Retinoblastoma protein induction by HIV viremia or CCR5 in monocytes exposed to HIV-1 mediates protection from activation-induced apoptosis: ex vivo and in vitro study

Journal of Leukocyte Biology

Andrea D. Raymond²  Karam Mounzer¹  Jay Kostman⁴  Bethsebah Gekonge²  Ronald G. Collman³  Xiangfan Yin²  Louise Showe and²  Luis J. Montaner² 

[1] Philadelphia Field Initiating Group for HIV- Trials (FIGHT), Philadelphia, Pennsylvania, USA;The Wistar Institute, Philadelphia, Pennsylvania, USA;Department of Medicine, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania, USA The Wistar Institute, Philadelphia, Pennsylvania, USA; Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA;

关键词: inflammation;    autophagy;    chemokines;    p53;    p21;    Beclin;   

DOI  :  10.1189/jlb.1111552

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

We have previously described an antiapoptotic steady-state gene expression profile in circulating human monocytes from asymptomatic viremic HIV+ donors, but the mechanism associated with this apoptosis resistance remains to be fully elucidated. Here, we show that Rb1 activation is a dominant feature of apoptosis resistance in monocytes exposed to HIV-1 in vivo (as measured ex vivo) and in vitro. Monocytes from asymptomatic viremic HIV+ individuals show a positive correlation between levels of hypophosphorylated (active) Rb1 and VL in conjunction with increases in other p53-inducible proteins associated with antiapoptosis regulation, such as p21 and PAI-1 (SERPINE1), when compared with circulating monocytes from uninfected donors. Monocytes exposed in vitro to HIV-1 R5 isolates but not X4 isolates showed lower caspase-3 activation after apoptosis induction, indicating a role for the CCR5 signaling pathway. Moreover, monocytes exposed to R5 HIV-1 or MIP-1β induced Rb1 and p21 expression and an accumulation of autophagy markers, LC3 and Beclin. The inhibition of Rb1 activity in HIV-1 R5 viral-exposed monocytes using siRNA led to increased apoptosis sensitivity, thereby confirming a central role for Rb1 in the antiapoptotic phenotype. Our data identify Rb1 induction in chronic asymptomatic HIV-1 infection as a mediator of apoptosis resistance in monocytes in association with protective autophagy and contributing to monocyte survival during immune activation and/or HIV-1 viremia.

【 授权许可】

Unknown