Protease inhibitors effectively block cell-to-cell spread of HIV-1 between T cells

• Type of Material: Article
• Authors: Boghuma Titanji, Emory University; Marlen Aasa-Chapman, University College London; Deenan Pillay, University College London; Clare Jolly, University College London
• Language: English
• Date: 2013-12-24
• Publisher: BIOMED CENTRAL LTD
• Publication Version: Final Published Version
• Copyright Statement: © 2013 Titanji et al.; licensee BioMed Central Ltd.
• License: Creative Commons Attribution 2.0 Generic
• Final Published Version (URL): http://dx.doi.org/10.1186/1742-4690-10-161
• Title of Journal or Parent Work: RETROVIROLOGY
• Volume: 10
• Start Page: 161
• End Page: 161
• Grant/Funding Information: This work was supported by a Commonwealth Scholarship to BT:, and a UK Medical Research Council Career Development Fellowship (G0800312) to CJ. We also acknowledge support from the European Union funded FP7 CHAIN program (HEALTH-2007 223131), the NIHR UCL Hospitals Biomedical Research Centre and the UCL/MRC Centre for Medical Molecular Virology.
• Keywords: SUPPRESSIVE ANTIRETROVIRAL THERAPY; TREATMENT INTENSIFICATION; Virology; Cell-cell spread; REPLICATION; Virological synapse; PHARMACOKINETICS; INFECTION; ART; VIROLOGICAL SYNAPSES; HIV-1; RALTEGRAVIR; Life Sciences & Biomedicine; Protease inhibitor; Science & Technology; IMMUNODEFICIENCY-VIRUS TYPE-1; TRANSMISSION; RESISTANCE
• Research Categories: Health Sciences, Immunology; Biology, Virology

Abstract

The Human Immunodeficiency Virus type-1 (HIV-1) spreads by cell-free diffusion and by direct cell-to-cell transfer, the latter being a significantly more efficient mode of transmission. Recently it has been suggested that cell-to-cell spread may permit ongoing virus replication in the presence of antiretroviral therapy (ART) based on studies performed using Reverse Transcriptase Inhibitors (RTIs). Protease Inhibitors (PIs) constitute an important component of ART; however whether this class of inhibitors can suppress cell-to-cell transfer of HIV-1 is unexplored. Here we have evaluated the inhibitory effect of PIs during cell-to-cell spread of HIV-1 between T lymphocytes. Using quantitative assays in cell line and primary cell systems that directly measure the early steps of HIV-1 infection we find that the PIs Lopinavir and Darunavir are equally potent against both cell-free and cell-to-cell spread of HIV-1. We further show that a protease resistant mutant maintains its resistant phenotype during cell-to-cell spread and is transmitted more efficiently than wild-type virus in the presence of drug. By contrast we find that T cell-T cell spread of HIV-1 is 4-20 fold more resistant to inhibition by the RTIs Nevirapine, Zidovudine and Tenofovir. Notably, varying the ratio of infected and uninfected cells in co-culture impacted on the degree of inhibition, indicating that the relative efficacy of ART is dependent on the multiplicity of infection. We conclude that if the variable effects of antiviral drugs on cell-to-cell virus dissemination of HIV-1 do indeed impact on viral replication and maintenance of viral reservoirs this is likely to be influenced by the antiviral drug class, since PIs appear particularly effective against both modes of HIV-1 spread.