Investigation of cellular mechanisms of PQBP1-dependant innate signaling of HIV‑1

Project Member

Dr. Renate König

Project Leader

Dr. Renate König

Phone: +49 6103 77 – 4019
Fax: +49 6103 77 – 1255
Renate.Koenig@pei.de
RKoenig@sbpdiscovery.org

Research Group König

Paul-Ehrlich-Insti­tut
Fed­er­al Insti­tute for Vac­cines
and Bio­med­i­cines
Paul-Ehrlich-Str. 51 – 59
63225 Lan­gen
Ger­many

Immu­ni­ty and Patho­gen­e­sis Pro­gram
San­ford Burn­ham Pre­bys (SBP)
Med­ical Dis­cov­ery Insti­tute
La Jol­la, CA 92037, USA

Dr. Nina Hein-Fuchs,
Post­doc

Maïwenn Bergez,
PhD Stu­dent

Project Summary

In a col­lab­o­ra­tive pub­li­ca­tion, PQBP1 was iden­ti­fied as an essen­tial com­po­nent of the cGAS/IR­F3-depen­dent innate response to HIV. PQBP1 binds to HIV1 DNA after reverse tran­scrip­tion, and acti­vates cGAS to pro­duce the sec­ond mes­sen­ger cGAMP to induce STING/​IRF3 sig­nalling. Inter­est­ing­ly, the require­ment for PQBP1 appears to be spe­cif­ic for lentivi­ral DNA, as oth­er types of DNA, includ­ing poxvirus, did not require PQBP1 to stim­u­late innate immune respons­es. How­ev­er, spe­cif­ic details of the PQBP1/​cGAS innate recep­tor com­plex and the under­ly­ing mech­a­nism influ­enc­ing sens­ing are not known (Yin et al., 2020). There­fore, in the first fund­ing peri­od, we were inter­est­ed, whether oth­er mem­bers of the Retro­viri­dae fam­i­ly are depen­dent on cGAS/IR­F3- and PQBP1-depen­dent innate respons­es (Bergez et al., 2019). Fur­ther­more, we gen­er­at­ed and char­ac­ter­ized hiP­SCs from PQBP1-mutat­ed Ren­pen­ning-syn­drome patients and healthy donor con­trols in order to pro­vide an unlim­it­ed pool of rel­e­vant pri­ma­ry innate cells to ana­lyze PQBP1 require­ment and func­tions (Fuchs NV et al., 2020; Fuchs NV et al., 2019). The main goals of the new fund­ing peri­od are to define the speci­fici­ty of PQBP1-depen­dent sens­ing and the under­ly­ing mech­a­nisms. Ini­tial­ly, we will exam­ine oth­er gen­era of the Retro­viri­dae fam­i­ly in com­par­i­son to DNA virus­es to under­stand the breadth of PQBP1 recog­ni­tion. More­over, we aim to detect the reverse tran­scribed DNA inter­me­di­ates bound to PQBP1 in order to under­stand their com­mon­al­i­ties. We aim to ana­lyze whether cGAS is required for this step. Fur­ther­more, we are inter­est­ed in the under­ly­ing mech­a­nisms. We will deter­mine whether infec­tion of virus­es rec­og­nized by PQBP1 specif­i­cal­ly enhance the bind­ing between PQBP1 and cGAS and whether spe­cif­ic PTMs are involved. Our results will pro­vide new insights into the cel­lu­lar mech­a­nism under­ly­ing PQBP1-depen­dant innate sig­nal­ing of HIV‑1.