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Articles by Christian Brander
Total Records ( 5 ) for Christian Brander
  Daniel Yerly , David Heckerman , Todd M. Allen , John V. Chisholm III , Kellie Faircloth , Caitlyn H. Linde , Nicole Frahm , Joerg Timm , Werner J. Pichler , Andreas Cerny and Christian Brander
  Hepatitis C virus (HCV) clearance has been associated with reduced viral evolution in targeted cytotoxic T-lymphocyte (CTL) epitopes, suggesting that HCV clearers may mount CTL responses with a superior ability to recognize epitope variants and prevent viral immune escape. Here, 40 HCV-infected subjects were tested with 406 10-mer peptides covering the vast majority of the sequence diversity spanning a 197-residue region of the NS3 protein. HCV clearers mounted significantly broader CTL responses of higher functional avidity and with wider variant cross-recognition capacity than nonclearers. These observations have important implications for vaccine approaches that may need to induce high-avidity responses in vivo.
  Aviva Joseph , Jian Hua Zheng , Antonia Follenzi , Teresa DiLorenzo , Kaori Sango , Jaime Hyman , Ken Chen , Alicja Piechocka-Trocha , Christian Brander , Erik Hooijberg , Dario A. Vignali , Bruce D. Walker and Harris Goldstein
  The human immunodeficiency virus type 1 (HIV-1)-specific CD8 cytotoxic T-lymphocyte (CTL) response plays a critical role in controlling HIV-1 replication. Augmenting this response should enhance control of HIV-1 replication and stabilize or improve the clinical course of the disease. Although cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection in immunocompromised patients can be treated by adoptive transfer of ex vivo-expanded CMV- or EBV-specific CTLs, adoptive transfer of ex vivo-expanded, autologous HIV-1-specific CTLs had minimal effects on HIV-1 replication, likely a consequence of the inherently compromised qualitative function of HIV-1-specific CTLs derived from HIV-1-infected individuals. We hypothesized that this limitation could be circumvented by using as an alternative source of HIV-1-specific CTLs, autologous peripheral CD8+ T lymphocytes whose antigen specificity is redirected by transduction with lentiviral vectors encoding HIV-1-specific T-cell receptor (TCR) α and β chains, an approach used successfully in cancer therapy. To efficiently convert peripheral CD8 lymphocytes into HIV-1-specific CTLs that potently suppress in vivo HIV-1 replication, we constructed lentiviral vectors encoding the HIV-1-specific TCR α and TCR β chains cloned from a CTL clone specific for an HIV Gag epitope, SL9, as a single transcript linked with a self-cleaving peptide. We demonstrated that transduction with this lentiviral vector efficiently converted primary human CD8 lymphocytes into HIV-1-specific CTLs with potent in vitro and in vivo HIV-1-specific activity. Using lentiviral vectors encoding an HIV-1-specific TCR to transform peripheral CD8 lymphocytes into HIV-1-specific CTLs with defined specificities represents a new immunotherapeutic approach to augment the HIV-1-specific immunity of infected patients.
  Arne Schneidewind , Mark A. Brockman , John Sidney , Yaoyu E. Wang , Huabiao Chen , Todd J. Suscovich , Bin Li , Rahma I. Adam , Rachel L. Allgaier , Bianca R. Mothe , Thomas Kuntzen , Cesar Oniangue-Ndza , Alicja Trocha , Xu G. Yu , Christian Brander , Alessandro Sette , Bruce D. Walker and Todd M. Allen
  Control of human immunodeficiency virus type 1 (HIV-1) by HLA-B27-positive subjects has been linked to an immunodominant CD8+ cytotoxic T-lymphocyte (CTL) response targeting the conserved KK10 epitope (KRWIILGLNK263-272) in p24/Gag. Viral escape in KK10 typically occurs through development of an R264K substitution in conjunction with the upstream compensatory mutation S173A, and the difficulty of the virus to escape from the immune response against the KK10 epitope until late in infection has been associated with slower clinical progression. Rare alternative escape mutations at R264 have been observed, but factors dictating the preferential selection of R264K remain unclear. Here we illustrate that while all observed R264 mutations (K, G, Q, and T) reduced peptide binding to HLA-B27 and impaired viral replication, the replicative defects of the alternative mutants were actually less pronounced than those for R264K. Importantly, however, none of these mutants replicated as well as an R264K variant containing the compensatory mutation S173A. In assessing the combined effects of viral replication and CTL escape using an in vitro coculture assay, we further observed that the compensated R264K mutant also displayed the highest replication capacity in the presence of KK10-specific CTLs. Comparisons of codon usage for the respective variants indicated that generation of the R264K mutation may also be favored due to a G-to-A bias in nucleotide substitutions during HIV-1 replication. Together, these data suggest that the preference for R264K is due primarily to the ability of the S173A-compensated virus to replicate better than alternative variants in the presence of CTLs, suggesting that viral fitness is a key contributor for the selection of immune escape variants.
  Philippa C. Matthews , Andrew Prendergast , Alasdair Leslie , Hayley Crawford , Rebecca Payne , Christine Rousseau , Morgane Rolland , Isobella Honeyborne , Jonathan Carlson , Carl Kadie , Christian Brander , Karen Bishop , Nonkululeko Mlotshwa , James I . Mullins , Hoosen Coovadia , Thumbi Ndung’u , Bruce D. Walker , David Heckerman and Philip J . R. Goulder
  Much uncertainty still exists over what T-cell responses need to be induced by an effective human immunodeficiency virus (HIV) vaccine. Previous studies have hypothesized that the effective CD8+ T-cell responses are those driving the selection of escape mutations that reduce viral fitness and therefore revert posttransmission. In this study, we adopted a novel approach to define better the role of reverting escape mutations in immune control of HIV infection. This analysis of sequences from 710 study subjects with chronic C-clade HIV type 1 infection demonstrates the importance of mutations that impose a fitness cost in the control of viremia. Consistent with previous studies, the viral set points associated with each HLA-B allele are strongly correlated with the number of Gag-specific polymorphisms associated with the relevant HLA-B allele (r = –0.56, P = 0.0034). The viral set points associated with each HLA-C allele were also strongly correlated with the number of Pol-specific polymorphisms associated with the relevant HLA-C allele (r = –0.67, P = 0.0047). However, critically, both these correlations were dependent solely on the polymorphisms identified as reverting. Therefore, despite the inevitable evolution of viral escape, viremia can be controlled through the selection of mutations that are detrimental to viral fitness. The significance of these results is in highlighting the rationale for an HIV vaccine that can induce these broad responses.
  Anthony Tanoto Tan , Elisabetta Loggi , Carolina Boni , Adeline Chia , Adam J. Gehring , Konduru S. R. Sastry , Vera Goh , Paola Fisicaro , Pietro Andreone , Christian Brander , Seng Gee Lim , Carlo Ferrari , Florian Bihl and Antonio Bertoletti
  Repertoire composition, quantity, and qualitative functional ability are the parameters that define virus-specific T-cell responses and are linked with their potential to control infection. We took advantage of the segregation of different hepatitis B virus (HBV) genotypes in geographically and genetically distinct host populations to directly analyze the impact that host and virus variables exert on these virus-specific T-cell parameters. T-cell responses against the entire HBV proteome were analyzed in a total of 109 HBV-infected subjects of distinct ethnicities (47 of Chinese origin and 62 of Caucasian origin). We demonstrate that HBV-specific T-cell quantity is determined by the virological and clinical profiles of the patients, which outweigh any influence of race or viral diversity. In contrast, HBV-specific T-cell repertoires are divergent in the two ethnic groups, with T-cell epitopes frequently found in Caucasian patients seldom detected in Chinese patients. In conclusion, we provide a direct biological evaluation of the impact that host and virus variables exert on virus-specific T-cell responses. The discordance between HBV-specific CD8 T-cell repertoires present in Caucasian and Chinese subjects shows the ability of HLA micropolymorphisms to diversify T-cell responses and has implications for the rational development of therapeutic and prophylactic vaccines for worldwide use.
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