SPP 1923:
Innate Sensing and Restriction of Retroviruses
DFG priority program.

Retro­virus­es com­prise a diverse group of exoge­nous and endoge­nous virus­es defined by their unique repli­ca­tion strat­e­gy to reverse-tran­scribe their RNA genome into a com­ple­men­tary DNA. Mil­lions of years of coevo­lu­tion with their mam­malian hosts gave rise to high­ly path­o­gen­ic as well as apath­o­gen­ic mem­bers of this fam­i­ly of virus­es. Evi­dence is emerg­ing that cell-type spe­cif­ic cell-autonomous com­po­nents of the innate immune sys­tem, includ­ing spe­cial­ized pat­tern recog­ni­tion recep­tors (PRRs) and broad­ly antivi­ral restric­tion fac­tors (RFs), rep­re­sent key deter­mi­nants of the fun­da­men­tal­ly dif­fer­ent out­comes of retro­vi­ral infec­tions. Spe­cif­ic para­me­ters under con­sid­er­a­tion include the effi­cien­cy of cross- and intra-species trans­mis­sion, patho­gen­e­sis, virus evo­lu­tion, and the abil­i­ty to estab­lish a chron­ic infec­tion in a new host.

The recent iden­ti­fi­ca­tion of a first set of PRRs and RFs that con­tribute to cell-autonomous immu­ni­ty against retro­virus­es has pro­vid­ed a strong impe­tus for the estab­lish­ment of an inter­dis­ci­pli­nary nation­al research net­work. This pri­or­i­ty pro­gram aims at the iden­ti­fi­ca­tion of the full mol­e­c­u­lar sens­ing and restric­tion machin­ery involved, its reg­u­la­tion, evolved virus-encod­ed coun­ter­mea­sures, and patho­phys­i­o­log­i­cal con­se­quences. To this end we will inte­grate retro­vi­rol­o­gists, immu­nol­o­gists, and experts in key tech­nolo­gies to accom­plish these goals in col­lab­o­ra­tive projects. Path­o­gen­ic and apath­o­gen­ic retro­virus­es will be inves­ti­gat­ed in cell sys­tems rang­ing from mono­typ­ic cell cul­tures to com­plex ex vivo and ani­mal mod­els (Fig. 1). These inte­grat­ed efforts will estab­lish an unprece­dent­ed spa­tio-tem­po­ral res­o­lu­tion of innate immune recog­ni­tion of retro­virus­es, quan­ti­fy and visu­al­ize the com­po­si­tion and dynam­ics of cel­lu­lar and viral nucleotides, and exploit phys­i­o­log­i­cal mod­els of trans­mis­sion and patho­gen­e­sis.

Insight into these fun­da­men­tal process­es of ongo­ing coevo­lu­tion of retro­virus­es and their hosts will not only close gaps in the land­scape of innate immu­ni­ty and inter­dis­ci­pli­nary method­ol­o­gy, but will inspire efforts to specif­i­cal­ly mod­u­late and exploit cell-autonomous recog­ni­tion events for the devel­op­ment of pre­ven­tive and ther­a­peu­tic strate­gies, for exam­ple in dis­ease caused by infec­tion with Human Immun­od­e­fi­cien­cy Virus (HIV). Since recent­ly emerg­ing evi­dence links anti-retro­vi­ral cell-autonomous immu­ni­ty to tumor devel­op­ment and autoim­mune dis­ease, knowl­edge gained with­in this pro­gram will be applic­a­ble to fields far beyond retro­vi­rol­o­gy.

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Fig. 1: Topol­o­gy of the addressed field of research at the inter­face of retro­virus biol­o­gy and cell-autonomous immu­ni­ty. Work in clas­si­cal cell cul­ture sys­tems (left) seeks to iden­ti­fy and under­stand at the mol­e­c­u­lar lev­el the full set of cell-autonomous recog­ni­tion fac­tors of retro­virus­es and result­ing effec­tor func­tions at high spa­tio-tem­po­ral res­o­lu­tion. These events under­lie cell sys­tem-spe­cif­ic reg­u­la­tion and their rel­e­vance will be eval­u­at­ed in pri­ma­ry cell and organ­otyp­ic infec­tion mod­els (mid­dle). The impact of innate recog­ni­tion will be defined for retro­vi­ral cross-species and human-to-human trans­mis­sion, evo­lu­tion­ary virus-host adap­ta­tion includ­ing poly­mor­phisms in innate genes/​viral antag­o­nists, and patho­gen­e­sis in the new host (right).

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