replication (Glesby et al., 1996; Mocroft et al., 1996). Together, these features imply that KS is not a true malignancy, but rather a polyclonal reactive hyperplasia. ...
... First, KS is typically observed in patients with higher circulating KSHV loads, indicating that lytic expression is necessary for the recruitment and de novo infection of cells (Campbell et al., 2000; Whitby et al., 1995). Second, ganciclovir and foscarnet have been shown to mediate the long-term remission of KS (Glesby et al., 1996; Mocroft et al., 1996), again indicating that ongoing lytic replication is necessary for lesion formation. Third, immunosuppression favours KS development, and this is connected with KSHV reactivation and lytic replication (Bourboulia et al., 2004; D.F. Martin et al., 1999). ...
... Cidofovir, a potent inhibitor of herpes virus DNA polymerase, was effective in resolving KS lesions in HIV and non-HIV patients but not in all cases [29,30]. The fact that KS tumor cells are latently infected by HHV-8 and do not express lytic genes may explain the lack of efficacy of antivirals as sole treatment for HHV-8-KS [31]. In our series, including seven patients with multiple site involvement and three patients with visceral involvement, only one death was related to KS treatment (bacterial sepsis in patient 6, while after chemotherapy for KS) whereas two patients with HIV-related lymphoma had a progression of the underlying disease after KS diagnosis. ...
The incidence, the clinical characteristics, and the outcome of Kaposi sarcoma (KS) in patients after hematopoietic stem cell transplantation (HSCT) were assessed. During the period 1987–2018, 13 cases of KS were diagnosed, 3 females and 10 males, median age of 50 years, median time from HSCT of 7 months. KS had an incidence of 0.17% in allogeneic and 0.05% in autologous HSCT. HHV-8 was documented in eight of nine tumor tissue samples assessed. The organ involvement was: skin in nine, lymph nodes in six, oral cavity in four, and visceral in three patients, respectively; seven patients had >1 organ involved. Five patients had immunosuppression withdrawn, whereas four and three patients received radiotherapy and chemotherapy, respectively. Eight patients are alive (median follow-up 48 months, range 5–128), whereas five patients died after a median time of 8 months from the diagnosis of KS. However, no death was caused by KS. We conclude that the incidence of KS after HSCT is very low. Although KS can be managed with the reduction of immunosuppression, visceral forms may require chemotherapy and/or radiotherapy. The low prevalence of KS indicates that screening for HHV-8 serology and surveillance for HHV-8 viremia are not indicated in HSCT patients.
... Additional information on preventing and treating KS-IRIS is warranted including optimal timing of cART initiation for patients who present with extensive skin lesions and lung involvement, the impact of HIV and HHV-8/ KSHV viral loads and CD4/CD8 counts as well as the production of inflammatory cytokines in diverse clinical scenarios as well as the role that other co-infections may have on the development of KS [55]. Anti-HHV-8/KSHV therapy should also be addressed, because both foscarnet and ganciclovir have proved activity in vitro [56] and epidemiological studies have shown that either antiviral given prophylactically for CMV infection diminishes the incidence of KS [57,58]. ...
Objective
To investigate the predictive factors for the development of Kaposi sarcoma-related immune reconstitution inflammatory syndrome (KS-IRIS) and long-term prognosis in patients starting combined antiretroviral therapy (cART). Methods
We studied a retrospective-cohort of consecutive antiretroviral-naïve patients with KS initiating cART from January 2005 to December 2011 and followed through June 2013. KS-IRIS was defined as ≥2 of the following: abrupt increase in number of KS lesions, appearance or exacerbation of lung-opacities or lymphedema, concomitantly with an increase in CD4+ cell-count ≥50 cells/mm3 and a decrease of >1 log in viral-load once started cART. We compared individuals who met KS-IRIS criteria with those that did not and described the long-term follow-up. ResultsWe included 89 patients, 88 males; 35 (39%) developed KS-IRIS at a median of 10 weeks (IQR 4–16). KS-IRIS patients had more pulmonary-involvement (60% vs. 16.6% of patients; p < 0.0001), eight died attributed to pulmonary-KS. Thrombocytopenia <100,000/mm3 at follow-up occurred in 36% of KS-IRIS vs. 4% in non-KS-IRIS patients (p = 0.0002), 45% KS-IRIS patients with thrombocytopenia died, non without KS-IRIS. Chemotherapy (bleomicyn–vincristine) was more frequently prescribed in KS-IRIS patients (88.6% vs. 29.6%) with no differences in outcome; 80% of all patients achieve KS complete remission, 52% of them never received chemotherapy. No difference between groups in the long-term follow-up (mean 52.4 ± 27.4 months) was found, only one patient developed a secondary malignancy (1.12%). Conclusions
Lung-involvement was predictive of IRIS development. Thrombocytopenia in KS-IRIS patients at week 12 follow-up after cART initiation was associated with high mortality. Over a third of patients with KS achieve remission without chemotherapy. Individuals that survive the initial period of KS-IRIS adhere to cART had a good long-term prognosis.
... Estos fármacos están indicados para el manejo de la infección por CMV en pacientes inmunosuprimidos, incluyendo pacientes con sida. En la era pre-TARAA, la evidencia clínica ha mostrado que los pacientes con sida que recibían ganciclovir o foscarnet profiláctico tenían un riesgo significativamente menor de desarrollar SK 15,16 . Adicionalmente, se ha demostrado que el foscarnet y el cidofovir lograron la erradicación del HHV8/KSHV de pacientes con y sin VIH con SK. ...
Ganciclovir has shown in vitro anti-human herpesvirus-8 activity, Kaposi sarcoma agent. We analyzed all Kaposi sarcoma patients from 1985 to 1996 pre-HAART era and identified Kaposi sarcoma/AIDS patients who achieved complete remission prior to HAART use.
Results:
We saw 155 Kaposi sarcoma patients up to 1996, 150 with enough information, only 12 received ganciclovir, eight of them for ≥ 21 days; four died within 16 weeks of ganciclovir administration. We identified four male patients with extensive Kaposi sarcoma with complete remission achieved after ganciclovir for CMV end-organ disease. Complete remission was achieved (9, 5, 10 and 5 months) after ganciclovir, which persisted even after antiretroviral therapy failure. All received two nucleosides and indinavir was later added with irregular compliance. The CD4 counts when ganciclovir was started: 11 (4%), 60 (5%), 127 (14%), and 38 (3%) and when they achieved complete remission: 37 (4%), 109 (9%), 313 (13%) and 136 (9%), respectively. Two patients died with no Kaposi sarcoma relapse three years later, with wasting syndrome and other pulmonary-embolism seven years later. One was lost to follow-up in complete remission in the year 2000, the other was alive in 2014 with 27% 820 CD4 cells/ml. The use of ganciclovir was statistically significantly associated with Kaposi sarcoma remission p = 0.001.
Conclusions:
Ganciclovir use was associated to complete remission of Kaposi sarcoma in the pre-HAART era.
... Previous studies have suggested that lytic HHV-8 replication plays an important role in KS pathogenesis [15,17,[22][23][24][25][26][27][28][29][30][31][32][33][34], but the clinical relevance of HHV-8 plasma load measurements in AIDS-KS is still controversial. Several investigators have demonstrated a correlation between HHV-8 plasma viraemia and KS manifestations [15][16][17][18][19], whereas others were not are able to confirm this finding [20]. ...
... Regarding the use of antiviral agents, HHV-8 has been found to be susceptible to cidofovir, ganciclovir, foscarnet, or adefovir, among others (133), but experience with antiviral therapy is still limited (52,72,93,119) and it is not considered common medical practice at present. Limited clinical results with foscarnet, ganciclovir, and cidofovir in KS patients with SOT or with HIV are encouraging (13,93,119,123,131). Antiviral-related nephrotoxicity should be carefully considered in SOT recipients. ...
Kaposi sarcoma (KS) accounts for 5%-10% of post-transplant neoplasms and is caused by the human herpes virus 8 (HHV-8). Transmission routes in solid organ transplant (SOT) recipients are under investigation, partly due to the availability of new diagnostic tests. We conducted a clinical and serologic study of SOT patients with KS. Polymerase chain reaction (PCR) was performed on biopsy specimens, and sera and antibodies against HHV-8 were determined in KS and control patients. Overall, 7/1;328 (0.5%) SOT patients developed KS. Incidence of KS was 0.8% after liver (3/350), 0.75% after heart (2/265), and 0.28% after kidney (2/713) transplantation. The male:female ratio was 6:1; the mean age was 56 years. KS involved only skin in 4 patients, was only extracutaneous in 1, and was both cutaneous and extracutaneous in 2 patients. KS was diagnosed a median of 24 months after SOT (range, 6-108 mo); it occurred earlier in extracutaneous cases (7 vs 49 mo). Therapy involved reduction of immunosuppression (6 patients), radiotherapy (2 patients), and chemotherapy (1 patient). Two patients died (28.5%), both with extracutaneous disease. Seroconversion was demonstrated in the 4 KS patients in whom it could be studied but in only 5% of the control patients. (Incidence rate of KS after seroconversions, 5.7%; confidence intervals 2.2%-7.8%; standard error: 2.8%.) Mean titers of seropositive control patients (1/160) were significantly lower than those of KS patients (1/1,186). All studied organ donors were seronegative. HHV-8 PCR was positive in the 6 available KS biopsies, and viremia was detected in 2 cases and in no controls. Posttransplant KS appears in 0.5% of SOT recipients in our institution. In our opinion, a high titer of anti HHV-8 antibodies or a recent seroconversion is a warning to survey a SOT recipient for the development of KS.
... Although HHV-8 infection may not respond to treatment with the nucleoside analogues acyclovir and ganciclovir as well as the other herpesviruses, long-term remission of KS has been reported following treatment with foscarnet, 477 and HIVpositive patients treated with foscarnet or ganciclovir have a decreased risk of KS development. 478 Also, clearance of HHV-8 DNA from the peripheral blood of an HIV-positive patient following treatment with the HIV protease inhibitor indinavir has been reported. 479 The use of highly active antiretroviral therapy (HAART) in AIDS-related KS is associated with a dramatic clinical response. ...
... Other than in prophylactic antiviral therapy, the use of antiviral drugs as effective treatment against KS is still a matter of debate. [4][5][6][7][8][9] At the present time, there is no definitive chemotherapy to treat KS and PEL. Therefore, the development of novel antitumor agents against KSHVinfected transformed cells such as PEL is necessary. ...
Several 9-(2-C-cyano-2-deoxy-l-beta-d-arabino-pentofuranosyl)purine derivatives were tested against Kaposi's sarcoma-associated herpesvirus (KSHV)-infected primary effusion lymphoma (PEL) cells. The guanine derivative (3, CNDAG), as well as the 2-amino-6-substituted-purine derivatives 4, 5, and 6, exhibited cell growth inhibitory activity against KSHV-infected cells, but showed no cytotoxicity against KSHV-negative cells at >15 microM concentrations. Therefore, it was found that compounds 3, 4, 5, and 6 showed selective cytotoxicity against PEL cells infected with KSHV.
Human herpesvirus 8 (HHV-8) infection is associated with Kaposi’s sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman’s disease. In this study, we used monoclonal antibodies (MAbs) directed against HHV-8 lytic cycle-associated proteins encoded by open reading frame (ORF) 59 (nuclear PF-8 protein) and ORF K8.1 (viral envelope glycoprotein K8.1 [gpK8.1]) to investigate HHV-8 lytic infection in single cells. Lytically infected cells were labeled with MAbs, stained with fluorescently conjugated secondary Abs, and analyzed by flow cytometry. A 3-day stimulation of HHV-8-positive PEL cell lines (BCBL-1 and BC-3) with 12- O -tetradecanoylphorbol-13-acetate (30 nM) or n -butyric acid (0.3 mM) maximized the expression of lytic-phase viral proteins and minimized cell toxicity. The absolute number of expressing cells was inducer and cell line dependent. Expression of PF-8 occurred earlier and more frequently (in up to 20% of cells) than did expression of gpK8.1. A subset of PF-8 positive cells (25%) co-expressed gpK8.1, representing the majority of gpK8.1 expressing cells. Acyclovir, foscarnet, cidofovir, and PMEA reduced the number of cells expressing gpK8.1, but not the number expressing the nonstructural early lytic gene product PF-8. By contrast, alpha interferon (IFN-α) and IFN-β reduced expression of both PF-8 and gpK8.1, implying an overall inhibitory effect on viral gene transcription or translation. In summary, we have characterized and quantified HHV-8 lytic infection in single cells by dual measurement of early- and late-lytic-cycle HHV-8 protein expression. This technique should prove useful for screening of possible antiherpesvirus agents and for detailed phenotypic characterization of HHV-8-infected cells in vitro and in patients with HHV-8-associated diseases.
The efficacy and toxicity of interferon-α2a (9MU/d) and bleomycin (15 mg every 2 weeks), each combined with zidovudine (2 × 250 mg/d), was compared in a randomized study in 26 men with progressing AIDS-related Kaposi's sarcoma (KS). The median CD4 count was 113/μl. Complete or partial response was achieved in one (8%) of 12 evaluable patients on interferon and in 2 (20%) of 10 patients on bleomycin (P=0.43) during 4.7 and 5.3 months of treatment, respectively. The tolerability was comparable. During extended follow up, survival time was 24 and 13 months in the interferon and bleomycin arm, respectively. In a multivariate Cox regression analysis, CD4 lymphocytes <200/μl (relative risk 3.74; 95% CI: 1.30–10.8) and randomization to interferon (relative risk 0.37; 95% CI: 0.15–0.90) were significantly predictive of mortality. New AIDS-related events occurred more frequently in patients who had received bleomycin. The antiviral activity of interferon-α or the chemotherapy-mediated increase in the risk for opportunistic infections may explain these differences.
Das Kaposi-Sarkom (KS) ist eine multifokale, von Gefäßzellen ausgehende Neoplasie unklarer Genese an Haut und inneren Organen, deren Erstbeschreibung durch Moritz Kaposi 1872 erfolgte.
Das Kaposi-Sarkom (KS) ist eine multifokale, von mesenchymalen Zellen ausgehende Neoplasie unklarer Genese an Haut und inneren Organen, deren Erstbeschreibung „Sarcoma idiopathicum multiplex haemorrhagicum“ durch Moritz Kaposi 1872 erfolgte [78]. Es wird auch als europäisches oder klassisches KS bezeichnet. Daneben finden sich das afrikanische KS und das KS bei iatrogener Immunsuppression. Vielfältiges wissenschaftliches Interesse erweckte dieser Tumor, nachdem Friedman-Kien et al. 1981 [49] über das gehäufte Auftreten von KS bei jungen homosexuellen Männern in New York berichteten, die gleichzeitig an einer erworbenen Immunschwäche erkrankt waren. Dieser Zusammenhang war so charakteristisch, daß ein Zusammenhang schon vor der Entdeckung des „human immunodeficiency virus“ (HIV) offensichtlich schien und das KS, verbunden mit einer nicht erklärbaren Immunschwäche, als AIDS-definierend eingestuft und diese Variante des KS als epidemisches KS bezeichnet wurde [50,92,104].
The human gammaherpesvirus family includes Epstein-Barr virus (EBV) and HHV-8, also known as Kaposi’s sarcoma-associated herpesvirus (KSHV). In HIV-infected patients, both EBV and KSHV have been implicated in the development of a wide range of tumors. KSHV-associated diseases include Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). EBV has been associated with the development of several malignancies, including Hodgkin's (HL) and non-Hodgkin’s lymphomas (NHLs).
HIV-associated Kaposi's sarcoma (KS) is a public health challenge in sub-Saharan Africa since both the causative agent, Kaposi's sarcoma associated-herpesvirus (KSHV), and the major risk factor, HIV, are prevalent. In a nested case-control study within a long-standing clinical cohort in rural Uganda, we used stored sera to examine the evolution of antibody titres against the KSHV antigens K8.1 and latency-associated nuclear antigen (LANA) among 30 HIV-infected subjects who subsequently developed HIV-related KS (cases), and among 108 matched HIV/KSHV co-infected controls who did not develop KS. Throughout the six years prior to diagnosis, antibody titres to K8.1 and LANA were significantly higher among cases than controls (p<0.0001) and titres increased prior to diagnosis in the cases. K8.1 titres differed more between KS cases and controls, compared to LANA titres. These differences in titre between cases and controls suggest a role for lytic viral replication in the pathogenesis of HIV-related KS in this setting. This article is protected by copyright. All rights reserved.
A comprehensive review of herpes virus drug discovery with an emphasis on the most recent advances in the field and their progression from early discovery to clinical development is presented. Small molecules against multiple herpes viruses with targets throughout the viral replication cycle are being developed. Many of these have activity in cell culture; some are making it to clinical trials. These inhibitors span the range in both target and mechanism: competitive kinase inhibitors, prodrug DNA polymerase inhibitors, allosteric protease inhibitors, and host-protein inhibitors. Derived from euphane triterpene natural product inhibitors of serine proteases, the 5,5-translactam scaffold similar to 60 has been optimized to achieve potent inhibition of human Cytomegalovirus (HCMV) protease. The work of Borthwick and co-researchers skillfully explored and optimized this novel class of inhibitors. Efforts to improve the original nucleoside analog, acyclovir, gave rise to compounds such as valaciclovir ganciclovir, and valganciclovir that are now standard of care treatments for herpesviral infection.
Kaposi sarcoma is an unusual vascular tumour caused by an oncogenic γ-herpesvirus, Kaposi Sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV 8). Kaposi Sarcoma (KS) lesions are characterized by an abundant inflammatory infiltrate, the presence of KSHV-infected endothelial cells that show signs of aberrant differentiation, as well as faulty angiogenesis/ vascularisation. Here we discuss the molecular mechanisms that lead to the development of these histological features of KS with an emphasis on the viral proteins that are responsible for their development.
Kaposi's sarcoma-associated herpesvirus (KSHV) is an etiological agent of several AIDS-associated malignancies, including Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). Its lytic replication cycle has been proven to be critical for the pathogenesis of KSHV-associated diseases. In KS lesions, lytic viral replication, production of virion particles, and reinfection of endothelial cells are essential to sustain the population of infected cells that otherwise would be quickly lost as spindle cells divide. Thus, antivirals that block KSHV replication could be a strategy in the treatment of KSHV-associated diseases. However, there is no effective anti-KSHV drug currently available. Our previous work showed that human topoisomerase II (Topo II) is indispensable for KSHV lytic replication and is suggested to be an effective target for antiviral drugs. Here, we report the discovery and characterization of a novel catalytic inhibitor of human Topo IIα, namely, (+)-rutamarin. The binding mode of (+)-rutamarin to the ATPase domain of human Topo IIα was established by docking and validated by molecular dynamics (MD) simulations. More importantly, (+)-rutamarin efficiently inhibits KSHV lytic DNA replication in BCBL-1 cells with a half-maximal inhibitory concentration (IC50) of 1.12 μM and blocks virion production with a half-maximal antiviral effective concentration (EC50) of 1.62 μM. It possesses low cytotoxicity, as indicated by the selectivity index (SI) of 84.14. This study demonstrated great potential for (+)-rutamarin to become an effective drug for treatment of human diseases associated with KSHV infection.
Unlabelled:
The ephrin receptor tyrosine kinase A2 (EphA2) is an entry receptor for Kaposi's sarcoma-associated herpesvirus (KSHV) that is engaged by the virus through its gH/gL glycoprotein complex. We describe here that natural ephrin ligands inhibit the gH/gL-EphA2 interaction. The effects of point mutations within EphA2 demonstrated that KSHV gH/gL interacts with EphA2 through a restricted set of the same residues that mediate binding of A-type ephrins. Two previously described inhibitors of the EphA2 interaction with ephrin A5 also inhibited binding of KSHV gH/gL to EphA2. The more potent of the two compounds inhibited KSHV infection of blood vessel and lymphatic endothelial cells in the micromolar concentration range. Our results demonstrate that interaction of KSHV with EphA2 occurs in a fashion similar to that of the natural ephrin ligands. Our data further indicate a new avenue for drug development against KSHV.
Importance:
Our study reports two important findings. First, we show that KSHV engages its receptor, the receptor tyrosine kinase EphA2, at a site that overlaps the binding site of the natural ephrin ligands. Second, we demonstrate that KSHV infection of target cells can be blocked by a small-molecule inhibitor of the viral glycoprotein-EphA2 interaction. These findings represent a novel avenue for the development of strategies to treat KSHV-associated diseases.
A 32-year-old man with HIV infection was admitted to a hospital in South Africa because of progressively worsening skin lesions, dyspnea, and cough. A CD4+ T-cell count was 268 per cubic millimeter. Diagnostic procedures were performed. Presentation of CaseDr. Emily K. Wong (Medicine, Massachusetts General Hospital): A 32-year-old man with human immunodeficiency virus (HIV) infection was admitted to a hospital in Durban, South Africa, because of dyspnea and cough. The hospital is associated with Massachusetts General Hospital. Five months before admission, the patient was seen in an outpatient clinic in South Africa for evaluation of a lesion on his left upper eyelid. On examination, violaceous, raised lesions were present on the left eyelid and right side of the chest (Figure 1A).Dr. Pratistadevi K. Ramdial: Pathological examination of an excisional biopsy specimen of the chest ...
Human gammaherpesviruses including Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are important pathogens as they persist in the host and cause various malignancies. However, few antiviral drugs are available to efficiently control gammaherpesvirus replication. Here we identified the antiviral activity of angelicin against murine gammaherpesvirus 68 (MHV-68), genetically and biologically related to human gammaherpesviruses. Angelicin, a furocoumarin naturally occurring tricyclic aromatic compound, efficiently inhibited lytic replication of MHV-68 in a dose-dependent manner following the virus entry. The IC50 of angelicin antiviral activity was estimated to be 28.95 μM, while the CC50 of angelicin was higher than 2,600 μM. Furthermore, incubation with angelicin efficiently inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced lytic replication of human gammahepresviruses in both EBV- and KSHV-infected cells. Taken together, these results suggest that MHV-68 can be a useful tool to screen novel antiviral agents against human gammaherepsviruses and that angelicin may provide a lead structure for the development of antiviral drug against gammaherpesviruses.
The current arsenal of antiviral agents available to the practitioner is expanding rapidly, such that by the time this article goes to press, new drugs may have already been added. Although the majority of approved drugs have been developed for use in only a few viral infections (eg, HIV, herpesviruses, and papillomavirus), discoveries made in the development of these drugs may lead to antiviral agents effective against other viruses. In addition, new uses for the currently available drugs are under evaluation. This review of antiviral agents discusses the treatments available for viral infections such as herpes simplex virus, varicella zoster virus, cytomegalovirus, human papillomavirus, chronic viral hepatitis, and others. (J Am Acad Dermatol 2002;47:581-99.)
After years of suspicion that Kaposi's sarcoma (KS) is caused by an infectious agent,126 in 1994 Chang and associates24 reported identification of a herpesvirus-like DNA sequence from tissue recovered from KS lesions of an AIDS patient. The sequences resembled, but were distinct from, those of herpesviruses of the family Gammaherpesvirinae: Epstein-Barr virus (EBV) and herpesvirus saimiri, a pathogen of nonhuman primates. Thus, the KS-associated virus appeared to be a new herpesvirus. In addition, the new virus, identified as KS-associated herpesvirus (KSHV) or, the more frequently used name, human herpesvirus type 8 (HHV-8),152 appears to represent a transmissible causal agent for several malignancies. KS is the most common malignancy in patients with HIV infection, reported as the initial AIDS-defining condition in over 20% of patients. The presence of HHV-8 infection has now been found in over 95% of KS tumors, supporting evidence that HHV-8 has a causal role in the development of KS. The discovery has contributed new avenues for understanding the epidemiology of KS and related conditions, the molecular basis of viral-induced carcinogenesis, and identification of novel therapeutic and prophylactic approaches for KS.
Human herpesvirus-8 (HHV-8), a new gammaherpesvirus, was recently detected in long-term stromal cultures derived from fresh bone marrow aspirates from myeloma patients. The association between HHV-8 and multiple myeloma and the question whether HHV-8 is of pathophysiologic significance in myeloma, remains controversial. Evidence supporting an association between this virus and multiple myeloma is, however, accumulating. It seems that the strain of HHV-8 found in myeloma harbors sequence variations within ORF65 unique to myeloma. HHV-8 encodes several genes homologous to eukaryotic genes involved in cellular proliferation, apoptosis, cell migration, and intercellular signaling, through which it may induce abnormal cellular proliferation and tumor formation in its hosts.
Management of human herpesviruses remains a considerable clinical challenge, in part due to their ability to cause both lytic and latent disease. Infection with the Herpesviridae results in lifelong infection, which can reactivate at any time. Control of herpesviruses is by the innate and adaptive immune systems. Herpesviruses must evade the host innate immune system to establish infection. Once infected, the adaptive immune response, primarily CD8(+) T-cells, is crucial in establishing and maintaining latency. Latent herpesviruses are characterised by the presence of viral DNA in infected cells and limited or no viral replication. These characteristics provide a challenge to clinicians and those developing antiviral agents. The scope of this review is two-fold. First, to provide an overview of all antivirals used against herpesviruses, including their mechanism of action, pharmacokinetics, side effects, resistance and clinical uses. And second, to address the management of each of the eight herpesviruses both in the immunocompetent and immunocompromised host, providing evidence for clinical management and therapeutic options, which is important to the clinician engaged in the management of these infections.
The search for anti-viral agents targeted against a variety of viruses other than HIV has continued to yield novel compounds for the treatment of nonHIV diseases. Some of these are herpes viruses, hepatitis B and C, influenza virus, respiratory syncytial virus. A retrospective analysis of the association of anti-herpesvirus treatment with the incidence of Kaposi's sarcoma in HIV infected individuals has shown that treatment with foscarnet or ganciclovir but not acyclovir reduce the risk of developing Kaposi's sarcoma. In harmony with this, HHV-8 (Kaposi sarcoma associated herpesvirus) has been found to be sensitive to ganciclovir, cidofovir, and foscarnet but not acyclovir. Another herpesvirus that has been associated with human malignancies, Epstein-Barr virus (EBV), is sensitive to the L-nucleoside L-FMAU in H1 cells. Among other anti-viral agents, topically applied cidofovir is active against Papilloma virus infections in humans. Cidofovir is also found to have activity in vitro against polyoma viruses and is efficacious in vivo in a murine model of polyoma virus infection. Various cysteine protease inhibitors are active against adenovirus replication, while interferon-α remains the only clinically approved treatment for hepatitis C, the recent determination of the structure of HCV NS3 protease by two independent groups has provided an opportunity for the exploitation of this target for the development of anti-viral agents.
KS is the most frequent malignancy in homo/bisexual male AIDS patients, affecting more than 30% of these patients. KS may present itself as a few innocent cutaneous lesions or may show progression resulting in severe morbidity and mortality. Approximately half of the patients may develop severe progressive disease. The prognosis of patients with progressive disease is poor, with a median survival of less than 6 months. There is no cure for AIDS-related KS, but several therapies are available for palliation. The treatment options may be applied locally or systemically. Radiotherapy is efficacious and safe, but only a few lesions may be treated at one time. For severe progressive KS, systemic therapy with various forms of chemotherapy is used. Three regimes in particular have been focused on, namely bleomycin/vincristine (BV), doxorubicin + BV (DBV), or liposomal daunorubicin (LD) administered every 2 weeks. The agents result in a clinically relevant response (in 50–80% of patients) 2–4 weeks after initiation, but few patients have complete remission of the KS (< 10%), and the tumour may relapse after 4–6 months despite continued therapy. BV is less effective but also less toxic compared with the other regimens. Time to response for DBV may be slightly better than for LD, but the overall efficacy of these 2 regimes is similar. LD treatment is associated with significantly fewer episodes of peripheral neuropathy and alopecia than treatment with DBV. Thus, the recommended order of use of chemotherapeutic agents is BV, LD and DBV. Alpha-interferon may have a role in the small percentage of patients with CD4 cell count > 200 mill/L. In conclusion, several therapeutic options are available for palliation of KS. All systemically applied therapies are associated with severe side-effects and the optimal choice of treatment is a careful balance between response and toxicity. The recent discovery of human herpes virus 8 as a putative causative agent for KS and new potent groups of anti-retroviral agents, may lead to the development of more effective treatments of KS.
Lytic replication of the Kaposi's sarcoma-associated herpesvirus (KSHV) is essential for the maintenance of both the infected state and characteristic angiogenic phenotype of Kaposi's sarcoma and thus represents a desirable therapeutic target. During the peak of herpesvirus lytic replication, viral glycoproteins are mass produced in the endoplasmic reticulum (ER). Normally, this leads to ER stress which, through an unfolded protein response (UPR), triggers phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α), resulting in inhibition of protein synthesis to maintain ER and cellular homeostasis. However, in order to replicate, herpesviruses have acquired the ability to prevent eIF2α phosphorylation. Here we show that clinically achievable nontoxic doses of the glucose analog 2-deoxy-d-glucose (2-DG) stimulate ER stress, thereby shutting down eIF2α and inhibiting KSHV and murine herpesvirus 68 replication and KSHV reactivation from latency. Viral cascade genes that are involved in reactivation, including the master transactivator (RTA) gene, glycoprotein B, K8.1, and angiogenesis-regulating genes are markedly decreased with 2-DG treatment. Overall, our data suggest that activation of UPR by 2-DG elicits an early antiviral response via eIF2α inactivation, which impairs protein synthesis required to drive viral replication and oncogenesis. Thus, induction of ER stress by 2-DG provides a new antiherpesviral strategy that may be applicable to other viruses.
Kaposi’s sarcoma-associated herpesvirus (KSHV) was first identified as the etiologic agent of Kaposi’s sarcoma (KS) in 1994.
KSHV infection is necessary, but not sufficient for the development of Kaposi sarcoma (KS), primary effusion lymphoma (PEL),
and multicentric Castleman disease (MCD). Advances in the prevention and treatment of KSHV-associated Diseases have been achieved,
even though current treatment options are ineffective, or toxic to many affected persons. The identification of new targets
for potential future therapies and the randomized trial to evaluate the efficacy of new antivirals are required.
KSHV has been established as the causative agent of KS, PEL, and MCD, malignancies occurring more frequently in AIDS patients. The aggressive nature of KSHV in the context of HIV infection suggests that interactions between the two viruses enhance pathogenesis. KSHV latent infection and lytic reactivation are characterized by distinct gene expression profiles, and both latency and lytic reactivation seem to be required for malignant progression. As a sophisticated oncogenic virus, KSHV has evolved to possess a formidable repertoire of potent mechanisms that enable it to target and manipulate host cell pathways, leading to increased cell proliferation, increased cell survival, dysregulated angiogenesis, evasion of immunity, and malignant progression in the immunocompromised host.
Worldwide, approximately 40.3 million people are currently living with HIV infection.2 Of these, a significant number are coinfected with KSHV.118,129,381 The complex interplay between the two viruses dramatically elevates the risk for development of KSHV-induced malignancies, KS, PEL, and MCD. Although HAART significantly reduces HIV viral load, the entire T-cell repertoire and immune function may not be completely restored.99 In fact, clinically significant immune deficiency is not necessary for the induction of KSHV-related malignancy.81 Because of variables such as lack of access to therapy, noncompliance with prescribed treatment, failure to respond to treatment and the development of drug-resistant strains of HIV, KSHV-induced malignancies will continue to present a major health concern.
Despite recent advances in our understanding of pathogenic mechanisms involved, the true nature of Kaposi sarcoma remains an enigma. Four clinical variants have been described for the disease, differing in natural history, site of predilection, and prognosis. All forms of Kaposi sarcoma may manifest in the oral cavity and Kaposi sarcoma-associated virus appears essential to development of all clinical variants. The spectrum of therapeutic strategies is broad and selection of appropriate intervention mandates a thorough understanding of disease spread and the patient's symptomatology, as well as risks and benefits of therapy. This article provides an overview of epidemiology, subtypes, clinical course, pathogenesis, and management strategies for Kaposi sarcoma.
Implementation of highly active antiretroviral therapy (HAART) has deeply changed the landscape of HIV-associated malignancies. Some AIDS-defining tumors, namely Primitive Lymphoma of Central Nervous System, have drastically declined, whereas a steady increase has been observed for non-AIDS-defining tumors, maybe due to longer survival of HIV-infected people. Easier immune restoration, subsequent to availability of a number of drugs targeting HIV at different points, has decreased opportunistic infections which hampered treatment of HIV-associated cancers. As a matter of fact these patients have been assimilated more and more with their negative counterpart, undergoing the same aggressive approach. Consistently, procedures that have been so far precluded to HIV+ subjects, such as transplant of hemopoietic stem cells, either autologous or allogenic, and liver transplant are expected to be performed more and more extensively in this population. Which also would mean a full removal of the stigma which has weighed on it. Hence, it is true-like that malignancies and related problems may in the next future make up a main concern for the HIV specialist. Old and new challenges might be the drug-drug interaction of antiretrovirals or biotherapy-related infections or the debated question of an earlier HAART implementation in the course of HIV disease, with CD4+ cells > 500/μl. In fact, if assimilation of HIV patients with cancer and the general population is a remarkable achieved goal, uniqueness of HIV infection in terms of immune status still makes HIV-associated cancer a unique chapter in the setting of Oncology.
Unlabelled:
Kaposi sarcoma (KS) remains a challenge. Its classic or Mediterranean form tends to be benign. In transplant recipients it may be less so. As part of the AIDS pandemic, of which it was an original defining component, it may be life-threatening. It is due to human herpesvirus-8, which is necessary but not sufficient to produce the disease. KS has a low prevalence in the general population of the United States and United Kingdom, with an intermediate rate in Italy and Greece, and a high one in parts of Africa. In Italy, hot spots include its southern regions, the Po River Valley, and Sardinia, possibly related to a high density of blood-sucking insects. An important challenge is to treat KS patients without immunocompromising them. The potential of effective anti-herpes virus therapy and the use of sirolimus in transplantation recipients have added new opportunities for KS prevention.
Learning objectives:
At the conclusion of this learning activity, participants should be able to provide the most recent information about Kaposi sarcoma in the context in which it occurs. Its classic or Mediterranean form, its pattern in transplant recipients and others iatrogenically immunosuppressed, and its occurrence as a potentially life-threatening part of the AIDS pandemic will be stressed. Its etiology and transmission will be discussed in detail to facilitate understanding of Kaposi sarcoma and of human herpesvirus-8 infection in the general population of the United States and United Kingdom, in Italy and Greece, and in certain parts of Africa. Its therapy, including the concept of doing it without immunocompromising the patient, will be stressed. New opportunities for Kaposi sarcoma prevention will also be discussed.
The reactivates of human sera with uninduced and phorbol ester (TPA)-induced human herpesvirus-8 (HHV-8)-infected BCBL-1 cells were examined by immunofluorescence assay (IFA) and by radioimmunoprecipitation reactions (RIP). The seroprevalence of HHV-8 infections is low in the United States general population and only low levels of HHV-8 antibodies were detected in the seropositive sera. In contrast, high levels of antibodies against HHV-8 lytic and latent antigens were detected by IFA in the sera from HIV+ Kaposi's sarcoma (KS)-positive individuals. These sera recognized several proteins and glycoproteins from BCBL-1 cells in RIP reactions. Two types of antibody responses were detected in the sera from HIV+ KS- homosexual men. In majority of the sera with and without detectable HHV-8 DNA in the peripheral blood mononuclear cells (PBMC), significantly low levels of HHV-8 antibodies were detected by IFA. These sera recognized only a subset of HHV-8 proteins and glycoproteins in RIP reactions. In contrast, in a subgroup of sera from HIV+ KS- homosexual men, higher levels of IFA antibodies against HHV-8 lytic and latent antigens were detected. These sera also recognized several viral proteins and glycoproteins in RIP reactions. These results suggest that antibody response profiles to HHV-8 infection vary significantly and serologic assays to detect antibody responses to a panel of both lytic and latent antibodies may be required for maximum sensitivity. Screening of a cDNA library from TPA-induced BCBL-1 cells with an HIV+ KS+ serum identified cDNAs encoding 12 HHV-8 proteins. Further characterization of these HHV-8 proteins would define the HHV-8 antigens useful for seroepidemiological studies and in discriminating lytic, latent, past, and/or reactivation infections.
Human herpesvirus 8 (HHV8) DNA was amplified from peripheral blood mononuclear cells (PBMCs) using PCR in 120 HIV-seropositive in- and outpatients who were enrolled in a cohort study between January 1994 and June 1995. Risk factors for HIV infection were homosexuality/bisexuality alone in 64 cases (30 with Kaposi's sarcoma (KS) and 34 without KS, 4 of whom had KS lesions that appeared during follow-up in the cohort), heterosexual contact alone in 32 cases (among whom 1 woman with KS who was the spouse of a bisexual with KS), and transfusion of blood or blood products alone in 24 cases. Three blood samples at 3-4-month intervals were scheduled for each patient. Twenty-five HIV1-seronegative patients served as controls. A total of 47.1% of homo- or bisexual males with KS and 26.7% of homo- or bisexual males without KS had positive HHV8 DNA detection as compared with 21.9% of patients contaminated by heterosexual contact, 8.3% of blood product recipients and 0% of controls. HHV8 DNA detection was intermittent in all but 3 patients according to sequential sampling. Multivariate analysis showed that AIDS-KS was associated with sexual transmission, mainly homo- or bisexual practices and with HHV8 infection assessed by PCR in PBMCs.
In this review, we highlight the importance of human herpesvirus 8 (HHV-8) lytic replication and the potential for antiviral therapies to prevent or treat HHV-8-related neoplasms.
Diseases caused by HHV-8 infection include Kaposi sarcoma, multicentric Castleman disease (MCD), and primary effusion lymphoma (PEL), which occur primarily in patients with HIV infection. Kaposi sarcoma is the most common AIDS-associated malignancy worldwide. MCD and PEL occur less commonly but, like Kaposi sarcoma, are associated with poor treatment outcomes. Like all herpesviruses, HHV-8 is capable of either latent or lytic infection of cells. Although HHV-8 infection of tumor cells is predominately latent, accumulating data point to the importance of both lytic phase viral gene products and production of infectious virus. Antiviral agents that target herpesvirus DNA synthesis, such as ganciclovir, inhibit HHV-8 lytic replication and can prevent Kaposi sarcoma. Several HIV protease inhibitors may interfere with tumor growth and angiogenesis, and one protease inhibitor, nelfinavir, directly inhibits HHV-8 replication in vitro.
Controlled trials are indicated to determine the clinical utility of antiviral suppression of HHV-8 replication, and identify the optimal antiretroviral regimens, for the prevention and treatment of Kaposi sarcoma.
Kaposi's sarcoma-associated herpesvirus (KSHV) establishes a latent infection in the host following an acute infection. Reactivation from latency contributes to the development of KSHV-induced malignancies, which include Kaposi's sarcoma (KS), the most common cancer in untreated AIDS patients, primary effusion lymphoma and multicentric Castleman's disease. However, the physiological cues that trigger KSHV reactivation remain unclear. Here, we show that the reactive oxygen species (ROS) hydrogen peroxide (H₂O₂) induces KSHV reactivation from latency through both autocrine and paracrine signaling. Furthermore, KSHV spontaneous lytic replication, and KSHV reactivation from latency induced by oxidative stress, hypoxia, and proinflammatory and proangiogenic cytokines are mediated by H₂O₂. Mechanistically, H₂O₂ induction of KSHV reactivation depends on the activation of mitogen-activated protein kinase ERK1/2, JNK, and p38 pathways. Significantly, H₂O₂ scavengers N-acetyl-L-cysteine (NAC), catalase and glutathione inhibit KSHV lytic replication in culture. In a mouse model of KSHV-induced lymphoma, NAC effectively inhibits KSHV lytic replication and significantly prolongs the lifespan of the mice. These results directly relate KSHV reactivation to oxidative stress and inflammation, which are physiological hallmarks of KS patients. The discovery of this novel mechanism of KSHV reactivation indicates that antioxidants and anti-inflammation drugs could be promising preventive and therapeutic agents for effectively targeting KSHV replication and KSHV-related malignancies.
The life cycle of Kaposi's sarcoma-associated herpesvirus (KSHV) consists of latent and lytic replication phases. During latent infection, only a limited number of KSHV genes are expressed. However, this phase of replication is essential for persistent infection, evasion of host immune response, and induction of KSHV-related malignancies. KSHV reactivation from latency produces a wide range of viral products and infectious virions. The resulting de novo infection and viral lytic products modulate diverse cellular pathways and stromal microenvironment, which promote the development of Kaposi's sarcoma (KS). The mechanisms controlling KSHV latency and reactivation are complex, involving both viral and host factors, and are modulated by diverse environmental factors. Here, we review the cellular and molecular basis of KSHV latency and reactivation with a focus on the most recent advancements in the field.
Introduction:
Kaposi's sarcoma (KS) is an angioproliferative disease that occurs in four clinical-epidemiological forms sharing the same immunological and histopathological features, suggesting common etiological and pathogenic factors. Infection with the human herpesvirus 8, cytokine- and angiogenic factor-induced growth together with an immuno-dysregulated state represent fundamental conditions for the development of this tumor. Despite the recent improvements in KS management, it remains an incurable disease.
Areas covered:
The growing knowledge of KS biology provides multiple opportunities for the development of rational, molecularly targeted therapies. The present review summarizes the current management of KS, including local and systemic conventional therapies, and thoroughly describes the results obtained with new pathogenesis-based anti-KS treatments.
Expert opinion:
Kaposi's sarcoma represents a paradigm of how the elucidation of disease pathogenesis can drive the development of molecularly targeted treatments. The multifactorial pathogenesis of KS has led to the evaluation of many experimental agents targeting one or more specific factors or pathways involved in the development or progression of the disease. Although targeted therapy so far represents investigational treatment, clinical evaluation of several of these agents is yielding promising results.
Kaposi's sarcoma (KS) is the most common HIV-associated cancer worldwide and is associated with high levels of morbidity and
mortality in some regions. Antiretroviral (ARV) combination regimens have had mixed results for KS progression and resolution.
Anecdotal case reports suggest that protease inhibitors (PIs) may have effects against KS that are independent of their effect
on HIV infection. As such, we evaluated whether PIs or other ARVs directly inhibit replication of Kaposi's sarcoma-associated
herpesvirus (KSHV), the gammaherpesvirus that causes KS. Among a broad panel of ARVs tested, only the PI nelfinavir consistently
displayed potent inhibitory activity against KSHV in vitro as demonstrated by an efficient quantitative assay for infectious KSHV using a recombinant virus, rKSHV.294, which expresses
the secreted alkaline phosphatase. This inhibitory activity of nelfinavir against KSHV replication was confirmed using virus
derived from a second primary effusion lymphoma cell line. Nelfinavir was similarly found to inhibit in vitro replication of an alphaherpesvirus (herpes simplex virus) and a betaherpesvirus (human cytomegalovirus). No activity was
observed with nelfinavir against vaccinia virus or adenovirus. Nelfinavir may provide unique benefits for the prevention or
treatment of HIV-associated KS and potentially other human herpesviruses by direct inhibition of replication.
Kaposi's sarcoma-associated herpesvirus (KSHV) seropositivity and lytic antibody titer are predictors for Kaposi's sarcoma.
We examined demographic, viral, and immunologic factors that influence KSHV latent and lytic antibodies in HIV-infected patients.
Detection rate of KSHV latent but not lytic antibodies was lower in patients with CD4 cells/mm3 less than 200 than greater than 200 (odds ratio [OR], 0.26; 95% confidence interval [CI], 0.11-0.61) and CD8 cells/mm3 less than 400 than greater than 400 (OR, 0.26; 95% CI, 0.07-0.67). Overall seropositivity rate was higher in patients with CD4 cells/mm3 less than 200 than greater than 200 (OR, 2.34; 95% CI, 1.37-4.02) and HIV copies/mL greater than 400 than less than 400 (OR, 1.70; 95% CI, 1.09-2.65). Lytic antibody level was inversely correlated with CD4 count (P < 0.001). Lytic seropositivity (OR, 2.47; 95% CI, 1.35-4.50) and antibody level (adjusted difference mean optical density, 0.324; 95% CI, 0.16-0.46) were higher in patients with HIV infection greater than 15 than less than 15 years. Hispanics had higher lytic seropositivity rate (OR, 1.71; 95% CI, 1.07-2.73) and antibody level (adjusted difference mean optical density, 0.111; 95% CI, 0.03-0.18) than non-Hispanics.
Lower CD4 and CD8 counts impair antibody response to KSHV latent antigens. Immune deterioration, long-term HIV infection, and Hispanic status are risk factors for Kaposi's sarcoma predictors.
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