Combination antiretroviral therapy and cell-cell spread of wild-type and drug-resistant human immunodeficiency virus-1

• Type of Material: Article
• Authors: Boghuma Titanji, Emory University; Deenan Pillay, University College London; Clare Jolly, University College London
• Language: English
• Date: 2017-04-01
• Publisher: MICROBIOLOGY SOC
• Publication Version: Final Published Version
• Copyright Statement: © 2017 The Authors
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1099/jgv.0.000728
• Title of Journal or Parent Work: JOURNAL OF GENERAL VIROLOGY
• Volume: 98
• Issue: 4
• Start Page: 821
• End Page: 834
• Grant/Funding Information: This work was supported by a Commonwealth Scholarship to B.T.; and a UK Medical Research Council Career Development Fellowship (G0800312) and a Wellcome Trust Investigator Award (108079/Z/15/Z) to C.J. We also acknowledge support from the European Union funded FP7 CHAIN programme (HEALTH-2007 223131), the NIHR UCL Hospitals Biomedical Research Centre and the UCL/MRC Centre for Medical Molecular Virology.
• Keywords: VIROLOGICAL SYNAPSES; CD4(+) T-CELLS; MUTATIONS; drug resistance; PROTEASE INHIBITORS; Virology; Biotechnology & Applied Microbiology; LATENT RESERVOIR; HIV-1 INFECTION; Science & Technology; HIV; REVERSE-TRANSCRIPTASE INHIBITORS; Life Sciences & Biomedicine; TRANSMISSION; cell-cell; SYNERGISTIC IN-VITRO; VIRAL REPLICATION; cART; T cell
• Research Categories: Biology, Cell; Biology, Virology; Health Sciences, Immunology

Abstract

Human immunodeficiency virus-1 (HIV-1) disseminates between T cells either by cell-free infection or by highly efficient direct cell–cell spread. The high local multiplicity that characterizes cell–cell infection causes variability in the effectiveness of antiretroviral drugs applied as single agents. Whereas protease inhibitors (PIs) are effective inhibitors of HIV-1 cell–cell and cell-free infection, some reverse transcriptase inhibitors (RTIs) show reduced potency; however, antiretrovirals are not administered as single agents and are used clinically as combination antiretroviral therapy (cART). Here we explored the efficacy of PI- and RTI-based cART against cell–cell spread of wild-type and drug-resistant HIV-1 strains. Using a quantitative assay to measure cell–cell spread of HIV-1 between T cells, we evaluated the efficacy of different clinically relevant drug combinations. We show that combining PIs and RTIs improves the potency of inhibition of HIV-1 and effectively blocks both cell-free and cell–cell spread. Combining drugs that alone are poor inhibitors of cell–cell spread markedly improves HIV-1 inhibition, demonstrating that clinically relevant combinations of ART can inhibit this mode of HIV-1 spread. Furthermore, comparison of wild-type and drug-resistant viruses reveals that PI- and RTI-resistant viruses have a replicative advantage over wild-type virus when spreading by cell–cell means in the presence of cART, suggesting that in the context of inadequate drug combinations or drug resistance, cell–cell spread could potentially allow for ongoing viral replication.