Browsing by Author "Knezevic, Aleksandra (22034890600)"

Until now, the treatment protocols for COVID-19 have been revised multiple times. The use and approval of therapeutic monoclonal antibodies (mAbs) for COVID-19 treatment represent exceptional achievements in modern science, technology and medicine. SARS-CoV-2 Omicron evasion of pre-existing immunity represents a serious public health problem nowadays. This systematic review with meta-analysis provided comprehensive and up-to-date evidence of the clinical efficacy of therapeutic anti-SARS-CoV-2 mAbs against Omicron subvariants in COVID-19 patients and included 10 articles. The prevalence of hospitalisation among Omicron-positive patients treated with anti-SARS-CoV-2 mAbs was 2.8% (89/3169) while it controls (Omicron-positive patients treated with other therapies) 11% (154/1371). There was a statistically significantly different number of hospitalisations between the two studied groups in favour of the anti-SARS-CoV-2 mAbs treated group. (OR = 0.56, 95% CI OR = 0.41–0.77, p < 0.001, respectively). Eight deaths (0.30%) out of 2619 Omicron-positive patients occurred in the anti-SARS-CoV-2 mAbs treated group, while in the control group (Omicron-positive patients treated with other therapies), 27 patients died out of 1401 (1.93%). There was a significantly different number of deaths between the two studied groups in favour of Omicron-positive patients treated with anti-SARS-CoV-2 mAbs (OR = 0.38, 95% CI OR = 0.17–0.85, p = 0.020). Using sotrovimab in treating Omicron-positive patients indicated a reduction of hospitalisation and mortality for 49% and 89% in favour of sotrovimab, respectively (OR = 0.51, 95% CI OR = 0.34–0.79, p = 0.002; OR = 0.11, 95% CI OR = 0.03–0.39, p = 0.001). We could only provide evidence of the positive impact in reducing hospitalisation and mortality rates when anti-SARS-CoV-2 mAbs were used to treat patients infected with Omicron variants BA.1 or BA.2 and not on other Omicron variants. © 2023 John Wiley & Sons Ltd.

Until now, the treatment protocols for COVID-19 have been revised multiple times. The use and approval of therapeutic monoclonal antibodies (mAbs) for COVID-19 treatment represent exceptional achievements in modern science, technology and medicine. SARS-CoV-2 Omicron evasion of pre-existing immunity represents a serious public health problem nowadays. This systematic review with meta-analysis provided comprehensive and up-to-date evidence of the clinical efficacy of therapeutic anti-SARS-CoV-2 mAbs against Omicron subvariants in COVID-19 patients and included 10 articles. The prevalence of hospitalisation among Omicron-positive patients treated with anti-SARS-CoV-2 mAbs was 2.8% (89/3169) while it controls (Omicron-positive patients treated with other therapies) 11% (154/1371). There was a statistically significantly different number of hospitalisations between the two studied groups in favour of the anti-SARS-CoV-2 mAbs treated group. (OR = 0.56, 95% CI OR = 0.41–0.77, p < 0.001, respectively). Eight deaths (0.30%) out of 2619 Omicron-positive patients occurred in the anti-SARS-CoV-2 mAbs treated group, while in the control group (Omicron-positive patients treated with other therapies), 27 patients died out of 1401 (1.93%). There was a significantly different number of deaths between the two studied groups in favour of Omicron-positive patients treated with anti-SARS-CoV-2 mAbs (OR = 0.38, 95% CI OR = 0.17–0.85, p = 0.020). Using sotrovimab in treating Omicron-positive patients indicated a reduction of hospitalisation and mortality for 49% and 89% in favour of sotrovimab, respectively (OR = 0.51, 95% CI OR = 0.34–0.79, p = 0.002; OR = 0.11, 95% CI OR = 0.03–0.39, p = 0.001). We could only provide evidence of the positive impact in reducing hospitalisation and mortality rates when anti-SARS-CoV-2 mAbs were used to treat patients infected with Omicron variants BA.1 or BA.2 and not on other Omicron variants. © 2023 John Wiley & Sons Ltd.

Disseminated neonatal herpes simplex virus (HSV) infection is characterized by progressive multiple organ failure and high mortality rates. It can result from infection with either HSV-1 or HSV-2. We report a case of disseminated neonatal herpes that was caused by HSV-1 and HSV-2.

Certain factors lead to increased reactivation of JC virus (JCV) and immunodeficiency seems to be the most important. JCV isolates can be classified into eight different genotypes and several subtypes based on nucleotide difference in the VP1 gene. JCV genotypes are strongly associated with particular ethnic groups and frequently used as genetic markers for human evolution and migration. The aim of this study was to determine the frequency of JCV urinary shedding and genotype distribution in Serbia among patients infected with HIV and healthy donors. Urine samples from 107 healthy donors and 93 patients infected with HIV were collected. PCR followed by sequence analysis was carried out using primers specific for VP1 and NCRR of the virus genome. Excretion rate of JCV-DNA in urine was higher in patients infected with HIV than in healthy donors (44.1% vs. 31.7%) although statistical significance was not found. Within the group infected with HIV, the degree of immunosuppression (measured by CD4+ cell count) did not influence JCV excretion rate. Sequence analysis of JCV NCRR from both patients infected with HIV and healthy donors showed a pattern identical to archetype structure. In healthy Serbian donors the predominant genotype was 1 (41.2%), followed by 4 (32.4%) and 2 (26.4%). On the other hand, genotype distribution pattern was different in patients infected with HIV: 2 (43.9%), 1 (31.7%), and 4 (24.4%). This study showed that European, Eurasian, and Indian types are circulating in Serbia and that distribution corresponds to the origin of the inhabitants of Serbia. J. Med. Virol. 86:411-418, 2014. © 2013 Wiley Periodicals, Inc.

Certain factors lead to increased reactivation of JC virus (JCV) and immunodeficiency seems to be the most important. JCV isolates can be classified into eight different genotypes and several subtypes based on nucleotide difference in the VP1 gene. JCV genotypes are strongly associated with particular ethnic groups and frequently used as genetic markers for human evolution and migration. The aim of this study was to determine the frequency of JCV urinary shedding and genotype distribution in Serbia among patients infected with HIV and healthy donors. Urine samples from 107 healthy donors and 93 patients infected with HIV were collected. PCR followed by sequence analysis was carried out using primers specific for VP1 and NCRR of the virus genome. Excretion rate of JCV-DNA in urine was higher in patients infected with HIV than in healthy donors (44.1% vs. 31.7%) although statistical significance was not found. Within the group infected with HIV, the degree of immunosuppression (measured by CD4+ cell count) did not influence JCV excretion rate. Sequence analysis of JCV NCRR from both patients infected with HIV and healthy donors showed a pattern identical to archetype structure. In healthy Serbian donors the predominant genotype was 1 (41.2%), followed by 4 (32.4%) and 2 (26.4%). On the other hand, genotype distribution pattern was different in patients infected with HIV: 2 (43.9%), 1 (31.7%), and 4 (24.4%). This study showed that European, Eurasian, and Indian types are circulating in Serbia and that distribution corresponds to the origin of the inhabitants of Serbia. J. Med. Virol. 86:411-418, 2014. © 2013 Wiley Periodicals, Inc.

Chronic inflammatory processes in periapical tissues caused by etiological agents of endodontic origin lead to apical periodontitis. Apart from bacteria, two herpesviruses, Epstein-Barr virus (EBV) and Human cytomegalovirus (HCMV) are recognized as putative pathogens in apical periodontitis. Although previous reports suggest the involvement of EBV in the pathogenesis of apical periodontitis, its exact role in periapical bone resorption has not yet been fully elucidated. We hypothesize that EBV infection in apical periodontitis is capable of inducing periapical bone resorption via stimulation of reactive oxygen species (ROS) overproduction. Increased levels of ROS induce expression of receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL). RANKL binding to receptor activator of nuclear factor κB (RANK) present on the surface of preosteoclasts induces their maturation and activation which consequently leads to bone resorption. The potential benefit of antiviral and antioxidant-based therapies in periapical bone resorption treatment remains to be assessed. © 2016 Elsevier Ltd

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the COVID-19 pandemic, has been evolving rapidly causing emergence of new variants and health uncertainties. Monitoring the evolution of the virus was of the utmost importance for public health interventions and the development of national and global mitigation strategies. Here, we report national data on the emergence of new variants, their distribution, and dynamics in a 3-year study conducted from March 2020 to the end of January 2023 in the Republic of Serbia. Nasopharyngeal and oropharyngeal swabs from 2,398 COVID-19-positive patients were collected and sequenced using three different next generation technologies: Oxford Nanopore, Ion Torrent, and DNBSeq. In the subset of 2,107 SARS-CoV-2 sequences which met the quality requirements, detection of mutations, assignment to SARS-CoV-2 lineages, and phylogenetic analysis were performed. During the 3-year period, we detected three variants of concern, namely, Alpha (5.6%), Delta (7.4%), and Omicron (70.3%) and one variant of interest—Omicron recombinant “Kraken” (XBB1.5) (<1%), whereas 16.8% of the samples belonged to other SARS-CoV-2 (sub)lineages. The detected SARS-CoV-2 (sub)lineages resulted in eight COVID-19 pandemic waves in Serbia, which correspond to the pandemic waves reported in Europe and the United States. Wave dynamics in Serbia showed the most resemblance with the profile of pandemic waves in southern Europe, consistent with the southeastern European location of Serbia. The samples were assigned to sixteen SARS-CoV-2 Nextstrain clades: 20A, 20B, 20C, 20D, 20E, 20G, 20I, 21J, 21K, 21L, 22A, 22B, 22C, 22D, 22E, and 22F and six different Omicron recombinants (XZ, XAZ, XAS, XBB, XBF, and XBK). The 10 most common mutations detected in the coding and untranslated regions of the SARS-CoV-2 genomes included four mutations affecting the spike protein (S:D614G, S:T478K, S:P681H, and S:S477N) and one mutation at each of the following positions: 5′-untranslated region (5’UTR:241); N protein (N:RG203KR); NSP3 protein (NSP3:F106F); NSP4 protein (NSP4:T492I); NSP6 protein (NSP6: S106/G107/F108 - triple deletion), and NSP12b protein (NSP12b:P314L). This national-level study is the most comprehensive in terms of sequencing and genomic surveillance of SARS-CoV-2 during the pandemic in Serbia, highlighting the importance of establishing and maintaining good national practice for monitoring SARS-CoV-2 and other viruses circulating worldwide. Copyright © 2024 Novkovic, Banovic Djeri, Ristivojevic, Knezevic, Jankovic, Tanasic, Radojicic, Keckarevic, Vidanovic, Tesovic, Skakic, Tolinacki, Moric and Djordjevic.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the COVID-19 pandemic, has been evolving rapidly causing emergence of new variants and health uncertainties. Monitoring the evolution of the virus was of the utmost importance for public health interventions and the development of national and global mitigation strategies. Here, we report national data on the emergence of new variants, their distribution, and dynamics in a 3-year study conducted from March 2020 to the end of January 2023 in the Republic of Serbia. Nasopharyngeal and oropharyngeal swabs from 2,398 COVID-19-positive patients were collected and sequenced using three different next generation technologies: Oxford Nanopore, Ion Torrent, and DNBSeq. In the subset of 2,107 SARS-CoV-2 sequences which met the quality requirements, detection of mutations, assignment to SARS-CoV-2 lineages, and phylogenetic analysis were performed. During the 3-year period, we detected three variants of concern, namely, Alpha (5.6%), Delta (7.4%), and Omicron (70.3%) and one variant of interest—Omicron recombinant “Kraken” (XBB1.5) (<1%), whereas 16.8% of the samples belonged to other SARS-CoV-2 (sub)lineages. The detected SARS-CoV-2 (sub)lineages resulted in eight COVID-19 pandemic waves in Serbia, which correspond to the pandemic waves reported in Europe and the United States. Wave dynamics in Serbia showed the most resemblance with the profile of pandemic waves in southern Europe, consistent with the southeastern European location of Serbia. The samples were assigned to sixteen SARS-CoV-2 Nextstrain clades: 20A, 20B, 20C, 20D, 20E, 20G, 20I, 21J, 21K, 21L, 22A, 22B, 22C, 22D, 22E, and 22F and six different Omicron recombinants (XZ, XAZ, XAS, XBB, XBF, and XBK). The 10 most common mutations detected in the coding and untranslated regions of the SARS-CoV-2 genomes included four mutations affecting the spike protein (S:D614G, S:T478K, S:P681H, and S:S477N) and one mutation at each of the following positions: 5′-untranslated region (5’UTR:241); N protein (N:RG203KR); NSP3 protein (NSP3:F106F); NSP4 protein (NSP4:T492I); NSP6 protein (NSP6: S106/G107/F108 - triple deletion), and NSP12b protein (NSP12b:P314L). This national-level study is the most comprehensive in terms of sequencing and genomic surveillance of SARS-CoV-2 during the pandemic in Serbia, highlighting the importance of establishing and maintaining good national practice for monitoring SARS-CoV-2 and other viruses circulating worldwide. Copyright © 2024 Novkovic, Banovic Djeri, Ristivojevic, Knezevic, Jankovic, Tanasic, Radojicic, Keckarevic, Vidanovic, Tesovic, Skakic, Tolinacki, Moric and Djordjevic.

Purpose of Review: This review describes the most recent findings on herpesviral infections and offers current concepts of herpesviral role in the pathogenesis of periapical periodontitis. Recent Findings: Thirty articles reported data on herpesviral infection in periapical periodontitis. Epstein-Barr virus and human cytomegalovirus are the most frequently detected herpesviruses in periapical samples. The main hypothesis postulates a bidirectional herpesviral-bacterial relationship in the etiopathogenesis of periapical periodontitis. A high heterogeneity of herpesviruses incidence was registered within the studies, in part, due to various methodological approaches used in laboratory testing, different inclusion criteria, study design, seroprevalence of herpesviruses, and sociodemographic characteristics of investigated populations. Summary: Herpesviruses have been shown to potentially impair local host defense in periapical tissue. Although it has been demonstrated that endodontic pathogenic bacteria are able to reactivate herpesviruses, further, in vitro studies should provide more data on herpesviruses as a factor in the pathogenesis of the periapical pathoses. It is, therefore, necessary to investigate potential benefits of antiviral therapy in well-designed controlled longitudinal studies. © 2018, Springer Nature Switzerland AG.

Purpose of Review: This review describes the most recent findings on herpesviral infections and offers current concepts of herpesviral role in the pathogenesis of periapical periodontitis. Recent Findings: Thirty articles reported data on herpesviral infection in periapical periodontitis. Epstein-Barr virus and human cytomegalovirus are the most frequently detected herpesviruses in periapical samples. The main hypothesis postulates a bidirectional herpesviral-bacterial relationship in the etiopathogenesis of periapical periodontitis. A high heterogeneity of herpesviruses incidence was registered within the studies, in part, due to various methodological approaches used in laboratory testing, different inclusion criteria, study design, seroprevalence of herpesviruses, and sociodemographic characteristics of investigated populations. Summary: Herpesviruses have been shown to potentially impair local host defense in periapical tissue. Although it has been demonstrated that endodontic pathogenic bacteria are able to reactivate herpesviruses, further, in vitro studies should provide more data on herpesviruses as a factor in the pathogenesis of the periapical pathoses. It is, therefore, necessary to investigate potential benefits of antiviral therapy in well-designed controlled longitudinal studies. © 2018, Springer Nature Switzerland AG.

We investigated the role of autophagy, a stress-inducible lysosomal self-digestion of cellular components, in modulation of herpes simplex virus type 1 (HSV-1)-triggered death of U251 human glioma cells. HSV-1 caused apoptotic death in U251 cells, characterized by phosphatidylserine externalization, caspase activation and DNA fragmentation. HSV-1-induced apoptosis was associated with the induction of autophagic response, as confirmed by the conversion of cytosolic LC3-I to autophagosome-associated LC3-II, increase in intracellular acidification, presence of autophagic vesicles, and increase in proteolysis of the selective autophagic target p62. HSV-1-triggered autophagy was not associated with the significant increase in the expression of proautophagic protein beclin-1 or downregulation of the major autophagy suppressor mammalian target of rapamycin (mTOR). Moreover, the phosphorylation of mTOR and its direct substrate p70 S6 kinase was augmented by HSV-1 infection, while the mTOR stimulator Akt and inhibitor AMPK-activated protein kinase (AMPK) were accordingly activated and suppressed, respectively. An shRNA-mediated knockdown of the autophagy-essential LC3β, as well as pharmacological inhibition of autophagy with bafilomycin A1 or 3-methyladenine, markedly accelerated apoptotic changes and ensuing cell death in HSV-1-infected glioma cells. These data indicate that AMPK/Akt/mTOR-independent autophagy could prolong survival of HSV-1-infected U251 glioma cells by counteracting the coinciding apoptotic response. © 2013 Institut Pasteur.

We investigated the role of autophagy, a stress-inducible lysosomal self-digestion of cellular components, in modulation of herpes simplex virus type 1 (HSV-1)-triggered death of U251 human glioma cells. HSV-1 caused apoptotic death in U251 cells, characterized by phosphatidylserine externalization, caspase activation and DNA fragmentation. HSV-1-induced apoptosis was associated with the induction of autophagic response, as confirmed by the conversion of cytosolic LC3-I to autophagosome-associated LC3-II, increase in intracellular acidification, presence of autophagic vesicles, and increase in proteolysis of the selective autophagic target p62. HSV-1-triggered autophagy was not associated with the significant increase in the expression of proautophagic protein beclin-1 or downregulation of the major autophagy suppressor mammalian target of rapamycin (mTOR). Moreover, the phosphorylation of mTOR and its direct substrate p70 S6 kinase was augmented by HSV-1 infection, while the mTOR stimulator Akt and inhibitor AMPK-activated protein kinase (AMPK) were accordingly activated and suppressed, respectively. An shRNA-mediated knockdown of the autophagy-essential LC3β, as well as pharmacological inhibition of autophagy with bafilomycin A1 or 3-methyladenine, markedly accelerated apoptotic changes and ensuing cell death in HSV-1-infected glioma cells. These data indicate that AMPK/Akt/mTOR-independent autophagy could prolong survival of HSV-1-infected U251 glioma cells by counteracting the coinciding apoptotic response. © 2013 Institut Pasteur.

Background: Oral reactivation of latent Herpes simplex virus (HSV) infection may easily occur in cancer patients. Virus reactivation can cause oral mucosa damage, worsen already existing lesions caused by stomatotoxic effect of cancer therapy and, whether symptomatic or asymptomatic, ample spreading and promote viral transmission. Methods: Polymerase chain reaction (PCR), cell-culture and direct immunofluorescence have been used to determine the frequency of oral HSV reactivation in 60 patients undergoing chemotherapy for different malignancies. Results: By means of PCR, the presence of viral DNA was detected in 71.7% of patients prior to chemotherapy and in 85.0% after chemotherapy. 33.3% of patients before and 40.0% after chemotherapy were viral-culture positive, while 3.3% of patients before and 11.7% after chemotherapy were positive as shown by direct immunofluorescence. No significant difference in HSV-1 reactivation was found before and after chemotherapy. In addition, no significant difference was found when comparing HSV-1 reactivation in patients with and without mucositis. HSV-2 was not detected in any of the patients. Conclusions: Reactivation of latent HSV is exceptionally frequent in cancer patients. The results of this study suggest that virus reactivation occurs independently of cancer chemotherapy. The potential role of HSV reactivation in oral mucosa damage remains unclear. © 2008 Blackwell Munksgaard.

Background: Oral reactivation of latent Herpes simplex virus (HSV) infection may easily occur in cancer patients. Virus reactivation can cause oral mucosa damage, worsen already existing lesions caused by stomatotoxic effect of cancer therapy and, whether symptomatic or asymptomatic, ample spreading and promote viral transmission. Methods: Polymerase chain reaction (PCR), cell-culture and direct immunofluorescence have been used to determine the frequency of oral HSV reactivation in 60 patients undergoing chemotherapy for different malignancies. Results: By means of PCR, the presence of viral DNA was detected in 71.7% of patients prior to chemotherapy and in 85.0% after chemotherapy. 33.3% of patients before and 40.0% after chemotherapy were viral-culture positive, while 3.3% of patients before and 11.7% after chemotherapy were positive as shown by direct immunofluorescence. No significant difference in HSV-1 reactivation was found before and after chemotherapy. In addition, no significant difference was found when comparing HSV-1 reactivation in patients with and without mucositis. HSV-2 was not detected in any of the patients. Conclusions: Reactivation of latent HSV is exceptionally frequent in cancer patients. The results of this study suggest that virus reactivation occurs independently of cancer chemotherapy. The potential role of HSV reactivation in oral mucosa damage remains unclear. © 2008 Blackwell Munksgaard.