@inproceedings{MoriRethwilmSchwinnetal.1990,
  author    = {Mori, Kazuyasu and Rethwilm, Axel and Schwinn, Andreas and Horak, Ivan},
  title     = {Replication of human immunodeficiency virus type 1 in human t-cells expressing antisense RNA},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-86426},
  year      = {1990},
  abstract  = {No abstract available.},
  subject      = {HIV},
  language  = {en}
}
@inproceedings{RethwilmBaunachMorietal.1990,
  author    = {Rethwilm, Axel and Baunach, Gerald and Mori, Kazuyasu and ter Meulen, Volker},
  title     = {Transactivation of HIV by human spumaretrovirus},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-86436},
  year      = {1990},
  abstract  = {To study the activation of HIV by human spumaretrovirus (HSRV) the long terminal repeats (LTRs) of HSRV, HIVl and HIV2 were examined with respect to their ability to function as transcriptional promoters in virus infected and uninfected cells. Transient transfections using plasmids in which the L TRs of the three viruses were coupled to the bacterial chloramphenicol acetyltransferase (CA T) gene revealed (i) the level of cat gene expression directed by the HSRV LTR was markedly increased in HSRV infected cells compared to uninfected cells, (ii) cat gene expression driven by the HIV1 LTR, but not by the HIV2 LTR could be enhanced upon HSRV infection, whereas (iii) neither in HIV1 nor in HIV2 infected cells an effect on HSRV LTR driven cat geneexpression was detected.},
  subject      = {HIV},
  language  = {en}
}
@article{KerkauGernertKneitzetal.1992,
  author    = {Kerkau, T. and Gernert, S. and Kneitz, C. and Schimpl, A.},
  title     = {Mechanism of MHC class I downregulation in HIV infected cells},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-56849},
  year      = {1992},
  abstract  = {HIV infection of CD4+ peripheral blood lymphocytes leads to a loss of MHC dass I molecules on the surface of the infected cells as detectable by monodonal antibody staining and flow cytometry. Incubation of the infected cells at 26 oe or treatment at 37 oe with peptides leads to upregulation of MHC dass I to levels equal to those found on uninfected cells cultured und er the same conditions. The data suggest that, after HIV infection, the mechanisms responsible for peptide generation, peptide transport and thus stable association between peptides and MHC dass I molecules are severely affected.},
  subject      = {HIV},
  language  = {en}
}
@phdthesis{Kleen2003,
  author    = {Kleen, Thomas Oliver},
  title     = {Dissociated expression of granzyme B and IFN-gamma by T lymphocytes in HIV-1 infected individuals and its implications for Tc1 effector diversity},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-8460},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2003},
  abstract  = {A CD8+ cell-mediated host defense relies on cognate killing of infected target cells and on local inflammation induced by the secretion of IFN-g. Using assays of single cell resolution, it was studied to what extent these two effector function of CD8+ cells are linked. Granzyme B (GzB) is stored in cytolytic granules of CD8+ cells and its secretion is induced by antigen recognition of these cells. Following entry into the cytosol GzB induces apoptosis in the target cells. It was measured whether GzB release by individual CD8+ cells is accompanied by the secretion of IFN-gƒnƒnand of other cytokines. HIV peptide libraries were tested on bulk peripheral blood mononuclear cells and on purified CD4+ and CD8+ cells obtained from HIV infected individuals. The library included a panel of previously defined HLA class I restricted HIV peptides and an overlapping 20-mer peptide-series that covered the entire gp120 molecule. To characterize the in vivo differentiation state of the T-cells, freshly isolated lymphocytes were tested in assays of 24h duration. The data showed that only ~20\% of the peptides triggered the release of both GzB and IFN-g from CD8+ cells. The majority of the HIV peptides induced either GzB or IFN-g, ~40\% in each category. The GzB positive, IFN-g negative CD8+ cells did not produce IL-4 or IL-5, which suggests that they do not correspond to Tc2 cells but represent a novel Tc1 subclass, which was termed Tc1c. Also the IFN-g positive, GzB negative CD8+ cell subpopulation represents a yet undefined CD8+ effector cell lineage that was termed Tc1b. Tc1b and Tc1c cells are likely to make different, possibly antagonistic contributions to the control of HIV infection. Since IFN-g activates HIV replication in latently infected macrophages, the secretion of this cytokine by Tc1b cells in the absence of killing may have adverse effects on the host defense. In contrast, cytolysis by Tc1c cells in the absence of IFN-g production might represent the protective class of response. Further studies in the field of Tc1 effector cell diversity should lead to valuable insights for management of infections and developing rationales for vaccine design.},
  subject      = {Antigen CD8},
  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}
}
@phdthesis{Jacobs2011,
  author    = {Jacobs, Graeme Brendon},
  title     = {HIV-1 resistance analyses from therapy-na{\"i}ve patients in South Africa, Tanzania and the characterization of a new HIV-1 subtype C proviral molecular clone},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-67319},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2011},
  abstract  = {The acquired immunodeficiency syndrome (AIDS) is currently the most infectious disease worldwide. It is caused by the human immunodeficiency virus (HIV). At the moment there are ~33.3 million people infected with HIV. Sub-Saharan Africa, with ~22.5 million people infected accounts for 68\% of the global burden. In most African countries antiretroviral therapy (ART) is administered in limited-resource settings with standardised first- and second-line ART regimens. During this study I analysed the therapy-na{\"i}ve population of Cape Town, South Africa and Mwanza, Tanzania for any resistance associated mutations (RAMs) against protease inhibitors, nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors. My results indicate that HIV-1 subtype C accounts for ~95\% of all circulating strains in Cape Town, South Africa. I could show that ~3.6\% of the patient derived viruses had RAMs, despite patients being therapy-na{\"i}ve. In Mwanza, Tanzania the HIV drug resistance (HIVDR) prevalence in the therapy-na{\"i}ve population was 14.8\% and significantly higher in the older population, >25 years. Therefore, the current WHO transmitted HIVDR (tHIVDR) survey that is solely focused on the transmission of HIVDR and that excludes patients over 25 years of age may result in substantial underestimation of the prevalence of HIVDR in the therapy-na{\"i}ve population. Based on the prevalence rates of tHIVDR in the study populations it is recommended that all HIV-1 positive individuals undergo a genotyping resistance test before starting ART. I also characterized vif sequences from HIV-1 infected patients from Cape Town, South Africa as the Vif protein has been shown to counteract the antiretroviral activity of the cellular APOBEC3G/F cytidine deaminases. There is no selective pressure on the HIV-1 Vif protein from current ART regimens and vif sequences was used as an evolutionary control. As the majority of phenotypic resistance assays are still based on HIV-1 subtype B, I wanted to design an infectious HIV-1 subtype C proviral molecular clone that can be used for in vitro assays based on circulating strains in South Africa. Therefore, I characterized an early primary HIV-1 subtype C isolate from Cape Town, South Africa and created a new infectious subtype C proviral molecular clone (pZAC). The new pZAC virus has a significantly higher transient viral titer after transfection and replication rate than the previously published HIV-1 subtype C virus from Botswana. The optimized proviral molecular clone, pZAC could be used in future cell culture and phenotypic HIV resistance assays regarding HIV-1 subtype C.},
  subject      = {HIV},
  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}
}
@phdthesis{Kaiser2012,
  author    = {Kaiser, Fabian Marc Philipp},
  title     = {Analysis of Cross-Clade Neutralizing Antibodies against HIV-1 Env Induced by Immunofocusing},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75494},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2012},
  abstract  = {Despite intense research efforts, a safe and effective HIV-1/AIDS vaccine still remains far away. HIV-1 escapes the humoral immune response through various mechanisms and until now, only a few nAbs have been identified. A promising strategy to identify new epitopes that may elicit such nAbs is to dissect and analyze the humoral immune response of sera with broadly reactive nAbs. The identified epitopes recognized by these antibodies might then be incorporated into a vaccine to elicit similar nAbs and thus provide protection from HIV-1 infection. Using random peptide phage display libraries, the Ruprecht laboratory has identified the epitopes recognized by polyclonal antibodies of a rhesus monkey with high-titer, broadly reactive nAbs that had been induced after infection with a SHIV encoding env of a recently transmitted HIV-1 clade C. The laboratory analyzed phage peptide inserts for conformational and linear homology with computational assistance. Several of the identified peptides mimicked domains of the original HIV-1 clade Env, such as conformational V3 loop epitopes and the conserved linear region of the gp120 C-terminus. As part of this work, these mimotopes were analyzed for cross-reactivity with other sera obtained from rhesus monkeys with nAbs and antibody recognition was shown for several mimotopes, particularly those representing the V3 loop. In addition, these mimotopes were incorporated into a novel DNA prime/phage boost strategy to analyze the immunogenicity of such phage-displayed peptides. Mice were primed only once with HIV-1 clade C gp160 DNA and subsequently boosted with mixtures of recombinant phages. This strategy was designed to focus the humoral immune response on a few, selected Env epitopes (immunofocusing) and induced HIV-1 clade C gp160 binding antibodies and cross-clade nAbs. Furthermore, the C-terminus of gp120, a conserved HIV Env region, was linked to the induction of nAbs for the first time. The identification of such conserved antigens may lead to the development of a vaccine that is capable of inducing broadly reactive nAbs that might confer protection form HIV-1 infection.},
  subject      = {Antik{\"o}rper},
  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{JacobsBockSchuchetal.2012,
  author    = {Jacobs, Graeme and Bock, Stefanie and Schuch, Anita and Moschall, Rebecca and Schrom, Eva-Maria and Zahn, Juliane and Reuter, Christian and Preiser, Wolfgang and Rethwilm, Axel and Engelbrecht, Susan and Krekau, Thomas and Bodem, Jochen},
  title     = {Construction of a high titer Infectious HIV-1 subtype C proviral clone from South Africa},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-76340},
  year      = {2012},
  abstract  = {The Human Immunodeficiency Virus type 1 (HIV-1) subtype C is currently the predominant subtype worldwide. Cell culture studies of Sub-Saharan African subtype C proviral plasmids are hampered by the low replication capacity of the resulting viruses, although viral loads in subtype C infected patients are as high as those from patients with subtype B. Here, we describe the sequencing and construction of a new HIV-1 subtype C proviral clone (pZAC), replicating more than one order of magnitude better than the previous subtype C plasmids. We identify the env-region for being the determinant for the higher viral titers and the pZAC Env to be M-tropic. This higher replication capacity does not lead to a higher cytotoxicity compared to previously described subtype C viruses. In addition, the pZAC Vpu is also shown to be able to down-regulate CD4, but fails to fully counteract CD317.},
  subject      = {HIV},
  language  = {en}
}