期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-28130-0
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资金
- ANRS [17218, 19206]
- Institut Pasteur (PasteurInnov TETRHIS)
- ANR [14 CE 16002901]
- Sidaction fellowship
- Pasteur Carnot MS fellowship
- ANRS fellowship
- MESR/Universite de Paris fellowship
Individuals who can naturally control HIV infection have lower levels of the viral co-receptor CCR5 in specific CD4 (+) T cells, which is due to mutations or receptor internalization. These individuals also maintain CD4 + T cells with high avidity for Gag antigens and potent effector functions. The downregulation of CCR5 in specific CD4 + T cells contributes to decreased susceptibility to CCR5-dependent HIV entry in these individuals.
Here, Claireaux et al. show that people who naturally control HIV infection express lower levels of the viral co-receptor CCR5 in specific CD4(+) T cells, and that this results from mutations or receptor internalization by CD4(+) T cell-produced chemokines. HIV elite controllers maintain a population of CD4 + T cells endowed with high avidity for Gag antigens and potent effector functions. How these HIV-specific cells avoid infection and depletion upon encounter with the virus remains incompletely understood. Ex vivo characterization of single Gag-specific CD4 + T cells reveals an advanced Th1 differentiation pattern in controllers, except for the CCR5 marker, which is downregulated compared to specific cells of treated patients. Accordingly, controller specific CD4 + T cells show decreased susceptibility to CCR5-dependent HIV entry. Two controllers carried biallelic mutations impairing CCR5 surface expression, indicating that in rare cases CCR5 downregulation can have a direct genetic cause. Increased expression of beta-chemokine ligands upon high-avidity antigen/TCR interactions contributes to autocrine CCR5 downregulation in controllers without CCR5 mutations. These findings suggest that genetic and functional regulation of the primary HIV coreceptor CCR5 play a key role in promoting natural HIV control.
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