title: High multiplicity HIV-1 cell-to-cell transmission from macrophages to CD4+ T cells limits antiretroviral efficacy.
abstract: OBJECTIVE
  Few studies have examined the efficacy of antiretroviral therapy (ART) in the context of cell-to-cell transmission. We aimed to determine whether the activity of ART is limited by the mode of HIV-1 spread between cells and the type of immune cell implicated in transmission, or is independent of these variables.
  
  
  METHODS
  ART activity was evaluated in primary cells using in-vitro cell-free and cell to-cell HIV-1 infection systems.
  
  
  METHODS
  HIV-1 cell-free or cell-to-cell transmission between infected monocyte-derived macrophages (MDMs) and autologous target CD4+ T cells was measured in the presence or absence of reverse transcriptase and integrase inhibitors. Viral infection was evaluated using luciferase-reporter infectious molecular HIV-1 clones carrying macrophage-tropic envelope glycoproteins (Envs). Cell-free HIV-1 was titrated to yield different multiplicities of CD4+ T-cell infection.
  
  
  RESULTS
  Whereas cell-free infection of CD4+ T cells was substantially reduced by all inhibitors, cell-to-cell spread from macrophages to CD4+ T cells was largely resistant to inhibition. However, when multiplicity of infection was controlled for, we observed no difference in antiretroviral inhibition of cell-to-cell or cell-free infection.
  
  
  CONCLUSIONS
  Cell-to-cell spread of HIV-1 reduces the probability of antiretroviral inhibition, but it is the number of infectious viruses transferred between cells rather than the specific mode of viral spread or transmitting cell type that governs antiretroviral activity. High multiplicity infection in vivo is more likely to occur by cell-to-cell transmission, and these data will inform use of ART against viral reservoirs.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Christopher J A
authors.initials: CJ
authors.lastname: Duncan
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Russell
authors.forename: Quentin J
authors.initials: QJ
authors.lastname: Sattentau
mesh_terms: D044966:Anti-Retroviral Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000821:virology*
chemical_list: D044966:Anti-Retroviral Agents