Absence of cGAS-mediated type I IFN responses in HIV-1–infected T cells

Abstract

The DNA sensor cGAS catalyzes the production of the cyclic dinucleotide cGAMP, resulting in type I interferon responses. We addressed the functionality of cGAS-mediated DNA sensing in human and murine T cells. Activated primary CD4+ T cells expressed cGAS and responded to plasmid DNA by upregulation of ISGs and release of bioactive interferon. In mouse T cells, cGAS KO ablated sensing of plasmid DNA, and TREX1 KO enabled cells to sense short immunostimulatory DNA. Expression of IFIT1 and MX2 was downregulated and upregulated in cGAS KO and TREX1 KO T cell lines, respectively, compared to parental cells. Despite their intact cGAS sensing pathway, human CD4+ T cells failed to mount a reverse transcriptase (RT) inhibitor-sensitive immune response following HIV-1 infection. In contrast, infection of human T cells with HSV-1 that is functionally deficient for the cGAS antagonist pUL41 (HSV-1ΔUL41N) resulted in a cGAS-dependent type I interferon response. In accordance with our results in primary CD4+ T cells, plasmid challenge or HSV-1ΔUL41N inoculation of T cell lines provoked an entirely cGAS-dependent type I interferon response, including IRF3 phosphorylation and expression of ISGs. In contrast, no RT-dependent interferon response was detected following transduction of T cell lines with VSV-G-pseudotyped lentiviral or gammaretroviral particles. Together, T cells are capable to raise a cGAS-dependent cell-intrinsic response to both plasmid DNA challenge or inoculation with HSV-1ΔUL41N. However, HIV-1 infection does not appear to trigger cGAS-mediated sensing of viral DNA in T cells, possibly by revealing viral DNA of insufficient quantity, length, and/or accessibility to cGAS.

HIV-2/SIV Vpx antagonises NF-κB activation by targeting p65

“…Thus, how Vpx impacts viral replication is very dependent on the nature of the assay, and the cells used. For example, during spreading infection in Jurkat T cells, which lack active SAMHD1 and cGAS, WT SIVmac and ∆vpx viruses replicate similarly, unless STING is activated with agonist (RR-S2 CDA), and then Vpx enhances infection, consistent with our data (28,33). The situation is certainly complex and incompletely understood.…”

Vpx enhances innate immune responses independently of SAMHD1 during HIV-1 infection

“…We and others previously reported that HIV-1 does not strongly induce innate immune responses, unless the virus is supplemented with accessory genes from other lentiviruses, carries structural or enzymatic mutations, or is treated with chemicals that alter its uncoating kinetics or interfere with its engagement with host factors [ 23 , 24 , 28 – 30 ]. We present here that ISG induction can occur when cells are challenged with excessively high virus concentrations (Fig.…”

The Role of Capsid in the Early Steps of HIV-1 Infection: New Insights into the Core of the Matter

“…Remarkably, HIV-1 evades innate immune sensing in macrophages [ 54 , 55 , 56 ] and in CD4 T-cells [ 57 ]. Instability of the capsid core during reverse transcription was shown to trigger sensing of the viral DNA by cGAS in macrophages and monocytic-like THP-1 cells [ 58 ].…”

“…The triphosphohydrolase SAMHD1 has also been shown to reduce the interferon (IFN)-type 1 response triggered by the cGAS-STING pathway, presumably because fewer viral DNA molecules are synthesised when dNTPs concentration is lowered by SAMHD1 [ 59 ]. However, capsid destabilisation did not seem to trigger cGAS sensing in CD4 T-cells [ 57 ]. Moreover, it is worth noting that the viral DNA in purified RTCs seems quite resistant to nuclease digestion [ 34 , 60 ], and fully reverse-transcribed, integration-competent “pre-integration complexes” can be extracted from the cytoplasm of acutely infected cells [ 61 , 62 ], which suggests that sensing of viral nucleic acids may be suppressed by more than one mechanism.…”