Promiscuous presentation of HLA class I restricted, HIV derived CTL epitopes CTL mediated cellular immunity is considered an important arm of the host defense against HIV infection and a number of HLA class I alleles have been associated with slow or fast HIV disease progression. Despite some significant advances in the field, the mechanisms by which HLA class I alleles mediate their beneficial or detrimental effects, are still unclear and may include multiple factors such as peptide binding, variability of targeted viral sequences, antigen processing and the kinetics of viral antigen expression. Recent data from murine studies have also linked T-cell receptor (TCR) repertoire diversity with relative control of viral infections. Comparing closely related MHC molecules presenting the identical epitope, these analyses revealed different TCR repertoire diversity depending on which MHC allele presented the targeted epitope and indicated that a narrow TCR repertoire was associated with CTL responses of low functional avidity and inability to control viral replication. Based on these recent reports and our own, extensive preliminary recent data, the present proposal aims to identify HIV encoded, promiscuously binding CTL epitopes that can be presented by HLA alleles differentially associated with HIV disease progression and to assess the functional avidity and TCR repertoire diversity of these CTL responses, depending on which allele the epitope is presented. Functional avidity and TCR repertoire diversity are then put in relation with the CTL's ability to efficiently recognize naturally occurring viral epitope variants and to drive viral evolution in response to immune selection pressure mediated by epitope presentation on alleles associated with wither fast or slow disease progression. Focusing on promiscuously binding CTL epitopes, the potential association between TCR repertoire diversity, functional avidity and rate of HIV disease progression can be assessed in the absence of a number of confounding effects that have limited similar analyses in the past. The emerging data will be of significant importance for HIV vaccine development and help the identification of true immune correlates of protective HIV immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI067077-01
Application #
7006836
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Wassef, Nabila M
Project Start
2005-06-15
Project End
2010-02-28
Budget Start
2005-06-15
Budget End
2006-02-28
Support Year
1
Fiscal Year
2005
Total Cost
$371,875
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Berger, Christoph T; Llano, Anuska; Carlson, Jonathan M et al. (2015) Immune screening identifies novel T cell targets encoded by antisense reading frames of HIV-1. J Virol 89:4015-9
Berger, Christoph T; Frahm, Nicole; Price, David A et al. (2011) High-functional-avidity cytotoxic T lymphocyte responses to HLA-B-restricted Gag-derived epitopes associated with relative HIV control. J Virol 85:9334-45
Berger, Christoph T; Carlson, Jonathan M; Brumme, Chanson J et al. (2010) Viral adaptation to immune selection pressure by HLA class I-restricted CTL responses targeting epitopes in HIV frameshift sequences. J Exp Med 207:61-75
Rousseau, Christine M; Daniels, Marcus G; Carlson, Jonathan M et al. (2008) HLA class I-driven evolution of human immunodeficiency virus type 1 subtype c proteome: immune escape and viral load. J Virol 82:6434-46
Frahm, Nicole; Yusim, Karina; Suscovich, Todd J et al. (2007) Extensive HLA class I allele promiscuity among viral CTL epitopes. Eur J Immunol 37:2419-33
Assarsson, Erika; Sidney, John; Oseroff, Carla et al. (2007) A quantitative analysis of the variables affecting the repertoire of T cell specificities recognized after vaccinia virus infection. J Immunol 178:7890-901
Frahm, Nicole; Kaufmann, Daniel E; Yusim, Karina et al. (2007) Increased sequence diversity coverage improves detection of HIV-specific T cell responses. J Immunol 179:6638-50
Frahm, Nicole; Kiepiela, Photini; Adams, Sharon et al. (2006) Control of human immunodeficiency virus replication by cytotoxic T lymphocytes targeting subdominant epitopes. Nat Immunol 7:173-8
Adnan, Sama; Balamurugan, Arumugam; Trocha, Alicja et al. (2006) Nef interference with HIV-1-specific CTL antiviral activity is epitope specific. Blood 108:3414-9
Kotton, Camille N; Lankowski, Alexander J; Scott, Nathaniel et al. (2006) Safety and immunogenicity of attenuated Salmonella enterica serovar Typhimurium delivering an HIV-1 Gag antigen via the Salmonella Type III secretion system. Vaccine 24:6216-24

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