Type I interferon responses are impaired in latently HIV infected cells

Abstract

Background The latent HIV-1 reservoir represents the primary barrier to the eradication of HIV-1 infection. The design of novel reservoir-clearance strategies, however, is impeded in part by the inability to distinguish latently HIV-infected cells from uninfected cells. Significant impairment of the type I interferon (IFN-I) response is observed during productive HIV-1 infection. Although this remains poorly described in the context of latent HIV-1 infection, presence of potential defects may serve as a novel therapeutic target. Therefore, IFN-I pathways were characterized using two latently HIV-1-infected cell lines, U1 and OM10.1, in comparison to their respective uninfected parental U937 and HL60 cell lines.FindingsConstitutive expression and induction of important mediators of IFN-I signaling including IFNα/β cytokines, IFNAR1, MHC-I, ISG15, and PKR were evaluated following exogenous IFNα or poly(I:C) treatment. Differences in basal expression of IFNAR1, MHC-I, and PKR were observed between the latently HIV-1 infected and uninfected cell lines. In parallel, significant impairments in the induction of MHC-I, ISG15 and PKR, as well as secretion of IFNα/β cytokines were observed in response to appropriate exogenous stimulation within the two latently HIV-infected U1 and OM10.1 cells, relative to their HIV-uninfected parental cells.ConclusionsIn comparison to the HIV-uninfected U937 and HL60 cell lines, widespread defects in IFN-I responsiveness were observed within the latently HIV-infected U1 and OM10.1 cells. These impairments represent novel therapeutic targets, which may be amenable to strategies currently employed in cancer therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-016-0302-9) contains supplementary material, which is available to authorized users.

Differentiating Immune Cell Targets in Gut-Associated Lymphoid Tissue for HIV Cure

“…26 In vitro studies also support this model, as widespread defects in IFN-I responsiveness are observed within latently HIVinfected cell lines. 27 Thus, latency may be established early after transmission to avoid an IFN-mediated inflammatory response, allowing the virus to surreptitiously traffic away from the mucosa and migrate into the lymphoid tissues, where IFN resistance promotes viral replication, while creating a target-rich environment in which the virus can spread.…”

The Significance of Type-I Interferons in the Pathogenesis and Therapy of Human Immunodeficiency Virus 1 Infection

“…Unfortunately, this response is usually ineffective to suppress HIV-1 activity, due to the ability of this virus to hijack host immune system and evade the IFN-mediated antiviral activities ( 4 ). Moreover, the persistent IFN-I secretion greatly disturbs the immune homeostasis, contributing to immune activation-dependent disease progression ( 15 , 16 ).…”

The Oncolytic Virus MG1 Targets and Eliminates Cells Latently Infected With HIV-1: Implications for an HIV Cure

“…These models are characterized by extremely low frequencies of cells latently infected with HIV-1, making them poorly suited for investigating biological mechanisms of reactivation and killing. As such, cell line models have been used to investigate important differences between cells latently infected with HIV-1 and cells that are uninfected, including activation of cell death pathways upon stimulation [ 8 ] and impairment of antiviral responses mediated by type I interferon (IFN-I) [ 9 ].…”

“…HIV-1 has evolved countermeasures to escape IFN-I–mediated immune control during productive infection, including degradation of pattern-recognition receptors [ 10 , 11 ], inhibition of IFN regulatory factors [ 12 ], and impairment of antiretroviral restriction factors [ 13 , 14 ]. While the ability to investigate IFN-I signaling defects during latent infection of primary cells remains a challenge, we have recently demonstrated that the induction of various IFN-stimulated genes following IFN-α or polyinosinic:polycytidylic acid stimulation is impaired in cell lines latently infected with HIV-1 [ 9 ]. Impaired IFN-I signaling in cell lines latently infected with HIV-1 may therefore represent a target for the design of therapeutic strategies intended to eliminate major HIV-1 reservoirs.…”