Besides CD4 T‑cells, macrophages con­sti­tute the major tar­get cells for HIV infec­tion. Macrophages com­prise a crit­i­cal in vivo-reser­voir and play an impor­tant role in shap­ing the immune response. Lit­tle is known about their innate sens­ing mech­a­nisms to detect HIV and the down­stream con­se­quences. Study­ing mono­cyte-derived macrophages (MDMs), we observed that HIV elic­its antivi­ral gene expres­sion at a step post-inte­gra­tion. More­over, deple­tion of the nucle­ic acid pat­tern recog­ni­tion recep­tors (PRRs) IFI16 or AIM2 marked­ly enhanced infec­tion and ear­ly HIV gene expres­sion. Notably, expres­sion of inter­fer­on-stim­u­lat­ed genes (ISGs) was upreg­u­lat­ed in HIV-infect­ed MDMs deplet­ed of IFI16 or AIM2, call­ing into ques­tion a direct role of these PRRs in the ini­ti­a­tion of antivi­ral respons­es. Employ­ing a nov­el macrophage trans-dif­fer­en­ti­a­tion sys­tem that is amenable to com­plex genet­ic manip­u­la­tion side-by-side with stud­ies in MDMs, we aim at deter­min­ing (i) the PRRs that are involved in the recog­ni­tion of HIV, (ii) the stages of the repli­ca­tion cycle at which engage­ment occurs, (iii) the viral nucle­ic acid and pro­tein com­po­nents that are rec­og­nized, and (iv) the func­tion­al con­se­quences of this innate pathogen sens­ing. Col­lec­tive­ly, these stud­ies will con­tribute to our under­stand­ing of the mech­a­nisms and func­tion­al con­se­quences of HIV recog­ni­tion by the innate immune sys­tem in macrophages.