HIV-1 Is a Poor Inducer of Innate Immune Responses

Abstract

Human immunodeficiency virus type 1 (HIV-1) continues to be a major burden to human health worldwide. How infected cells recognize and respond to HIV-1 infection is important in order to better understand the biology of the virus and the cellular pathways activated upon infection and to identify potential targets that interfere with viral replication. In this study, we investigated innate immune responses of different cell types following infection with single-cycle (replication-defective) HIV-1 reporter virus. We report that infection with a commonly used HIV-1 strain (lacking the env, nef, and vpr genes) does not measurably activate cellular defense mechanisms and that the virus is able to avoid recognition by cellular sensors.

Disrupting HIV ‐1 capsid formation causes cGAS sensing of viral DNA

“…Infection of PMA-treated THP-1 shSAMHD1 cells with HIV-1 GFP that had been produced in the presence of increasing doses of LPV led to a virus and LPV dose-dependent increase in the expression of ISGs CXCL-10, IFIT-2 and MxA at the mRNA level ( Fig 1D-F), and CXCL-10 protein secretion ( Fig 1G). In agreement with previous reports (Cingoz & Goff, 2019), HIV-1 GFP produced in the absence of LPV induced very little, or no ISG expression in THP-1 cells at the doses tested, consistent with the hypothesis that HIV-1 shields its PAMPs from cellular PRRs (see Fig 1D-G, 0 nM drug dose). Virus dose in these experiments was normalised according to RT activity, as measured by SG-PERT (see Methods), which differed no more than fivefold in the LPV-treated versus LPV-untreated virus.…”

“…Of course, detection of infection by sensing is not universal and viruses are expected to hide their PAMPs and typically have mechanisms to antagonise specific sensors and downstream restriction factors. Work from our laboratory, and others, has demonstrated that primary monocyte-derived macrophages (MDMs) (Tsang et al, 2009;Rasaiyaah et al, 2013) and THP-1 cells (Cingoz & Goff, 2019) can be infected by wild-type (WT) HIV-1 without significant innate immune induction. However, MDM senses HIV-1 if, for example, mutations are made in the capsid protein to prevent the recruitment of cellular cofactors such as CPSF6 and cyclophilin A (Rasaiyaah et al, 2013), after depletion of the cellular exonuclease TREX1 (Yan et al, 2010;Rasaiyaah et al, 2013) and HIV can be sensed by a process requiring NONO if restriction by SAMHD1 is overcome (Lahaye et al, 2018).…”

Transcriptome Profiling of Human Monocyte-Derived Macrophages Upon CCL2 Neutralization Reveals an Association Between Activation of Innate Immune Pathways and Restriction of HIV-1 Gene Expression

“…Macrophages are potent cells of the innate immune system that initiate and regulate wide-ranging immunological responses. A body of evidence suggests that the role of macrophages in cellular host defense may be compromised by HIV-1 infection, which also appears to be ineffective in triggering innate immune activation in these as well as in other cells (9,10). By interfering with innate responses, HIV-1 can circumvent host antiviral signaling and establish persistent viral reservoirs.…”

HIV-1 Vpr antagonizes innate immune activation by targeting karyopherin-mediated NF-κB/IRF3 nuclear transport

“…We propose that Vpr interacts with karyopherin KPNA1 ( Figure 7) to inhibit nuclear transport of activated IRF3 and NF-ĸB (Figure 5-7) and subsequent gene expression changes downstream of innate immune sensing (Figures 1-3). Thus, HIV-1 Vpr antagonizes the consequences of innate immune activation by HIV-derived, and non-HIV derived PAMPs alike, explaining its importance for maximal replication in macrophages because activated T cells, and most cell lines, respond to innate immune agonists poorly, particularly DNA based PAMPs ( Figure 1) (Cingöz & Goff, 2019;de Queiroz et al, 2019;Heiber & Barber, 2012;. We propose that previous demonstrations of Vpr dependent HIV-1 replication in macrophages, that depended on Vpr-NPC association, or nuclear transport factors, are explained by Vpr inhibition of innate immune sensing and subsequent antiviral responses Vodicka et al, 1998).…”

“…Yan et al, 2010;Zila et al, 2019). Cingoz et al reported failure of VSV-G pseudotyped HIV-1 (∆Env, ∆Nef, ∆Vpr) to activate sensing in a variety of cell lines (Cingöz & Goff, 2019). However, other studies have demonstrated sensing of wild type HIV-1 DNA by cGAS (Gao et al, 2013;Lahaye et al, 2013), and here we observed cGASdependent, Vpr-sensitive, induction of CXCL10 or NF-ĸB reporter by high dose (MOI 3) VSV-G pseudotyped single round HIV-1 GFP vector in THP-1 cells (Figure 1, 6).…”