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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: 10/22/2013

Publications

Le Gall S, Erdtmann L, Benichou S, Berlioz C, Liu LX, Heard JM, Schwartz O. Nef interacts with subunits of clathrin adaptor complexes and reveals a cryptic sorting signal in MHC-I molecules. Immunity 1998; 8:483-95.

Buseyne F, Le Gall S, Boccaccio C, Abastado JP, Lifson JD, Arthur LO, Riviere Y, Heard JM, Schwartz O. MHC-I-restricted presentation of HIV-1 virion antigens without viral replication. Nature Medecine 2001; 7(3):344-9.

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

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. PMID: 19505257

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 1;121(6):2480-92. PMCID: PMC3104749

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