Persistent resistance to HIV-1 infection in CD4 T cells from exposed uninfected Vietnamese individuals is mediated by entry and post-entry blocks.
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.
Sáez-Cirión
Asier
A
Unité de Régulation des Infections Rétrovirales, Institut Pasteur, Paris, France. asiersc@pasteur.fr
Versmisse
Pierre
P
Truong
Lien X
LX
Chakrabarti
Lisa A
LA
Carpentier
Wassila
W
Barré-Sinoussi
Françoise
F
Scott-Algara
Daniel
D
Pancino
Gianfranco
G
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
C106311:CCR6 protein, human; D054399:Receptors, CCR6; D019707:Receptors, Chemokine