title: N-Butyldeoxynojirimycin is a broadly effective anti-HIV therapy significantly enhanced by targeted liposome delivery.
abstract: OBJECTIVE
  N-Butyldeoxynojirimycin (NB-DNJ), an inhibitor of HIV gp120 folding, was assessed as a broadly active therapy for the treatment of HIV/AIDS. Furthermore, to reduce the effective dose necessary for antiviral activity, NB-DNJ was encapsulated inside liposomes and targeted to HIV-infected cells.
  
  
  METHODS
  Thirty-one primary isolates of HIV (including drug-resistant isolates) were cultured in peripheral blood mononuclear cells to quantify the effect of NB-DNJ on viral infectivity. pH-sensitive liposomes capable of mediating the intracellular delivery of NB-DNJ inside peripheral blood mononuclear cells were used to increase drug efficacy.
  
  
  RESULTS
  NB-DNJ decreased viral infectivity with a single round of treatment by an average of 80% in HIV-1-infected and 95% in HIV-2-infected cultures. Two rounds of treatment reduced viral infectivity to below detectable levels for all isolates tested, with a calculated IC50 of 282 and 211 micromol/l for HIV-1 and HIV-2, respectively. When encapsulated inside liposomes, NB-DNJ inhibited HIV-1 with final concentrations in the nmol/l range (IC50 = 4 nmol/l), a 100 000-fold enhancement in IC50 relative to free NB-DNJ. Targeting liposomes to the gp120/gp41 complex with a CD4 molecule conjugated to the outer bilayer increased drug/liposome uptake five-fold in HIV-infected cells compared with uninfected cells. NB-DNJ CD4 liposomes demonstrated additional antiviral effects, reducing viral secretion by 81% and effectively neutralizing free viral particles to prevent further infections.
  
  
  CONCLUSIONS
  The use of targeted liposomes encapsulating NB-DNJ provides an attractive therapeutic option against all clades of HIV, including drug-resistant isolates, in an attempt to prevent disease progression to AIDS.
authors.affiliation: Oxford Antiviral Drug Discovery Unit, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, UK.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Pollock
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Dwek
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.forename: Nicole
authors.initials: N
authors.lastname: Zitzmann