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Articles by Alessandro Sette
Total Records ( 4 ) for Alessandro Sette
  Erik Depla , Annegret Van der Aa , Brian D. Livingston , Claire Crimi , Koen Allosery , Veronique De Brabandere , Jonathan Krakover , Sidharta Murthy , Manley Huang , Scott Power , Lilia Babe , Carol Dahlberg , Denise McKinney , Alessandro Sette , Scott Southwood , Ramilla Philip , Mark J. Newman and Lydie Meheus
  Protein sequences from multiple hepatitis B virus (HBV) isolates were analyzed for the presence of amino acid motifs characteristic of cytotoxic T-lymphocyte (CTL) and helper T-lymphocyte (HTL) epitopes with the goal of identifying conserved epitopes suitable for use in a therapeutic vaccine. Specifically, sequences bearing HLA-A1, -A2, -A3, -A24, -B7, and -DR supertype binding motifs were identified, synthesized as peptides, and tested for binding to soluble HLA. The immunogenicity of peptides that bound with moderate to high affinity subsequently was assessed using HLA transgenic mice (CTL) and HLA cross-reacting H-2bxd (BALB/c x C57BL/6J) mice (HTL). Through this process, 30 CTL and 16 HTL epitopes were selected as a set that would be the most useful for vaccine design, based on epitope conservation among HBV sequences and HLA-based predicted population coverage in diverse ethnic groups. A plasmid DNA-based vaccine encoding the epitopes as a single gene product, with each epitope separated by spacer residues to enhance appropriate epitope processing, was designed. Immunogenicity testing in mice demonstrated the induction of multiple CTL and HTL responses. Furthermore, as a complementary approach, mass spectrometry allowed the identification of correctly processed and major histocompatibility complex-presented epitopes from human cells transfected with the DNA plasmid. A heterologous prime-boost immunization with the plasmid DNA and a recombinant MVA gave further enhancement of the immune responses. Thus, a multiepitope therapeutic vaccine candidate capable of stimulating those cellular immune responses thought to be essential for controlling and clearing HBV infection was successfully designed and evaluated in vitro and in HLA transgenic mice.
  Nicholas J. Maness , Levi J. Yant , Chungwon Chung , John T. Loffredo , Thomas C. Friedrich , Shari M. Piaskowski , Jessica Furlott , Gemma E. May , Taeko Soma , Enrique J. Leon , Nancy A. Wilson , Helen Piontkivska , Austin L. Hughes , John Sidney , Alessandro Sette and David I. Watkins
  The association between particular major histocompatibility complex class I (MHC-I) alleles and control of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication implies that certain CD8+ T-lymphocyte (CD8-TL) responses are better able than others to control viral replication in vivo. However, possession of favorable alleles does not guarantee improved prognosis or viral control. In rhesus macaques, the MHC-I allele Mamu-B*17 is correlated with reduced viremia and is overrepresented in macaques that control SIVmac239, termed elite controllers (ECs). However, there is so far no mechanistic explanation for this phenomenon. Here we show that the chronic-phase Mamu-B*17-restricted repertoire is focused primarily against just five epitopes—VifHW8, EnvFW9, NefIW9, NefMW9, and envARFcRW9—in both ECs and progressors. Interestingly, Mamu-B*17-restricted CD8-TL do not target epitopes in Gag. CD8-TL escape variation occurred in all targeted Mamu-B*17-restricted epitopes. However, recognition of escape variant peptides was commonly observed in both ECs and progressors. Wild-type sequences in the VifHW8 epitope tended to be conserved in ECs, but there was no evidence that this enhances viral control. In fact, no consistent differences were detected between ECs and progressors in any measured parameter. Our data suggest that the narrowly focused Mamu-B*17-restricted repertoire suppresses virus replication and drives viral evolution. It is, however, insufficient in the majority of individuals that express the "protective" Mamu-B*17 molecule. Most importantly, our data indicate that the important differences between Mamu-B*17-positive ECs and progressors are not readily discernible using standard assays to measure immune responses.
  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.
  Courtney Dow , Carla Oseroff , Bjoern Peters , Courtney Nance-Sotelo , John Sidney , Michael Buchmeier , Alessandro Sette and Bianca R. Mothe
  Activation of CD4+ T cells helps establish and sustain other immune responses. We have previously shown that responses against a broad set of nine CD4+ T-cell epitopes were present in the setting of lymphocytic choriomeningitis virus (LCMV) Armstrong infection in the context of H-2d. This is quite disparate to the H-2b setting, where only two epitopes have been identified. We were interested in determining whether a broad set of responses was unique to H-2d or whether additional CD4+ T-cell epitopes could be identified in the setting of the H-2b background. To pursue this question, we infected C57BL/6 mice with LCMV Armstrong and determined the repertoire of CD4+ T-cell responses using overlapping 15-mer peptides corresponding to the LCMV Armstrong sequence. We confirmed positive responses by intracellular cytokine staining and major histocompatibility complex (MHC)-peptide binding assays. A broad repertoire of responses was identified, consisting of six epitopes. These epitopes originate from the nucleoprotein (NP) and glycoprotein (GP). Out of the six newly identified CD4+ epitopes, four of them also stimulate CD8+ T cells in a statistically significant manner. Furthermore, we assessed these CD4+ T-cell responses during the memory phase of LCMV Armstrong infection and after infection with a chronic strain of LCMV and determined that a subset of the responses could be detected under these different conditions. This is the first example of a broad repertoire of shared epitopes between CD4+ and CD8+ T cells in the context of viral infection. These findings demonstrate that immunodominance is a complex phenomenon in the context of helper responses.
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