Abstract
Cells latently infected with human immunodeficiency virus (HIV) evade immune- and drug-mediated clearance. These cells harbor intracellular signaling defects, including impairment of the antiviral type I interferon response. Such defects have also been observed in several cancers and have been exploited for the development of therapeutic oncolytic viruses, including the recombinant Maraba virus (MG1). We therefore hypothesized that MG1 would infect and eliminate cells latently infected with HIV-1, while sparing healthy uninfected cells. Preferential infection and elimination by MG1 was first demonstrated in cell lines latently infected with HIV-1. Following this, a reduction in HIV-1 DNA and inducible HIV-1 replication was observed following MG1 infection of latently infected, resting CD4+ T cells generated using an in vitro model of latency. Last, MG1 infection resulted in a reduction in HIV-1 DNA and inducible HIV-1 replication in memory CD4+ T cells isolated from effectively treated, HIV-1-infected individuals. Our results therefore highlight a novel approach to eliminate the latent HIV-1 reservoir.
Highlights
Latent human immunodeficiency virus type 1 (HIV-1) is maintained within long-lived cellular reservoirs as replication-competent, proviral DNA [1, 2]
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]
MG1 binding and entry into HIV-1–infected cells was assessed by measuring the expression of low-density lipoprotein receptor (LDL-R), the primary receptor for Maraba virus [28,29,30]
Summary
Latent human immunodeficiency virus type 1 (HIV-1) is maintained within long-lived cellular reservoirs as replication-competent, proviral DNA [1, 2]. These reservoirs are composed primarily of resting memory CD4+ T cells, which evade immune- and drug-mediated clearance and serve as a source of infectious virus upon treatment cessation [3, 4]. Impaired IFN-I signaling in cell lines latently infected with HIV-1 may represent a target for the design of therapeutic strategies intended to eliminate major HIV-1 reservoirs. Given that IFN-I signaling defects have been observed during HIV-1 infection and, importantly, in latently infected cell lines, MG1 and Cells Latently Infected With HIV-1 JID 2018:217 (1 March) 721
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