title: Persistent resistance to HIV-1 infection in CD4 T cells from exposed uninfected Vietnamese individuals is mediated by entry and post-entry blocks.
abstract: BACKGROUND
  We have previously reported that CD4 T cells from some exposed uninfected (EU) Vietnamese intravenous drug users are relatively resistant to HIV infection in vitro. Here, we further characterized the restriction of viral replication in CD4 T cells from five EUs and assessed its persistence in serial samples.
  
  
  RESULTS
  CD4 T cells and/or PBMC sampled during a period of between 2 and 6 years were challenged with replication-competent HIV-1 and other retroviral particles pseudotyped with envelope proteins of various tropisms. CCR5 expression and function in resistant CD4 T cells was evaluated. The step at which HIV-1 replication is restricted was investigated by real-time PCR quantification of HIV-1 reverse transcripts. We identified three patterns of durable HIV-1 restriction in EU CD4 T cells. CD4 T cells from four of the five EU subjects were resistant to HIV-1 R5 infection. In two cases this resistance was associated with low CCR5 surface expression, which was itself associated with heterozygous CCR5 mutations. In the other two cases, CD4 T cells were resistant to HIV-1 R5 infection despite normal CCR5 expression and signaling function, and normal beta-chemokine secretion upon CD4 T cell activation. Instead, restriction appeared to be due to enhanced CD4 T cell sensitivity to beta-chemokines in these two subjects. In the fifth EU subject the restriction involved post-entry steps of viral replication and affected not only HIV-1 but also other lentiviruses. The restriction was not overcome by a high viral inoculum, suggesting that it was not mediated by a saturable inhibitory factor.
  
  
  CONCLUSIONS
  Various constitutive mechanisms of CD4 T cell resistance to HIV-1 infection, affecting entry or post-entry steps of viral replication, are associated with resistance to HIV-1 in subjects who remain uninfected despite long-term high-risk behavior.
authors.affiliation: Unité de Régulation des Infections Rétrovirales, Institut Pasteur, Paris, France. asiersc@pasteur.fr
authors.forename: Asier
authors.initials: A
authors.lastname: Sáez-Cirión
authors.forename: Pierre
authors.initials: P
authors.lastname: Versmisse
authors.forename: Lien X
authors.initials: LX
authors.lastname: Truong
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Chakrabarti
authors.forename: Wassila
authors.initials: W
authors.lastname: Carpentier
authors.forename: Françoise
authors.initials: F
authors.lastname: Barré-Sinoussi
authors.forename: Daniel
authors.initials: D
authors.lastname: Scott-Algara
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Pancino
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D005260:Female; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology / Q000472:pathogenicity*; D006801:Humans; D007113:Immunity, Innate; D016086:Lentivirus / Q000276:immunology / Q000472:pathogenicity; D008297:Male; D008875:Middle Aged; D054399:Receptors, CCR6; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D053586:Virus Internalization; D014779:Virus Replication / Q000502:physiology
chemical_list: C106311:CCR6 protein, human; D054399:Receptors, CCR6; D019707:Receptors, Chemokine