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C102 Cell-intrinsic mechanisms of HIV-1 immune defense in elite controllers

Leng Jin; Ho, Hsin-Pin; Yu, Xu G.; Chang, Emmanuel; Lichterfeld, Mathias
JAIDS Journal of Acquired Immune Deficiency Syndromes: April 2013
doi: 10.1097/01.qai.0000429220.61759.1b
Abstracts: PDF Only

Elite controllers represent a rare group of HIV-1 infected persons who maintain undetectable HIV-1 viral loads in the absence of antiretroviral therapy, and may serve as a model for a functional cure of HIV-1 infection. HIV-1-specific CD8 T cells are likely to represent an important mechanism of HIV-1 immune defense in these patients, however, growing evidence suggest that cell-intrinsic mechanisms that restrict various HIV-1 replication steps in CD4 target cells may also critically contribute to HIV-1 immune defense in this patients population. In previous studies, we have shown that CD4 T cells from elite controllers recruited through the HIV Controller Consortium are less susceptible to HIV-1 infection, and similar findings were reported in patients recruited in an alternative cohort of elite controllers in France. Both studies agreed that inhibition of early, pre-integration viral replication steps contributed to reduced CD4 T cell susceptibility to viral infection, but underlying mechanisms remained unclear. In this presentation, we will present new data demonstrating that a selective upregulation of cell-intrinsic cyclin-dependent kinase inhibitors (CDKI) in CD4 T cells from elite controllers can effectively reduce viral reverse transcription. We show that HIV-1 reverse transcriptase is phosphorylated at a highly conserved residue by cytoplasmic cyclin-dependent kinases (CDK), which increases the effectiveness of HIV-1 reverse transcription in CD4 T cells. This CDK-dependent activation of Reverse Transcriptase is effectively inhibited by cell-intrinsic CDKI. Thus, these data demonstrate a novel, indirect mechanism that can effectively reduce HIV-1 reverse transcription in elite controllers.

© 2013 Lippincott Williams & Wilkins, Inc.