ANTIGENIC VARIATION & IMMUNE EVASION Fondation Mérieux Conference Center “Les Pensières” Veyrier-du-Lac - France March 30 - April 1, 2009 Steering Committee: • Simona BARZU • Alister CRAIG • Catherine DUTEL • Bernard IVANOFF • Christophe LONGUET • José Juan LOPEZ-RUBIO • Jacques LOUIS This meeting was made possible through unrestricted educational grants from Sanofi Pasteur. Welcome Letter March 30, 2009 Dear Participant, It is our pleasure to welcome you to the symposium entitled: “Antigenic Variation and Immune Evasion” in Fondation Mérieux’s Conference Center “Les Pensières.” We hope you will enjoy this meeting, which brings together some of the world’s foremost experts. The format of the discussion is intended to generate discussion and interaction among participants and to foster the dissemination of new information on this topic. The conference will provide an opportunity for specialists to exchange their knowledge and experience through collaboration with researchers from around the world. Over the next three days, the team at Les Pensières will be on hand to help you with any questions you may have and to make your stay and conference as comfortable and valuable as possible. Benoît Miribel Directeur Général Fondation Mérieux For more information: www.fondation-merieux.org Background and rationale Multicellular organisms possess very sophisticated defense mechanisms that are designed to counter the continual microbial insult of the environment within the vertebrate host. The interaction between a pathogen and the mammalian immune system resulted in two basic transmission patterns. In the first one, pathogens replicate rapidly and are transmitted early, before the development of an effec- tive immune response. The second transmission pattern is typified by persistent infection until there is an opportunity for transmission, which might not occur until long after a fully mature and effective immune res- ponse has developed. Evasion of host immune defenses may be achieved by antigenic variation, which is common in vector-bor- ne and mucosally-transmitted pathogens. Although strain-to-strain variation in antigenic molecules (antigen diversity) is common, antigenic variation refers to a single strain specifically changing a subset of its anti- gens either to sustain ongoing infection or re-infect hosts even though the first infection was successfully cleared. Antigenic variation concerns proteins or glycoproteins (i) expressed at the surface of extracellular patho - gens or at the surface of cells infected by intracellular ones, (ii) involved in adhesion or invasion to host cells or in cytoadhesion of infected cells, and (iii) often immunodominant. In parasites and bacteria, antigenic variation sensu stricto often involves specific multigene families devo- ted to that function and generally occurs at rates orders of magnitude faster than gradual accumulation of genetic alterations associated with random, non targeted mutational events. The genetic information for producing a family of antigenic variants is available in the cell but only one variant is expressed at a given time. Switching between members of a multigene family involves a complicated mechanism of activation and silencing. The mechanisms underlying antigenic variation are either based on transcriptional and epigenetic control (in situ switching), like in Plasmodium falciparum or Giardia lamblia, or on gene conversion (unidirectional recombination), described in parasites (Trypanosoma brucei, Babesia bovis) and bacteria (Borrelia hermsii, Neisseria gonorrhoeae, and Anaplasma marginale). A major conceptual issue is how sequential dominance of antigenic variants is achieved by a population of parasites within a host, each independently expressing a variant. Several theories have been developed, mainly from studies of Trypanosoma, Plasmodium and Borrelia. Exceptions to these rules have been recently demonstrated: organisms with diverse antigenic variants may co-exist within the same host (Treponema pallidum, M. genitalium) and the mechanism for antigenic varia- tion may be reciprocal recombination, as opposed to gene conversion (M. genitalium). Antigenic variation also occurs in viruses, facilitating, in addition to immune escape or immune subversion mechanisms, persistent infections. Variation is not based on switching between members of multigene fami lies, but rather on spontaneous mutations during viral replication. Examples are lentiviruses (HIV, FIV), HCV (hepatitis C virus), caliciviruses. Infection with one isolate also leads to multiple antigenic variants wi- thin one host. For some of the pathogens cited, which represent dramatic disease burdens within human or animal populations, numerous vaccine approaches have been tested with limited success. The immunodominant character and the roles in pathogenesis of the variant antigens represent difficult challenges. In the face of the highly efficient antigenic variation strategy of the immunodominant unique surface protein VSG, vacci- nes for protection against Trypanosoma brucei are not contemplated. Some 20 candidates are currently in development at different phases for malaria prophylaxis. Moreover, virulence evolution in response to vacci nation needs to be considered during vaccine development. Genome sequencing of bacterial and parasite pathogens opens however new perspectives for prophylactic approaches. Immune evasion mechanisms other than antigenic variation (based on host immune system regulation or subversion) will not be discussed in this meeting (they were the main topic of previous meetings). Scientific Program Monday March 30, 2009 17h30 - 18h30 Registration 18h30 - 18h45 Welcome Address Christophe LONGUET Keynote Lecture : Antigenic varia- 18h45 - 19h15 Etienne PAYS tion as adaptive process 19h45 Dinner Tuesday March 31, 2009 Session 1 Parasites and bacteria: antigenic variation through transcriptional control Chaired by Lars Hviid and Chris Newbold Epigenetic regulation of antigenic 08h30 - 08h50 Jose Juan LOPEZ RUBIO variation in Plasmodium falciparum 08h50 - 09h10 Discussion Constrains of antigenic variation 09h10 - 09h30 on the development of vaccines Alister CRAIG against Malaria 09h30 - 09h50 Discussion 09h50 - 10h30 Coffee break Giardia lamblia mechanisms and 10h30 - 10h50 Theodore NASH vaccines 10h50 - 11h10 Discussion Ehrlichia canis, E.chaffeensis, 11h10 - 11h30 their p28 paralogs, and mechanism David WALKER of persistence Scientific Program 11h30 - 11h50 Discussion 12h00 - 14h00 Lunch Session 2 Parasites and bacteria: antigenic variation through gene conversion Chaired by David Barry and David Soll African trypanosomes: can variant surface glycoprotein gene conver- 14h00 - 14h20 Richard MC CULLOCH sion be considered a target for disease intervention? 14h20 - 14h40 Discussion Gene conversion in Babesia bovis 14h40 - 15h00 antigenic variation and its implica- David ALLRED tions for vaccine development 15h00 - 15h20 Discussion 15h20 - 15h50 Coffee Break Gene conversion in bacteria: the 15h50 - 16h10 Alan BARBOUR Borrelia models 16h10 - 16h30 Discussion Implication of antigenic variation 16h30 - 16h50 for vaccine development: the Ana- Kelly BRAYTON plasma marginale model 16h50 - 17h10 Discussion 19h00 Dinner Scientific Program Wednesday April 1, 2009 Session 3 Antigenic variation in viruses Chaired by Luisa Figueirido and James Mullins Consequences of antigenic varia- 08h30 - 08h50 Bluma BRENNER tion in terms of treatment in HIV 08h50 - 09h10 Discussion 09h10 - 09h30 Feline Caliciviruses Hervé POULET 09h30 - 09h50 Discussion 09h50 - 10h20 Coffee Break Humoral response against 10h20 - 10h40 Dimitri LAVILLETTE Hepatitis C virus 10h40 - 11h00 Discussion Molecular basis on antigenic 11h00 - 11h20 Bette KORBER variation in HIV 11h20 - 11h40 Discussion 12h00 - 14h00 Lunch Consequences of antigenic 14h00 - 14h20 Brigitte AUTRAN variation in terms of vaccines 14h20 - 14h40 Discussion Scientific Program Session 4 Microbial evolution in response to vaccination Chaired by Luc Vanhamme Evolution of pathogens in 14h40 - 15h00 Vitaly GANUSOV response to vaccination 15h00 - 15h20 Discussion 15h20 - 15h40 The case of Malaria Margaret MACKINNON 15h40 - 16h00 Discussion 16h00 - 16h20 Conclusion 16h20 End of the meeting Keynote Lecture Antigenic variation as adaptive process ............................................................... Antigenic variation as adaptive process ............................................................... Etienne PAYS Université Libre Bruxelles - Belgium ............................................................... ............................................................... Antigenic variation is classically presented as a way for parasitic organisms to escape the immune defences of their hosts. In the ............................................................... case of African trypanosomes, this process is particularly important, as the entire surface of the cell is regularly changed after only a ............................................................... few days. Moreover, the variant antigenic surface is strikingly ho- mogeneous, as it consists in a single glycoprotein species (VSG, for Variant Surface Glycoprotein) present in 10 million copies. With ............................................................... such an obvious antigen presentation, it is clear that the system is not meant to avoid the immune reaction, but rather to trigger a res- ............................................................... ponse for the benefit of the parasite.