Impairment of the type I interferon response by HIV-1: Potential targets for HIV eradication

Abstract

By interfering with the type I interferon (IFN1) response, human immunodeficiency virus 1 (HIV-1) can circumvent host antiviral signalling and establish persistent viral reservoirs. HIV-1-mediated defects in the IFN pathway are numerous, and include the impairment of protein receptors involved in pathogen detection, downstream signalling cascades required for IFN1 upregulation, and expression or function of key IFN1-inducible, antiviral proteins. Despite this, the activation of IFN1-inducible, antiviral proteins has been shown to facilitate the killing of latently HIV-infected cells in vitro. Understanding how IFN1 signalling is blocked in physiologically-relevant models of HIV-1 infection, and whether these defects can be reversed, is therefore of great importance for the development of novel therapeutic strategies aimed at eradicating the HIV-1 reservoir.

Type I interferon and HIV: Subtle balance between antiviral activity, immunopathogenesis and the microbiome

“…In particular, HIV-1 has evolved to use host cofactors, such as CPSF6 and cyclophilins recuited to its capsid, to cloak its moltiplaction, permitting evasion of PRRs and cGAS, and type I IFN secretion and initiation of an antiviral state [92]. Further defects in innate viral sensing during HIV-1 infection involve the PRRs, cGAS and IFI16 by inducing TREX1 expression and inhibiting NF-κB activation by HIV-1 Vpu [93]. Moreover, an impaired TLRs and RIG1 response can be recorded during HIV-1 infection [93].…”

“…Further defects in innate viral sensing during HIV-1 infection involve the PRRs, cGAS and IFI16 by inducing TREX1 expression and inhibiting NF-κB activation by HIV-1 Vpu [93]. Moreover, an impaired TLRs and RIG1 response can be recorded during HIV-1 infection [93]. HIV-1 can also affect PRR-mediated signaling through the inhibition of several downstream effectors including IRF3 and IRF7 levels and/or activity [89,90,93].…”

“…Moreover, an impaired TLRs and RIG1 response can be recorded during HIV-1 infection [93]. HIV-1 can also affect PRR-mediated signaling through the inhibition of several downstream effectors including IRF3 and IRF7 levels and/or activity [89,90,93]. Following type I IFN production, HIV-1 can also subvert their mechanism of action ( Fig.…”

“…PKR, 2-5 OAS, and ISG15) and the recently identified retroviral restriction factors (e.g. APOBEC3, BST-2, and Mx2) [85,93]. Controversial results have been reported on the ability of type I IFNs to directly induce the restriction factor, namely SAMHD1 [97,98].…”

“…Controversial results have been reported on the ability of type I IFNs to directly induce the restriction factor, namely SAMHD1 [97,98]. However, besides the established ability of HIV-2 to subvert SAMHD1 activity through the vpx gene, SAMHD1 can be regulated by type I IFN treatment by phosphorylation at threonine 592 and IRF3 can be responsible for the direct induction of SAMHD1 [93,99]. Hence, it is clear that in order to replicate efficiently, HIV-1 has evolved multiple strategies to circumvent the 'first line of defense' embodied by type I IFN.…”