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55: Is human herpesvirus 6 linked to histiocytic necrotizing lymphadenitis?
S112 Abstracts, 5th Int. Conf. on HHV-6 & 7, 1–3 May 2006, Barcelona, Spain / Journal of Clinical Virology 37 Suppl. 1 (2006) S97–118 Results: 118 cases (0-89 years old) were analyzed. Of those, 63.7% of causative drugs were anticonvulsants (especially carbamazepine). The other common causative drugs were sulfonamides, mexilletine (an antiarrhythmic drug) and allopurinol. The symptoms developed 3 weeks or more after the beginning of causative drug administration in 80.5% of the patients. Recurrence of the symptoms was observed in 40% of the patients. The mortality rate was 3.6%. Reactivation of HHV-6 was detected in 83.9% of the patients by the increase of HHV-6 IgG and/or increase of HHV-6 DNA in the peripheral blood. Reactivation of cytomegalovirus was observed not only in the patients with HHV-6 reactivation but also in 4 patients without HHV-6 reactivation. Conclusions: DIHS is a complex disease involving human herpesviruses and drug allergy.
55 Is human herpesvirus 6 linked to histiocytic necrotizing lymphadenitis? S.-M. Choi *, S.H. Park, D.-G. Lee, J.-H. Choi, J.-H. Yoo, W.-S. Shin. Division of Infectious Diseases, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea E-mail address: [email protected] Background: Recently, human herpes virus-6 (HHV-6) has been proposed to be a viral cause of the histiocytic necrotizing lymphadenitis (HNL). Objectives: To detect the genome of herpesviridae in the specimens of the HNL and other forms of lymphadenitis. Study Design: PCR for EBV, CMV and HHV-6 was performed on lymph node (LN), serum and peripheral blood mononuclear cells (PBMC). Results: Pathologically, the diagnosis of the cases consisted of 9 HNL, 4 reactive hyperplasia (RH), 6 tuberculous lymphadenitis (TBL) and 1 metastatic adenocarcinoma. HHV-6 DNA was detected in 70% (14/20), while EBV DNA showed 65% (13/20) positivity in the LN. Both HHV-6 and EBV simultaneously showed positive signal in HNL and RH. In TBL, more cases were HHV-6 positive (66.7%, 4/6) than EBV (33.3%, 2/6). Only one case of RH and one case of TBL showed positive for EBV on serum and PBMC. Conclusions: These results indicate that the presence of HHV-6 genome is not specifically related to HNL, and that this virus could hibernate in a latent form in the LN. Rather, at least cooperative role of HHV-6 along with EBV might be possible in the event of awakening from latency in the LN.
Antivirals & Other Treatments 56 Antiviral activity of diverse classes of broad-acting agents and natural compounds in HHV-6-infected lymphoblasts L. Naesens *, E. De Clercq. Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium E-mail address: [email protected] Background: Replication of HHV-6 in its host cell results from complex and poorly understood interactions between viral and cellular factors. Objectives: In an attempt to discover new targets for antiviral therapy, we initiated a study with several classes of natural compounds or broadacting pharmacological agents. Study Design: The inhibitory effect on HHV-6 replication in T-lymphoblasts was determined in a 10-day assay, using HHV-6A (strain GS)-infected HSB-2 cells and HHV-6B (strain Z29)-infected MOLT-3 cells. Virus replication was quantified by microscopic evaluation of the cytopathic effect and by real-time PCR assay for HHV-6 DNA. Foscarnet, which produces a strong and reproducible
inhibition of HHV-6 replication, was included as the reference compound. Results: Among the 16 natural compounds tested, artemisinin was found to be inactive, while ‘red marine algae’ (an extract rich in polysulfated polysaccharides) was shown to have strong and selective activity when added during the initial virus adsorption stage. Among the broad-acting pharmacological agents, chloroquine, hypericin, ribavirin, resveratrol and glycyrrhizic acid were all found to be inactive. The proton channel blocker amantadine produced some inhibition of HHV-6 replication at high (subtoxic) concentrations. Several currently used anti-epileptic drugs were shown to have no activity, or weak activity at subtoxic concentrations. In addition, we investigated several antiviral compounds which we previously identified as potently active against HHV-6, including non-nucleoside inhibitors such as CMV423 and acyclic nucleoside phosphonate compounds such as cidofovir. In the latter series, we observed a striking anti-HHV-6 activity for 9-(S)-[3-hydroxy-2(phosphonomethoxy)propyl]-3-deazaadenine, the effect being particulary pronounced in HHV-6-infected fresh cord blood lymphocytes. Conclusion: These data suggest that further optimization of compounds belonging to diverse classes of antiherpetic agents for their specific use against HHV-6 is warranted. This work was partly supported by the HHV-6 Foundation. 57 Antiviral activity of cyclopropavir and ether lipid esters of cidofovir against HHV6 and other human herpesviruses M.N. Prichard *. University of Alabama School of Medicine, Department of Pediatrics Division of Infectious Diseases, Birmingham, AL, USA E-mail address: [email protected] Background: Drugs with improved efficacy against human herpesvirus 6 (HHV-6) are needed to treat infections with this virus. Objectives: The antiviral activity of two series of compounds with activity against human cytomegalovirus was evaluated against HHV-6A, HHV-6B and other human herpesviruses. Study Design: Antiviral activity was determined against the GS strain of HHV-6A in HSB-2 cells and against the Z29 strain of HHV-6B in MOLT-3 cells. Viral replication was measured by flow cytometry or DNA hybridization against HHV-6A, HHV6B, and HHV8. Standard plaque reduction assays were used to determine antiviral activity for the other viruses. Results: Ether lipid esters of cidofovir (CDV) exhibited marked antiviral activity against HHV-6A and B, as well as the other human herpesviruses. While CDV yielded EC50 values of the 2.7 and 5.4 mM against the A and B variants, respectively, the hexadecyloxypropyl ester of CDV had EC50 values of 3 and 7 nM. This represented a several hundred-fold improvement in antiviral activity and is consistent with increased efficacy observed against other herpesviruses. These compounds are also highly active against other DNA viruses including the orthopoxviruses. A new series of methylenecyclopropane analogs also exhibited good antiviral activity against HHV-6. Of particular interest is cyclopropavir, which yielded EC50 values of 7.8 and 0.7 mM for A and B variants of HHV-6, respectively and 1.2 mM for human cytomegalovirus. The spectrum of activity of these analogs is more restricted than the CDV analogs and appears to be largely limited to the betaherpesviruses. Conclusions: Both these series of compounds warrant further evaluation and hold promise as potential therapies for the treatment of HHV-6 infections.
55 Is human herpesvirus 6 linked to histiocytic necrotizing lymphadenitis? S.-M. Choi *, S.H. Park, D.-G. Lee, J.-H. Choi, J.-H. Yoo, W.-S. Shin. Division of Infectious Diseases, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea E-mail address: [email protected] Background: Recently, human herpes virus-6 (HHV-6) has been proposed to be a viral cause of the histiocytic necrotizing lymphadenitis (HNL). Objectives: To detect the genome of herpesviridae in the specimens of the HNL and other forms of lymphadenitis. Study Design: PCR for EBV, CMV and HHV-6 was performed on lymph node (LN), serum and peripheral blood mononuclear cells (PBMC). Results: Pathologically, the diagnosis of the cases consisted of 9 HNL, 4 reactive hyperplasia (RH), 6 tuberculous lymphadenitis (TBL) and 1 metastatic adenocarcinoma. HHV-6 DNA was detected in 70% (14/20), while EBV DNA showed 65% (13/20) positivity in the LN. Both HHV-6 and EBV simultaneously showed positive signal in HNL and RH. In TBL, more cases were HHV-6 positive (66.7%, 4/6) than EBV (33.3%, 2/6). Only one case of RH and one case of TBL showed positive for EBV on serum and PBMC. Conclusions: These results indicate that the presence of HHV-6 genome is not specifically related to HNL, and that this virus could hibernate in a latent form in the LN. Rather, at least cooperative role of HHV-6 along with EBV might be possible in the event of awakening from latency in the LN.
Antivirals & Other Treatments 56 Antiviral activity of diverse classes of broad-acting agents and natural compounds in HHV-6-infected lymphoblasts L. Naesens *, E. De Clercq. Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium E-mail address: [email protected] Background: Replication of HHV-6 in its host cell results from complex and poorly understood interactions between viral and cellular factors. Objectives: In an attempt to discover new targets for antiviral therapy, we initiated a study with several classes of natural compounds or broadacting pharmacological agents. Study Design: The inhibitory effect on HHV-6 replication in T-lymphoblasts was determined in a 10-day assay, using HHV-6A (strain GS)-infected HSB-2 cells and HHV-6B (strain Z29)-infected MOLT-3 cells. Virus replication was quantified by microscopic evaluation of the cytopathic effect and by real-time PCR assay for HHV-6 DNA. Foscarnet, which produces a strong and reproducible
inhibition of HHV-6 replication, was included as the reference compound. Results: Among the 16 natural compounds tested, artemisinin was found to be inactive, while ‘red marine algae’ (an extract rich in polysulfated polysaccharides) was shown to have strong and selective activity when added during the initial virus adsorption stage. Among the broad-acting pharmacological agents, chloroquine, hypericin, ribavirin, resveratrol and glycyrrhizic acid were all found to be inactive. The proton channel blocker amantadine produced some inhibition of HHV-6 replication at high (subtoxic) concentrations. Several currently used anti-epileptic drugs were shown to have no activity, or weak activity at subtoxic concentrations. In addition, we investigated several antiviral compounds which we previously identified as potently active against HHV-6, including non-nucleoside inhibitors such as CMV423 and acyclic nucleoside phosphonate compounds such as cidofovir. In the latter series, we observed a striking anti-HHV-6 activity for 9-(S)-[3-hydroxy-2(phosphonomethoxy)propyl]-3-deazaadenine, the effect being particulary pronounced in HHV-6-infected fresh cord blood lymphocytes. Conclusion: These data suggest that further optimization of compounds belonging to diverse classes of antiherpetic agents for their specific use against HHV-6 is warranted. This work was partly supported by the HHV-6 Foundation. 57 Antiviral activity of cyclopropavir and ether lipid esters of cidofovir against HHV6 and other human herpesviruses M.N. Prichard *. University of Alabama School of Medicine, Department of Pediatrics Division of Infectious Diseases, Birmingham, AL, USA E-mail address: [email protected] Background: Drugs with improved efficacy against human herpesvirus 6 (HHV-6) are needed to treat infections with this virus. Objectives: The antiviral activity of two series of compounds with activity against human cytomegalovirus was evaluated against HHV-6A, HHV-6B and other human herpesviruses. Study Design: Antiviral activity was determined against the GS strain of HHV-6A in HSB-2 cells and against the Z29 strain of HHV-6B in MOLT-3 cells. Viral replication was measured by flow cytometry or DNA hybridization against HHV-6A, HHV6B, and HHV8. Standard plaque reduction assays were used to determine antiviral activity for the other viruses. Results: Ether lipid esters of cidofovir (CDV) exhibited marked antiviral activity against HHV-6A and B, as well as the other human herpesviruses. While CDV yielded EC50 values of the 2.7 and 5.4 mM against the A and B variants, respectively, the hexadecyloxypropyl ester of CDV had EC50 values of 3 and 7 nM. This represented a several hundred-fold improvement in antiviral activity and is consistent with increased efficacy observed against other herpesviruses. These compounds are also highly active against other DNA viruses including the orthopoxviruses. A new series of methylenecyclopropane analogs also exhibited good antiviral activity against HHV-6. Of particular interest is cyclopropavir, which yielded EC50 values of 7.8 and 0.7 mM for A and B variants of HHV-6, respectively and 1.2 mM for human cytomegalovirus. The spectrum of activity of these analogs is more restricted than the CDV analogs and appears to be largely limited to the betaherpesviruses. Conclusions: Both these series of compounds warrant further evaluation and hold promise as potential therapies for the treatment of HHV-6 infections.