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.
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-1 β 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.
Wistar Institute, Philadelphia, Pennsylvania, USA.
Bethsebah
B
Gekonge
Andrea D
AD
Raymond
Xiangfan
X
Yin
Jay
J
Kostman
Karam
K
Mounzer
Ronald G
RG
Collman
Louise
L
Showe
Luis J
LJ
Montaner
D017209:Apoptosis / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000821:virology*; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D015533:Transcriptional Activation / Q000276:immunology; D014766:Viremia / Q000276:immunology; D038301:Virus Inactivation
D019713:Receptors, CCR5; D016160:Retinoblastoma Protein