The over­all goal of this fol­low-up research pro­pos­al is to define the con­tri­bu­tion of base-line, cell-intrin­sic innate immu­ni­ty to HIV‑1 laten­cy estab­lish­ment and rever­sal. The over­ar­ch­ing hypoth­e­sis is that cur­rent “shock-and-kill” strate­gies suf­fer from the pres­ence of cell-intrin­sic innate immu­ni­ty and/​or its con­cur­rent acti­va­tion by the “shock” ele­ment, which impairs full-blown HIV‑1 reac­ti­va­tion due to the con­tri­bu­tion of ton­ic expres­sion lev­els of PRRs, includ­ing cGAS, and cel­lu­lar restric­tion fac­tors with post-inte­gra­tional antivi­ral activ­i­ty. Based on our recent find­ings and our pre­vi­ous exper­tise on cell-intrin­sic immu­ni­ty in T‑cells in the con­text of HIV‑1 infec­tion, we will estab­lish the cGAS-depen­dent gene expres­sion pro­file in HIV-1-rel­e­vant tar­get cells and define the expres­sion pro­files of key pat­tern recog­ni­tion recep­tors and antivi­ral inter­fer­on-stim­u­lat­ed genes upon treat­ment with indi­vid­ual laten­cy-revers­ing agents and com­bi­na­tions there­of. Using estab­lished mod­el cell lines and cells from aviremic HIV‑1 patients, we will inves­ti­gate to which degree cGAS con­tributes to HIV‑1 laten­cy estab­lish­ment and ana­lyze the impact of cGAS on phar­ma­co­log­i­cal reac­ti­va­tion of HIV‑1. Final­ly, we will probe inhi­bi­tion of cGAS activ­i­ty and sig­nal­ing as a strat­e­gy to improve LRA-medi­at­ed HIV‑1 reac­ti­va­tion in T‑cells. This work has the poten­tial to widen our under­stand­ing on the inter­play of HIV‑1 laten­cy and cell-intrin­sic innate immu­ni­ty, and to improve cur­rent­ly inef­fi­cient “shock-and-kill” approach­es of HIV‑1 cure.