@article{KasangKalluvyaMajingeetal.2016,
  author    = {Kasang, Christa and Kalluvya, Samuel and Majinge, Charles and Kongola, Gilbert and Mlewa, Mathias and Massawe, Irene and Kabyemera, Rogatus and Magambo, Kinanga and Ulmer, Albrecht and Klinker, Hartwig and Gschmack, Eva and Horn, Anne and Koutsilieri, Eleni and Preiser, Wolfgang and Hofmann, Daniela and Hain, Johannes and M{\"u}ller, Andreas and D{\"o}lken, Lars and Weissbrich, Benedikt and Rethwilm, Axel and Stich, August and Scheller, Carsten},
  title     = {Effects of Prednisolone on Disease Progression in Antiretroviral-Untreated HIV Infection: A 2-Year Randomized, Double-Blind Placebo-Controlled Clinical Trial},
  series = {PLoS One},
  volume    = {11},
  journal   = {PLoS One},
  number    = {1},
  doi       = {10.1371/journal.pone.0146678},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146479},
  pages     = {e0146678},
  year      = {2016},
  abstract  = {Background HIV-disease progression correlates with immune activation. Here we investigated whether corticosteroid treatment can attenuate HIV disease progression in antiretroviral-untreated patients. Methods Double-blind, placebo-controlled randomized clinical trial including 326 HIV-patients in a resource-limited setting in Tanzania (clinicaltrials.gov NCT01299948). Inclusion criteria were a CD4 count above 300 cells/μl, the absence of AIDS-defining symptoms and an ART-na{\"i}ve therapy status. Study participants received 5 mg prednisolone per day or placebo for 2 years. Primary endpoint was time to progression to an AIDS-defining condition or to a CD4-count below 200 cells/μl. Results No significant change in progression towards the primary endpoint was observed in the intent-to-treat (ITT) analysis (19 cases with prednisolone versus 28 cases with placebo, p = 0.1407). In a per-protocol (PP)-analysis, 13 versus 24 study participants progressed to the primary study endpoint (p = 0.0741). Secondary endpoints: Prednisolone-treatment decreased immune activation (sCD14, suPAR, CD38/HLA-DR/CD8+) and increased CD4-counts (+77.42 ± 5.70 cells/μl compared to -37.42 ± 10.77 cells/μl under placebo, p < 0.0001). Treatment with prednisolone was associated with a 3.2-fold increase in HIV viral load (p < 0.0001). In a post-hoc analysis stratifying for sex, females treated with prednisolone progressed significantly slower to the primary study endpoint than females treated with placebo (ITT-analysis: 11 versus 21 cases, p = 0.0567; PP-analysis: 5 versus 18 cases, p = 0.0051): No changes in disease progression were observed in men. Conclusions This study could not detect any significant effects of prednisolone on disease progression in antiretroviral-untreated HIV infection within the intent-to-treat population. However, significant effects were observed on CD4 counts, immune activation and HIV viral load. This study contributes to a better understanding of the role of immune activation in the pathogenesis of HIV infection.},
  language  = {en}
}
@article{OberlaenderPletinckxDaehleretal.2011,
  author    = {Oberl{\"a}nder, Uwe and Pletinckx, Katrien and D{\"a}hler, Anja and M{\"u}ller, Nora and Lutz, Manfred and Arzberger, Thomas and Riederer, Peter and Gerlach, Manfred and Koutsilieri, Eleni and Scheller, Carsten},
  title     = {Neuromelanin is an Immune Stimulator for Dendritic Cells in vitro},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-69210},
  year      = {2011},
  abstract  = {Background: Parkinson's disease (PD) is characterized at the cellular level by a destruction of neuromelanin (NM)-containing dopaminergic cells and a profound reduction in striatal dopamine. It has been shown recently that antimelanin antibodies are increased in sera of Parkinson patients, suggesting that NM may act as an autoantigen. In this study we tested whether NM is being recognized by dendritic cells (DCs), the major cell type for inducing Tand B-cell responses in vivo. This recognition of NM by DCs is a prerequisite to trigger an adaptive autoimmune response directed against NM-associated structures. Results: Murine DCs were treated with NM of substantia nigra (SN) from human subjects or with synthetic dopamine melanin (DAM). DCs effectively phagocytized NM and subsequently developed a mature phenotype (CD86high/MHCIIhigh). NM-activated DCs secreted the proinflammatory cytokines IL-6 and TNF-a. In addition, they potently triggered T cell proliferation in a mixed lymphocyte reaction, showing that DC activation was functional to induce a primary T cell response. In contrast, DAM, which lacks the protein and lipid components of NM but mimics the dopamine-melanin backbone of NM, had only very little effect on DC phenotype and function. Conclusions: NM is recognized by DCs in vitro and triggers their maturation. If operative in vivo, this would allow the DC-mediated transport and presentation of SN antigens to the adaptive immune system, leading to autoimmmunity in susceptible individuals. Our data provide a rationale for an autoimmune-based pathomechanism of PD with NM as the initial trigger.},
  subject      = {Immunstimulation},
  language  = {en}
}
@article{KasangKalluvyaMajingeetal.2011,
  author    = {Kasang, Christa and Kalluvya, Samuel and Majinge, Charles and Stich, August and Bodem, Jochen and Kongola, Gilbert and Jacobs, Graeme B. and Mllewa, Mathias and Mildner, Miriam and Hensel, Irina and Horn, Anne and Preiser, Wolfgang and van Zyl, Gert and Klinker, Hartwig and Koutsilieri, Eleni and Rethwilm, Axel and Scheller, Carsten and Weissbrich, Benedikt},
  title     = {HIV drug resistance (HIVDR) in antiretroviral therapy-naive patients in Tanzania not eligible for WHO threshold HIVDR survey is dramatically high},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-69024},
  year      = {2011},
  abstract  = {Background: The World Health Organization (WHO) has recommended guidelines for a HIV drug resistance (HIVDR) survey for resource-limited countries. Eligibility criteria for patients include age below 25 years in order to focus on the prevalence of transmitted HIVDR (tHIVDR) in newly-infected individuals. Most of the participating sites across Africa have so far reported tHIVDR prevalences of below 5\%. In this study we investigated whether the rate of HIVDR in patients ,25 years is representative for HIVDR in the rest of the therapy-naive population. Methods and Findings: HIVDR was determined in 88 sequentially enrolled ART-naive patients from Mwanza, Tanzania (mean age 35.4 years). Twenty patients were aged, 25 years and 68 patients were aged 25-63 years. The frequency of HIVDR in the study population was 14.8\% (95\%; CI 0.072-0.223) and independent of NVP-resistance induced by prevention of mother-to-child transmission programs. Patients .25 years had a significantly higher HIVDR frequency than younger patients (19.1\%; 95\% CI 0.095-0.28) versus 0\%, P = 0.0344). In 2 out of the 16 patients with HIVDR we found traces of antiretrovirals (ARVs) in plasma. Conclusions: ART-naive patients aged over 25 years exhibited significantly higher HIVDR than younger patients. Detection of traces of ARVs in individuals with HIVDR suggests that besides transmission, undisclosed misuse of ARVs may constitute a significant factor in the generation of the observed high HIVDR rate. The current WHO tHIVDR survey that is solely focused on the transmission of HIVDR and that excludes patients over 25 years of age may therefore result in substantial underestimation of the prevalence of HIVDR in the therapy-naive population. Similar studies should be performed also in other areas to test whether the so far reported optimistic picture of low HIVDR prevalence in young individuals is really representative for the rest of the ART-naive HIV-infected population.},
  subject      = {Tansania},
  language  = {en}
}
@article{KasangKalluvyaMajingeetal.2011,
  author    = {Kasang, Christa and Kalluvya, Samuel and Majinge, Charles and Stich, August and Bodem, Jochen and Kongola, Gilbert and Jacobs, Graeme B. and Mlewa, Mathias and Mildner, Miriam and Hensel, Irina and Horn, Anne and Preiser, Wolfgang and van Zyl, Gert and Klinker, Hartwig and Koutsilieri, Eleni and Rethwilm, Axel and Scheller, Carsten and Weissbrich, Benedikt},
  title     = {HIV Drug Resistance (HIVDR) in Antiretroviral Therapy-Na{\"i}ve Patients in Tanzania Not Eligible for WHO Threshold HIVDR Survey Is Dramatically High},
  series = {PLoS One},
  volume    = {6},
  journal   = {PLoS One},
  number    = {8},
  doi       = {10.1371/journal.pone.0023091},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137988},
  pages     = {e23091},
  year      = {2011},
  abstract  = {Background The World Health Organization (WHO) has recommended guidelines for a HIV drug resistance (HIVDR) survey for resource-limited countries. Eligibility criteria for patients include age below 25 years in order to focus on the prevalence of transmitted HIVDR (tHIVDR) in newly-infected individuals. Most of the participating sites across Africa have so far reported tHIVDR prevalences of below 5\%. In this study we investigated whether the rate of HIVDR in patients <25 years is representative for HIVDR in the rest of the therapy-na{\"i}ve population. Methods and Findings HIVDR was determined in 88 sequentially enrolled ART-na{\"i}ve patients from Mwanza, Tanzania (mean age 35.4 years). Twenty patients were aged <25 years and 68 patients were aged 25-63 years. The frequency of HIVDR in the study population was 14.8\% (95\%; CI 0.072-0.223) and independent of NVP-resistance induced by prevention of mother-to-child transmission programs. Patients >25 years had a significantly higher HIVDR frequency than younger patients (19.1\%; 95\% CI 0.095-0.28) versus 0\%, P = 0.0344). In 2 out of the 16 patients with HIVDR we found traces of antiretrovirals (ARVs) in plasma. Conclusions ART-na{\"i}ve patients aged over 25 years exhibited significantly higher HIVDR than younger patients. Detection of traces of ARVs in individuals with HIVDR suggests that besides transmission, undisclosed misuse of ARVs may constitute a significant factor in the generation of the observed high HIVDR rate. The current WHO tHIVDR survey that is solely focused on the transmission of HIVDR and that excludes patients over 25 years of age may therefore result in substantial underestimation of the prevalence of HIVDR in the therapy-na{\"i}ve population. Similar studies should be performed also in other areas to test whether the so far reported optimistic picture of low HIVDR prevalence in young individuals is really representative for the rest of the ART-na{\"i}ve HIV-infected population.},
  language  = {en}
}
@article{HornSchellerduPlessisetal.2013,
  author    = {Horn, Anne and Scheller, Carsten and du Plessis, Stefan and Arendt, Gabriele and Nolting, Thorsten and Joska, John and Sopper, Sieghart and Maschke, Matthias and Obermann, Mark and Husstedt, Ingo W. and Hain, Johannes and Maponga, Tongai and Riederer, Peter and Koutsilieri, Eleni},
  title     = {Increases in CSF dopamine in HIV patients are due to the dopamine transporter 10/10-repeat allele which is more frequent in HIV-infected individuals},
  series = {Journal of Neural Transmission},
  volume    = {120},
  journal   = {Journal of Neural Transmission},
  doi       = {10.1007/s00702-013-1086-x},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132385},
  pages     = {1411-1419},
  year      = {2013},
  abstract  = {Dysfunction of dopaminergic neurotransmission has been implicated in HIV infection. We showed previously increased dopamine (DA) levels in CSF of therapy-na{\"i}ve HIV patients and an inverse correlation between CSF DA and CD4 counts in the periphery, suggesting adverse effects of high levels of DA on HIV infection. In the current study including a total of 167 HIV-positive and negative donors from Germany and South Africa (SA), we investigated the mechanistic background for the increase of CSF DA in HIV individuals. Interestingly, we found that the DAT 10/10-repeat allele is present more frequently within HIV individuals than in uninfected subjects. Logistic regression analysis adjusted for gender and ethnicity showed an odds ratio for HIV infection in DAT 10/10 allele carriers of 3.93 (95 \% CI 1.72-8.96; p = 0.001, Fishers exact test). 42.6 \% HIV-infected patients harbored the DAT 10/10 allele compared to only 10.5 \% uninfected DAT 10/10 carriers in SA (odds ratio 6.31), whereas 68.1 versus 40.9 \%, respectively, in Germany (odds ratio 3.08). Subjects homozygous for the 10-repeat allele had higher amounts of CSF DA and reduced DAT mRNA expression but similar disease severity compared with those carrying other DAT genotypes. These intriguing and novel findings show the mutual interaction between DA and HIV, suggesting caution in the interpretation of CNS DA alterations in HIV infection solely as a secondary phenomenon to the virus and open the door for larger studies investigating consequences of the DAT functional polymorphism on HIV epidemiology and progression of disease.},
  language  = {en}
}
@article{ProttengeierKoutsilieriScheller2014,
  author    = {Prottengeier, Johannes and Koutsilieri, Eleni and Scheller, Carsten},
  title     = {The effects of opioids on HIV reactivation in latently-infected T-lymphoblasts},
  series = {AIDS Research and Therapy},
  volume    = {11},
  journal   = {AIDS Research and Therapy},
  number    = {17},
  issn      = {1742-6405},
  doi       = {10.1186/1742-6405-11-17},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115860},
  year      = {2014},
  abstract  = {Background: Opioids may have effects on susceptibility to HIV-infection, viral replication and disease progression. Injecting drug users (IDU), as well as anyone receiving opioids for anesthesia and analgesia may suffer the clinical consequences of such interactions. There is conflicting data between in vitro experiments showing an enhancing effect of opioids on HIV replication and clinical data, mostly showing no such effect. For clarification we studied the effects of the opioids heroin and morphine on HIV replication in cultured CD4-positive T cells at several concentrations and we related the observed effects with the relevant reached plasma concentrations found in IDUs. Methods: Latently-infected ACH-2 T lymphoblasts were incubated with different concentrations of morphine and heroine. Reactivation of HIV was assessed by intracellular staining of viral Gag p24 protein and subsequent flow cytometric quantification of p24-positive cells. The influence of the opioid antagonist naloxone and the antioxidants N-acetyl-cysteine (NAC) and glutathione (GSH) on HIV reactivation was determined. Cell viability was investigated by 7-AAD staining and flow cytometric quantification. Results: Morphine and heroine triggered reactivation of HIV replication in ACH-2 cells in a dose-dependent manner at concentrations above 1 mM (EC50 morphine 2.82 mM; EC50 morphine 1.96 mM). Naloxone did not interfere with heroine-mediated HIV reactivation, even at high concentrations (1 mM). Opioids also triggered necrotic cell death at similar concentrations at which HIV reactivation was observed. Both opioid-mediated reactivation of HIV and opioid-triggered cell death could be inhibited by the antioxidants GSH and NAC. Conclusions: Opioids reactivate HIV in vitro but at concentrations that are far above the plasma levels of analgesic regimes or drug concentrations found in IDUs. HIV reactivation was mediated by effects unrelated to opioid-receptor activation and was tightly linked to the cytotoxic activity of the substances at millimolar concentrations, suggesting that opioid-mediated reactivation of HIV was due to accompanying effects of cellular necrosis such as activation of reactive oxygen species and NF-kB.},
  language  = {en}
}
@article{KasangUlmerDonhauseretal.2012,
  author    = {Kasang, Christa and Ulmer, Albrecht and Donhauser, Norbert and Schmidt, Barabara and Stich, August and Klinker, Hartwig and Kalluvya, Samuel and Koutsilieri, Eleni and Rethwilm, Axel and Scheller, Carsten},
  title     = {HIV patients treated with low-dose prednisolone exhibit lower immune activation than untreated patients},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75100},
  year      = {2012},
  abstract  = {Background: HIV-associated general immune activation is a strong predictor for HIV disease progression, suggesting that chronic immune activation may drive HIV pathogenesis. Consequently, immunomodulating agents may decelerate HIV disease progression. Methods: In an observational study, we determined immune activation in HIV patients receiving low-dose (5 mg/day) prednisolone with or without highly-active antiretroviral therapy (HAART) compared to patients without prednisolone treatment. Lymphocyte activation was determined by flow cytometry detecting expression of CD38 on CD8(+) T cells. The monocyte activation markers sCD14 and LPS binding protein (LBP) as well as inflammation markers soluble urokinase plasminogen activated receptor (suPAR) and sCD40L were determined from plasma by ELISA. Results: CD38-expression on CD8+ T lymphocytes was significantly lower in prednisolone-treated patients compared to untreated patients (median 55.40\% [percentile range 48.76-67.70] versus 73.34\% [65.21-78.92], p = 0.0011, Mann-Whitney test). Similarly, we detected lower levels of sCD14 (3.6 μg/ml [2.78-5.12] vs. 6.11 μg/ml [4.58-7.70]; p = 0.0048), LBP (2.18 ng/ml [1.59-2.87] vs. 3.45 ng/ml [1.84-5.03]; p = 0.0386), suPAR antigen (2.17 μg/ml [1.65-2.81] vs. 2.56 μg/ml [2.24-4.26]; p = 0.0351) and a trend towards lower levels of sCD40L (2.70 pg/ml [1.90-4.00] vs. 3.60 pg/ml [2.95-5.30]; p = 0.0782). Viral load in both groups was similar (0.8 × 105 ng/ml [0.2-42.4 × 105] vs. 1.1 × 105 [0.5-12.2 × 105]; p = 0.3806). No effects attributable to prednisolone were observed when patients receiving HAART in combination with prednisolone were compared to patients who received HAART alone. Conclusions: Patients treated with low-dose prednisolone display significantly lower general immune activation than untreated patients. Further longitudinal studies are required to assess whether treatment with low-dose prednisolone translates into differences in HIV disease progression.},
  subject      = {HIV},
  language  = {en}
}
@article{DecloedtFreemanHowellsetal.2016,
  author    = {Decloedt, Eric H. and Freeman, Carla and Howells, Fleur and Casson-Crook, Martine and Lesosky, Maia and Koutsilieri, Eleni and Lovestone, Simon and Maartens, Gary and Joska, John A.},
  title     = {Moderate to severe HIV-associated neurocognitive impairment : A randomized placebo-controlled trial of lithium},
  series = {Medicine},
  volume    = {95},
  journal   = {Medicine},
  number    = {46},
  doi       = {10.1097/MD.0000000000005401},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165838},
  pages     = {e5401},
  year      = {2016},
  abstract  = {Background: HIV-associated neurocognitive disorder (HAND) remains highly prevalent despite effective anti-retroviral therapy (ART). A number of adjunctive pharmacotherapies for HAND have been studied with disappointing results, but preliminary data suggest that lithium may provide clinical benefit. In addition, the low cost of lithium would facilitate access in low- and middle-income countries which carry the greatest burden of HIV. Methods: Our objective was to evaluate the 24-week efficacy and safety of lithium in patients with moderate to severe HAND. Our primary efficacy endpoint was the change in Global Deficit Score (GDS) from baseline to 24 weeks, whereas our secondary endpoint was the change in proton magnetic resonance spectroscopy (1H-MRS) brain metabolite concentrations. We conducted a 24-week randomized placebo-controlled trial of lithium as adjunctive pharmacotherapy. We enrolled participants with moderate to severe HAND, on ART for at least 6 months, with suppressed viral loads and attending public sector primary care clinics in Cape Town, South Africa. We randomized 66 participants to lithium (n = 32) or placebo (n = 34). Lithium or placebo was dosed 12-hourly and titrated to achieve the maintenance target plasma concentration of 0.6 to 1.0 mmol/L. Sham lithium concentrations were generated for participants receiving placebo. Results: Totally 61 participants completed the study (lithium arm = 30; placebo arm = 31). Participants at enrolment had a mean age of 40 years and a median CD4+ T-cell count of 500 cells/μL. The median change in GDS between baseline and week 24 for the lithium and placebo arms were -0.57 (95\% confidence interval [CI] -0.77, -0.32) and -0.56 (-0.69, -0.34) respectively, with a mean difference of -0.054 (95\% CI -0.26, 0.15); P = 0.716. The improvement remained similar when analyzed according to age, severity of impairment, CD4+ count, time on ART, and ART regimen. Standard 1H-MRS metabolite concentrations were similar between the treatment arms. The study drug was well tolerated in both study arms. Six serious adverse events occurred, but none were considered related to the study drug. Conclusion: Adjunctive lithium pharmacotherapy in patients on ART with HAND was well tolerated but had no additional benefit on neurocognitive impairment.},
  language  = {en}
}
@article{PradaMaagSiegmundetal.2022,
  author    = {Prada, Juan Pablo and Maag, Luca Estelle and Siegmund, Laura and Bencurova, Elena and Liang, Chunguang and Koutsilieri, Eleni and Dandekar, Thomas and Scheller, Carsten},
  title     = {Estimation of R0 for the spread of SARS-CoV-2 in Germany from excess mortality},
  series = {Scientific Reports},
  volume    = {12},
  journal   = {Scientific Reports},
  number    = {1},
  doi       = {10.1038/s41598-022-22101-7},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-301415},
  year      = {2022},
  abstract  = {For SARS-CoV-2, R0 calculations in the range of 2-3 dominate the literature, but much higher estimates have also been published. Because capacity for RT-PCR testing increased greatly in the early phase of the Covid-19 pandemic, R0 determinations based on these incidence values are subject to strong bias. We propose to use Covid-19-induced excess mortality to determine R0 regardless of RT-PCR testing capacity. We used data from the Robert Koch Institute (RKI) on the incidence of Covid cases, Covid-related deaths, number of RT-PCR tests performed, and excess mortality calculated from data from the Federal Statistical Office in Germany. We determined R0 using exponential growth estimates with a serial interval of 4.7 days. We used only datasets that were not yet under the influence of policy measures (e.g., lockdowns or school closures). The uncorrected R0 value for the spread of SARS-CoV-2 based on RT-PCR incidence data was 2.56 (95\% CI 2.52-2.60) for Covid-19 cases and 2.03 (95\% CI 1.96-2.10) for Covid-19-related deaths. However, because the number of RT-PCR tests increased by a growth factor of 1.381 during the same period, these R0 values must be corrected accordingly (R0corrected = R0uncorrected/1.381), yielding 1.86 for Covid-19 cases and 1.47 for Covid-19 deaths. The R0 value based on excess deaths was calculated to be 1.34 (95\% CI 1.32-1.37). A sine-function-based adjustment for seasonal effects of 40\% corresponds to a maximum value of R0January = 1.68 and a minimum value of R0July = 1.01. Our calculations show an R0 that is much lower than previously thought. This relatively low range of R0 fits very well with the observed seasonal pattern of infection across Europe in 2020 and 2021, including the emergence of more contagious escape variants such as delta or omicron. In general, our study shows that excess mortality can be used as a reliable surrogate to determine the R0 in pandemic situations.},
  language  = {en}
}