Cellular and Viral Determinants of Innate HIV Recognition in Macrophages

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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. During the first funding period within SPP1923 we demonstrate that (a) lentiviral Vpx proteins can overcome a SAMHD1- and dNTP-independent restriction at the level of HIV reverse transcription in resting CD4 T-cells, but not in primary macrophages, (b) trans-differentiated BLaER1 cells express myeloid surface markers, the known restriction factors SAMHD1 and Mx2, and are highly phagocytic, and (c) IFNα-induced Mx2 restricts HIV-1 infection in the trans-differentiated BLaER1 cell model as well as in primary macrophages at the level of nuclear import. (d) An educated screening for putative sensors and restriction factors of lentiviruses in the trans-differentiated BLaER1 cell model indicates a thus far unappreciated suppressive role of NLRP3 and DDX1 on HIV-1 infection in myeloid cells. Building on these findings we will during the second funding period further dissect the cellular and viral determinants, PRR sensing pathways and outcomes of innate HIV recognition and restriction in human macrophages and related myeloid models. To this end, the following specific aims will be pursued: (i) Gain insight into the regulation of the Mx2-imposed restriction to HIV-1 infection, (ii) study the impact and mode of action of NLRP3 and DDX1 on infection and sensing of HIV pre-integration, (iii) define the HIV PAMPs involved in pre- and post-integration sensing, and (iv) identify the putative post-integration sensor for HIV in myeloid cells. Collectively, these studies will contribute to our understanding of the mechanisms and functional consequences of HIV recognition by the innate immune system in macrophages.