The RNA and cDNA of HIV‑1 (human immun­od­e­fi­cien­cy virus type 1) can be rec­og­nized and sensed by macrophage and den­drit­ic cell-expressed endo­so­mal Toll-like recep­tors and cytoso­lic sen­sor, cGAS respec­tive­ly. cGAS-cDNA inter­ac­tion induces cGAMP pro­duc­tion, which stim­u­lates STING dimer­iza­tion and acti­va­tion. STING medi­ates TBK1 acti­va­tion, which sub­se­quent­ly phos­pho­ry­lates IRF3, dri­ving IFN‑α/​β induc­tion. IFN‑α/​β sig­nals back via the IFN‑α recep­tor 1 and 2 (IFNAR1/​2), induc­ing a pletho­ra of IFN stim­u­lat­ed gene (ISGs), includ­ing ISG15 and p21. p21 exhibits antivi­ral activ­i­ty against retro­virus­es by acti­vat­ing SAMHD1 restric­tion func­tion and repress­ing key enzymes involved in de novo dNTP biosyn­the­sis. ISG15 exhibits antivi­ral activ­i­ty by acti­vat­ing cel­lu­lar fac­tors required to block viral infec­tion through ISGylation.

USP18 is an ISG15-spe­cif­ic isopep­ti­dase, and neg­a­tive­ly reg­u­lates IFN sig­nal­ing. USP18 also abro­gates NF-κB sig­nal­ing by medi­at­ing TAK1 and NEMO deu­biq­ui­ti­na­tion in a pro­tease depen­dent and inde­pen­dent man­ner. Although USP18 plays an impor­tant role in innate immune respons­es by neg­a­tive­ly reg­u­lat­ing type I and III IFNs and medi­ates deIS­Gy­la­tion of key antivi­ral pro­teins, its role in HIV‑1 infec­tion, recog­ni­tion and sens­ing in innate tar­get cells has not been explored.

With­in the frame­work of SPP1923, we showed in our first pub­li­ca­tion that HIV‑1 induces USP18 expres­sion and the pres­ence of USP18 con­tributes to HIV‑1 repli­ca­tion by abro­gat­ing p21 antivi­ral func­tion. In a fol­low-up work, we pro­vid­ed a mech­a­nis­tic detail to USP18-medi­at­ed abro­ga­tion of p21 antivi­ral activ­i­ty. We con­firmed that p53 is HIV-1-inducible. How­ev­er, USP18, by its pro­tease activ­i­ty, accu­mu­lat­ed mis­fold­ed dom­i­nant neg­a­tive p53, which abro­gat­ed wild type p53 trans­ac­ti­va­tion of p21 lead­ing to an expand­ed intra­cel­lu­lar dNTP pool, inac­ti­vat­ed SAMHD1 and increased HIV‑1 reverse tran­scrip­tion products.