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. 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 iden­ti­fi­ca­tion of a series of PRRs and RFs that con­tribute to cell-autonomous immu­ni­ty against retro­virus­es pro­vid­ed a strong impe­tus for the estab­lish­ment of the inter­dis­ci­pli­nary nation­al research net­work SPP1923. The over­all goal of SPP1923 is to inte­grate experts in retro­vi­rol­o­gy and innate immu­ni­ty to assem­ble a nation­al net­work that address­es key open ques­tions on the inter­play of retro­virus­es with the cell-autonomous immune sys­tem of their hosts in col­lab­o­ra­tive projects. By these com­bined efforts, we aim at the iden­ti­fi­ca­tion of the full mol­e­c­u­lar sens­ing and restric­tion machin­ery involved, its reg­u­la­tion, evolved virus-encod­ed coun­ter­mea­sures, and patho­phys­i­o­log­i­cal con­se­quences. Path­o­gen­ic and apath­o­gen­ic retro­virus­es will be inves­ti­gat­ed in cell sys­tems rang­ing from mono­typ­ic cell cul­tures to com­plex ex vivo and ani­mal mod­els (Fig. 1). At these dif­fer­ent lev­els of com­plex­i­ty, SPP1923 aims at dis­sect­ing mech­a­nisms of innate immune recog­ni­tion, viral eva­sion and coun­ter­ac­tion there­of and at defin­ing the func­tion­al con­se­quences of these virus-host inter­ac­tions.

With­in the fam­i­ly of retro­virus­es, sev­er­al vari­a­tions of this repli­ca­tion strat­e­gy exist that result in expo­sure of dis­tinct PAMPs to host cell PRRs at dif­fer­ent stages of their life cycle (Fig. 2). Elu­ci­dat­ing the sim­i­lar­i­ties and dif­fer­ences of the inter­play and patho­log­i­cal impact of these dif­fer­ent class­es of retro­virus­es with the innate immune sys­tem of humans, non-human pri­mates and rodents will pro­vide insights into both virus and host coevo­lu­tion and con­sti­tutes anoth­er cen­tral goal of this ini­tia­tive. Class­es of retro­virus­es stud­ied with­in SPP1923 include path­o­gen­ic exoge­nous orthoretro­virus­es (e.g. HIV‑1), Spumaretro­virus­es (e.g. Foamy virus) as well as endoge­nous retro­virus­es and retro­vi­ral ele­ments.

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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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