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My laboratory studies the mechanisms of viral protein degradation, epitope processing and presentation, focusing on HIV infection.

HIV-specific CD8 T cells represent a critical arm of the immune response against HIV-1 infection. They control HIV replication by recognizing HIV epitopes produced via intracellular processing pathways and presented by MHC-I molecules. Thus the processing of viral peptides and their intracellular association with HLA class I represent key steps leading to immune recognition and any change in the processing of such epitopes may alter the efficiency of HIV-specific CD8 T cell responses. Likewise, antigen processing is a key step in the elicitation of vaccine-induced immune responses as one needs to ensure that epitopes included in a vaccine will be properly processed and presented to virus-specific CD8 T cells.

Our recent work demonstrates that antigen processing contributes to the frequency of certain HIV-specific CD8 T cells by favoring the production of some epitopes and destruction of others. We also identified portable flanking sequences that allow us to increase or decrease the production and antigenicity of the epitope they surround. This lead us to the current working hypothesis that variations at multiple steps of epitope processing are driven by specific sequences that determine the kinetics of processing and amount of epitopes presented at the cell surface and impact the functionality of CD8 T cell responses. Using degradation assays and computational analysis, we aim at defining cellular peptidases and viral sequence signatures driving the efficient of HIV protein degradation into epitopes in subcellular compartments of cells targeted by the virus.

We are also assessing the effect of HIV infection on the antigen processing machinery both in in vitro infected cells and ex vivo in primary cells from HIV-infected individuals during the course of the disease. Whether HIV-infected persons who control viremia and rapid progressors have the same capacity to produce and present HIV epitopes is under investigation.
Finally we have identified mutations outside epitopes impairing epitope production and recognition of infected cells by immune cells. We are investigating the impact of viral evolution on the processing and presentation of HIV epitopes and its contribution to immune escape.

Our laboratory uses a large array of techniques, including enzymatic assays, molecular biology techniques to analyze gene and protein expression, subcellular fractionation, biochemical assays to follow in vitro degradation of peptides or proteins followed by HPLC and mass spectrometry analysis of the peptides produced, as well as immunological assays to correlate epitope processing in antigen presenting cells and CD8 T cell killing capacity.

I am the Director of the Education and Training Program for the Ragon Institute that initiates and trains highly motivated students from high school through PhD levels to research on HIV and infectious diseases in a state-of-art and multi-disciplinary biomedical research environment.

Last Update: 12/16/2014

Publications

1. Draenert R, Le Gall S. et al. Immune selection for altered antigen processing leads to cytotoxic T lymphocyte escape in chronic HIV-1 infection. J Exp Med 199, 905-15 (2004).

2. Kavanagh DG, Kaufmann DE, Sunderji S, Frahm N, Le Gall S, Boczkowski D, Rosenberg ES, Stone DR, Johnston MN, Wagner BS, Zaman MT, Brander C, Gilboa E, Walker BD, Bhardwaj N. Expansion of HIV-specific CD4+ and CD8+ T cells by dendritic cells transfected with mRNA encoding cytoplasm- or lysosome-targeted Nef. Blood. 2006 107(5):1963-9. PMC1895708.

3. Le Gall S, Stamegna P., Walker BD. Portable flanking sequences modulate CTL epitope processing. J Clin Invest. 2007 Nov; 117(11):3563-75.

4. Troyer RM, McNevin J, Liu Y, Zhang SC, Krizan RW, Abraha A, Tebit DM, Zhao H, Avila S, Lobritz MA, McElrath MJ, Le Gall S, Mullins JI, Arts EJ. Variable fitness impact of HIV-1 escape mutations to cytotoxic T lymphocyte (CTL) response. PLoS Pathog. 2009 Apr;5(4):e1000365. PMC2659432.

5. Lazaro E, Godfrey SB, Stamegna P, Ogbechie T, Kerrigan C, Zhang M, Walker BD, Le Gall S. Differential HIV epitope processing in monocytes and CD4 T cells affects cytotoxic T lymphocyte recognition. J Infect Dis. 2009 Jul 15;200(2):236-43.

6. The major genetic determinants influencing HIV-1 control map to discrete amino acids involved in HLA class I peptide presentation. The International HIV Controllers Study. Science 2010 Dec 10;330(6010):1551-7

7. Kessler JH, Khan S, Seifert U, Le Gall S, Chow KM, Paschen A, Bres-Vloemans SA, de Ru A, van Montfoort N, Franken KL, Benckhuijsen WE, Brooks JM, van Hall T, Ray K, Mulder A, Doxiadis II, van Swieten PF, Overkleeft HS, Prat A, Tomkinson B, Neefjes J, Kloetzel PM, Rodgers DW, Hersh LB, Drijfhout JW, van Veelen PA, Ossendorp F, Melief CJ. Antigen processing by nardilysin and thimet oligopeptidase generates cytotoxic T cell epitopes. Nature Immunology 2011 Jan;12(1):45-53.

8. Lazaro E., Kadie C., Stamegna P., Zhang S.C., Gourdain P., Lai N.Y., Zhang M., Martinez S.M., Heckerman D., Le Gall S. Variable cytosolic oligopeptide stability plays a critical role in HIV epitope presentation and immune escape J. Clin. Invest. 2011 Jun: 121(6):2480-92.

9. Zhang SC, Martin E, Shimada M, Godfrey SB, Fricke J, Locastro S, Lai NY, Liebesny P, Carlson JM, Brumme CJ, Ogbechie OA, Chen H, Walker BD, Brumme ZL, Kavanagh DG, Le Gall S. Aminopeptidase substrate preference affects HIV epitope presentation and predicts immune escape patterns in HIV-infected individuals. J. Immunol 2012 Jun 15;188(12):5924-34

10. Balamurugan A, Ali A, Boucau J, Le Gall S, Ng HL, Yang OO. HIV-1 gag cytotoxic T lymphocyte epitopes vary in presentation kinetics relative to HLA class I downregulation. J Virol. 2013 Aug;87(15):8726-34

11. Vaithilingam A, Lai NY, Duong E, Boucau J, Xu Y, Shimada M, Gandhi M, Le Gall S. A simple methodology to assess endolysosomal protease activity involved in antigen processing in human primary cells. BMC Cell Biol. 2013 Aug 9;14:35

12. Gourdain P, Boucau J, Kourjian G, Lai NY, Duong E, Le Gall S. A real-time killing assay to follow viral epitope presentation to CD8 T cells. J Immunol Methods. 2013 Dec 15;398-399:60-7

13. Kourjian G, Xu Y, Mondesire-Crump I, Shimada M, Gourdain P, Le Gall S. Sequence-Specific alteration of Epitope Production by HIV Protease Inhibitors J Immunol. 2014 Mar 10 [Epub ahead of print]

14. Dinter J, Gourdain P, Lai NY, Duong E, Bracho-Sanchez E, Rucevic M, Liebesny PH, Xu Y, Shimada M, Ghebremichael M, Kavanagh DG, Le Gall S. Different Antigen-Processing Activities in Dendritic Cells, Macrophages, and Monocytes Lead to Uneven Production of HIV Epitopes and Affect CTL Recognition. J. Immunology. 2014 2014 Nov 1;193(9):4322-34. PMID230751

15. Rucevic M, Boucau J, Dinter J, Kourjian G, Le Gall S. Mechanisms of HIV protein degradation into epitopes: implications for vaccine design. Viruses. 2014 Aug 21;6(8):3271-92. PMID:25196483 \

16. Boucau J, Rucevic M, Le Gall S. HIV Antigen Processing and Presentation.
Encyclopedia of AIDS. Edited: Dr. Thomas Hope, Dr. Douglas D. Richman, Dr. Mario Stevenson.
SpringerReference 2014

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