Cutting Edge: Class I Presentation of Host Peptides Following HIV Infection

Hickman, Heather D.; Luis, Angela D.; Bardet, Wilfried; Buchli, Rico; Battson, Casey L.; Shearer, Michael H.; Jackson, Kenneth W.; Kennedy, Ronald C.; Hildebrand, William H.

doi:10.4049/jimmunol.171.1.22

Cited by 68 publications

(58 citation statements)

References 17 publications

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“…The structural HIV-1 protein Gag is highly conserved and is among the most common targets of the virus-specific cell-mediated immune response, while Tat and Nef are more variable, yet critical, regulatory proteins important in viral gene expression and pathogenesis, and they frequently induce T-cell immune responses early in infection. Engineered COT proteins were well expressed, a fundamental requirement for the immunogenicity of vaccine candidates, especially for the usually poorly expressed HIV-1 proteins (16,40). Moreover, these proteins are capable of eliciting CTL immune responses in mice.…”

Section: Discussionmentioning

confidence: 99%

Reconstruction and Function of Ancestral Center-of-Tree Human Immunodeficiency Virus Type 1 Proteins

Rolland

Jensen

Nickle

et al. 2007

J Virol

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The extensive diversity of human immunodeficiency virus type 1 (HIV-1) and its capacity to mutate and escape host immune responses are major challenges for AIDS vaccine development. Ancestral sequences, which minimize the genetic distance to circulating strains, provide an opportunity to design immunogens with the potential to elicit broad recognition of HIV epitopes. We developed a phylogenetics-informed algorithm to reconstruct ancestral HIV sequences, called Center of Tree (COT). COT sequences have potentially significant benefits over isolate-based strategies, as they minimize the evolutionary distances to circulating strains. COT sequences are designed to surmount the potential pitfalls stemming from sampling bias with the consensus method and outlier bias with the most-recent-common-ancestor approach. We computationally derived COT sequences from circulating HIV-1 subtype B sequences for the genes encoding the major viral structural protein (Gag) and two regulatory proteins, Tat and Nef. COT genes were synthesized de novo and expressed in mammalian cells, and the proteins were characterized. COT Gag was shown to generate virus-like particles, while COT Tat transactivated gene expression from the HIV-1 long terminal repeat and COT Nef mediated downregulation of cell surface major histocompatibility complex class I. Thus, retrodicted ancestral COT proteins can retain the biological functions of extant HIV-1 proteins. Additionally, COT proteins were immunogenic, as they elicited antigen-specific cytotoxic T-lymphocyte responses in mice. These data support the utility of the COT approach to create novel and biologically active ancestral proteins as a starting point for studies of the structure, function, and biological fitness of highly variable genes, as well as for the rational design of globally relevant vaccine candidates.

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Section: Discussionmentioning

confidence: 99%

Reconstruction and Function of Ancestral Center-of-Tree Human Immunodeficiency Virus Type 1 Proteins

Rolland

Jensen

Nickle

et al. 2007

J Virol

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“…The affinity binding capacity was calculated as the MFI of the test peptide compared to the MFI of T2 cells without added peptide. We also examined the binding of these peptides to soluble HLA A‫1020ء‬ by using the HLA PolyTest kit (Pure Protein, Oklahoma City, Okla.) according to the manufacturer's instructions (24). A fluorescently labeled control peptide and soluble HLA were incubated with each peptide until equilibration of peptide replacement was reached as read on an Analyst AD plate reader (Molecular Devices, Sunnyvale, Calif.).…”

Section: Methodsmentioning

confidence: 99%

Processing and Presentation of Exogenous HLA Class I Peptides by Dendritic Cells from Human Immunodeficiency Virus Type 1-Infected Persons

Huang¹,

Zheng²,

Colleton³

et al. 2005

J Virol

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Dendritic cells (DCs) loaded with viral peptides are a potential form of immunotherapy of human immunodeficiency virus type 1 (HIV-1) infection. We show that DCs derived from blood monocytes of subjects with chronic HIV-1 infection on combination antiretroviral drug therapy have increases in expression of HLA, T-cell coreceptor, and T-cell activation molecules in response to the DC maturation factor CD40L comparable to those from uninfected persons. Mature DCs (mDCs) loaded with HLA A‫-1020ء‬restricted viral peptides of the optimal length (9-mer) were more efficient at activating antiviral CD8 ؉ T cells than were immature DCs or peptide alone. Optimal presentation of these exogenous peptides required uptake and vesicular trafficking and was comparable in DCs derived from HIV-1-infected and uninfected persons. Furthermore, DCs from HIV-1-infected and uninfected persons had similar capacities to process viral peptides with C-terminal and N-terminal extensions through their proteasomal and cytosolic pathways, respectively. We conclude that DCs derived from HIV-1-infected persons have similar abilities to process exogenous peptides for presentation to CD8 ؉ T cells as those from uninfected persons. This conclusion supports the use of DCs loaded with synthetic peptides in immunotherapy of HIV-1 infection.

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“…In other words, antigen processing should be modeled after the U.S. Senate, not the House of Representatives. Such nonrepresentational sampling, whereas of debatable value for democracy, is perfectly suited to detecting alterations in the metabolic state of tissues [41,42], including virus-infected cells, where a large fraction of altered peptides can be derived from host genes [43,44].…”

Section: Drips Flower: Kinetic Immunopeptidomicsmentioning

confidence: 99%

Translating DRiPs: MHC class I immunosurveillance of pathogens and tumors

Antón

Yewdell

2014

Journal of Leukocyte Biology

110

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MHC class I molecules display oligopeptides on the cell surface to enable T cell immunosurveillance of intracellular pathogens and tumors. Speed is of the essence in detecting viruses, which can complete a full replication cycle in just hours, whereas tumor detection is typically a finding-the-needle-in-the-haystack exercise. We review current evidence supporting a nonrandom, compartmentalized selection of peptidogenic substrates that focuses on rapidly degraded translation products as a main source of peptide precursors to optimize immunosurveillance of pathogens and tumors.

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Cutting Edge: Class I Presentation of Host Peptides Following HIV Infection

Cited by 68 publications

References 17 publications

Reconstruction and Function of Ancestral Center-of-Tree Human Immunodeficiency Virus Type 1 Proteins

Reconstruction and Function of Ancestral Center-of-Tree Human Immunodeficiency Virus Type 1 Proteins

Processing and Presentation of Exogenous HLA Class I Peptides by Dendritic Cells from Human Immunodeficiency Virus Type 1-Infected Persons

Translating DRiPs: MHC class I immunosurveillance of pathogens and tumors

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