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.