Research
Persistent resistance to HIV-1 infection in CD4 T cells from exposed uninfected Vietnamese individuals is mediated by entry and post-entry blocks
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* Corresponding author: Gianfranco Pancino gpancino@pasteur.fr
1 Unité de Régulation des Infections Rétrovirales, Institut Pasteur, Paris, France
2 Retrovirology and Viral Hepatitis Laboratory, Institut Pasteur, Ho Chi Minh City, Vietnam
3 Laboratoire de Pathogénie Virale Moléculaire, Institut Pasteur, Paris, France
4 Laboratoire d'Immunologie Cellulaire, UR INSERM 543, Faculté de Médecine Pitié-Salpétrière, Paris, France
5 Unité d'Immunogénétique Cellulaire, Institut Pasteur, Paris, France
Retrovirology 2006, 3:81 doi:10.1186/1742-4690-3-81
Published: 8 November 2006Abstract
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 β-chemokine secretion upon CD4 T cell activation. Instead, restriction appeared to be due to enhanced CD4 T cell sensitivity to β-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.
Conclusion
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.