title: Combination antiretroviral therapy and cell-cell spread of wild-type and drug-resistant human immunodeficiency virus-1.
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.
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6BT, UK.|Department of Medicine, Emory University School of Medicine, Atlanta, USA.
authors.forename: Boghuma Kabisen
authors.initials: BK
authors.lastname: Titanji
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6BT, UK.|Africa Centre for Health and Population Sciences, University of KwaZulu-Natal, KwaZulu-Natal, South Africa.
authors.forename: Deenan
authors.initials: D
authors.lastname: Pillay
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6BT, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Jolly
mesh_terms: D044966:Anti-Retroviral Agents / Q000494:pharmacology*; D023241:Antiretroviral Therapy, Highly Active; D002460:Cell Line; D024882:Drug Resistance, Viral; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D013601:T-Lymphocytes / Q000821:virology; D014776:Virus Cultivation; D053586:Virus Internalization / Q000187:drug effects*; D057074:Virus Release / Q000187:drug effects*
chemical_list: D044966:Anti-Retroviral Agents; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors