HIV-Infected Macrophages Are Infected and Killed by the Interferon-Sensitive Rhabdovirus MG1
Open Access
- 12 April 2021
- journal article
- research article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 95 (9)
- https://doi.org/10.1128/jvi.01953-20
Abstract
The use of unique cell surface markers to target and eradicate HIV-infected cells has been a longstanding objective of HIV-1 cure research. This approach, however, overlooks the possibility that intracellular changes present within HIV-infected cells may serve as valuable therapeutic targets. For example, the identification of dysregulated antiviral signaling in cancer has led to the characterization of oncolytic viruses capable of preferentially killing cancer cells. Since impairment of cellular antiviral machinery has been proposed as a mechanism by which HIV-1 evades immune clearance, we hypothesized that HIV-infected macrophages (an important viral reservoir in vivo) would be preferentially killed by the interferon-sensitive oncolytic Maraba virus MG1. We first showed that HIV-infected monocyte-derived macrophages (MDM) were more susceptible to MG1 infection and killing than HIV-uninfected cells. As MG1 is highly sensitive to type I interferons (IFN-I), we then investigated whether we could identify IFN-I signaling differences between HIV-infected and uninfected MDM and found evidence of impaired IFN-α responsiveness within HIV-infected cells. Finally, to assess whether MG1 could target a relevant, primary cell reservoir of HIV-1, we investigated its effects in alveolar macrophages (AM) obtained from effectively treated individuals living with HIV-1. As observed with in vitro-infected MDM, we found that HIV-infected AM were preferentially eliminated by MG1. In summary, the oncolytic rhabdovirus MG1 appears to preferentially target and kill HIV-infected cells via impairment of antiviral signaling pathways and may therefore provide a novel approach to an HIV-1 cure. IMPORTANCE Human immunodeficiency virus type 1 (HIV-1) remains a treatable, but incurable, viral infection. The establishment of viral reservoirs containing latently infected cells remains the main obstacle in the search for a cure. Cure research has also focused on only one cellular target of HIV-1 (the CD4+ T cell) while largely overlooking others (such as macrophages) that contribute to HIV-1 persistence. In this study, we address these challenges by describing a potential strategy for the eradication of HIV-infected macrophages. Specifically, we show that an engineered rhabdovirus—initially developed as a cancer therapy—is capable of preferential infection and killing of HIV-infected macrophages, possibly via the same altered antiviral signaling seen in cancer cells. As this rhabdovirus is currently being explored in phase I/II clinical trials, there is potential for this approach to be readily adapted for use within the HIV-1 cure field.Funding Information
- Gouvernement du Canada | Canadian Institutes of Health Research (HIG-133050)
- Gouvernement du Canada | Canadian Institutes of Health Research (153082)
This publication has 68 references indexed in Scilit:
- Non-replicating rhabdovirus-derived particles (NRRPs) eradicate acute leukemia by direct cytolysis and induction of antitumor immunityBlood Cancer Journal, 2013
- LDL receptor and its family members serve as the cellular receptors for vesicular stomatitis virusProceedings of the National Academy of Sciences of the United States of America, 2013
- Differential expression of HIV-1 interfering factors in monocyte-derived macrophages stimulated with polarizing cytokines or interferonsScientific Reports, 2012
- Vesicular Stomatitis Virus Has Extensive Oncolytic Activity against Human Sarcomas: Rare Resistance Is Overcome by Blocking Interferon PathwaysJournal of Virology, 2011
- RIG-I-Mediated Antiviral Signaling Is Inhibited in HIV-1 Infection by a Protease-Mediated Sequestration of RIG-IJournal of Virology, 2011
- Identification of Genetically Modified Maraba Virus as an Oncolytic RhabdovirusMolecular Therapy, 2010
- ADAR1 Interacts with PKR during Human Immunodeficiency Virus Infection of Lymphocytes and Contributes to Viral ReplicationJournal of Virology, 2009
- Desensitization to type I interferon in HIV-1 infection correlates with markers of immune activation and disease progressionBlood, 2009
- Increased expression of suppressor of cytokine signaling-1 (SOCS-1): A mechanism for dysregulated T helper-1 responses in HIV-1 diseaseVirology, 2009
- Cytokine production by human leukocytes with different expressions of natural antiviral immunity and the effect of antibodies against interferons and TNF-±Archivum Immunologiae et Therapiae Experimentalis, 2007