IFI16 senses DNA forms of the lentiviral replication cycle and controls HIV-1 replication

The emerging role of human PYHIN proteins in innate immunity: Implications for health and disease

“…As mentioned earlier IFI16 is an important sensor for HIV DNA in multiple cell types [46,51]. This work was further supported with findings from HIV patients demonstrating that they have elevated IFI16 levels, possibly arising as a result of chronic immune activation.…”

“…In contrast to AIM2, DNA recognition by IFI16 can occur in both the cytosolic and nuclear compartments. For example DNA which has been transfected, lentiviral DNA that has accumulated or herpesvirus DNA which has been exposed in the cytosol can be detected by cytosolic IFI16 [2,46,48] while DNA from nuclear viruses such as HCMV is detected in the nucleus [10,49]. As mentioned earlier, the NLS of IFI16 is required for the nuclear localisation of IFI16.…”

“…Importantly, in macrophages IFI16 was shown to bind not only dsDNA, but also ssDNA containing long stem structures and terminal loop regions that form a duplex structure, both which are produced during the HIV lentiviral life cycle [46]. As such, in macrophages IFI16 contributes to the detection and early control of HIV in these cells.…”

“…As with AIM2, the sequence independent DNA binding by IFI16 is achieved by electrostatic attraction between positively charged HIN domain residues and the dsDNA sugar phosphate backbone [41]. This allows IFI16 to detect dsDNA from many sources including Kaposi's sarcoma-related herpesvirus (KSHV) [11], Epstein-Barr virus (EBV) [44], herpes simplex virus 1 (HSV-1) [45] and human immunodeficiency virus (HIV-1) [46]. On the contrary, dsDNA sensing by IFI16 is length dependent [2], with dsDNA fragments of 150 base pairs reportedly being favourable for the formation of an optimal binding cluster of approximately ten IFI16 protomers [47].…”

“…Recently, IFI16 has been identified as a host receptor responsible for the detection of HIV DNA in macrophages and CD4 + T cells [46,51]. Importantly, in macrophages IFI16 was shown to bind not only dsDNA, but also ssDNA containing long stem structures and terminal loop regions that form a duplex structure, both which are produced during the HIV lentiviral life cycle [46].…”