IFI16 DNA Sensor Is Required for Death of Lymphoid CD4 T Cells Abortively Infected with HIV

Abstract

The progressive depletion of quiescent “bystander” CD4 T-cells, which are non-permissive to HIV infection, is a principal driver of the acquired immunodeficiency syndrome (AIDS). These cells undergo abortive infection characterized by the cytosolic accumulation of incomplete HIV reverse transcripts. These viral DNAs are sensed by an unidentified host sensor that triggers an innate immune response, leading to caspase-1 activation and pyroptosis. Using unbiased proteomic and targeted biochemical approaches as well as two independent methods of lentiviral shRNA-mediated gene knockdown in primary CD4 T-cells, we identify Interferon gamma Inducible protein 16 (IFI16) as a host DNA sensor required for CD4 T-cell death due to abortive HIV infection. These findings provide insights into a key host pathway that plays a central role in CD4 T-cell depletion during disease progression to AIDS.

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.…”

“…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].…”

“…As such, in macrophages IFI16 contributes to the detection and early control of HIV in these cells. However, abortive infection of CD4 + T cells with HIV, which leads to accumulation of HIV DNA, causes IFI16-dependent pyroptosis [51], since like AIM2, IFI16 activation can also promote inflammasome activation in some contexts. IFI16-dependent inflammasome activation has been reported to also occur after infection with herpes viruses such as KSHV, HSV-1 and EBV [11,44,45].…”

“…Caspase-1, which is activated following HIV DNA recognition by IFI16 [51] has been targeted using a caspase-1 inhibitor that is safe for use in humans. This inhibitor has been shown to block caspase-1 cleavage, IL-1b secretion and CD4 + T cell death [70], demonstrating that inhibiting IFI16 induced signalling in HIV patients has great therapeutic promise.…”

Burn the house, save the day: pyroptosis in pathogen restriction

“…Depletion of CD4 T cells is a hallmark of HIV pathophysiology, and is the main driver of acquired immunodeficiency syndrome (AIDS) [42]. Two recent studies unravelled mechanisms of CD4 T cell depletion during HIV infection [43,44]. The authors demonstrated that abortive HIV infection in quiescent CD4 T cells triggered caspase-1-mediated pyroptosis.…”