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178 Targeting Cell Cycle to Enhance the Potency of Antiretroviral Therapeutic Agents

Redfield, Robert R M.D.

JAIDS Journal of Acquired Immune Deficiency Syndromes: April 2011 - Volume 56 - Issue - p 74
doi: 10.1097/01.qai.0000397361.91663.c8

Institute of Human Virology, Baltimore MD

HIV exploits cell cycle and key host cell pathways to complete its viral life cycle. As such, both cell cycle and specific host cell pathways could serve as potential therapeutic targets. Two examples of targeting cell cycle and specific host cell pathways will be discussed: targeting CCR5 density via use of agents causing a prolongation of G1- S phase transition; and targeting ribonucleotide reductase in association with induction of prolongation of S phase. CCR5 receptor density is a key factor in terms of its ability to infect target cells. CCR5 receptor density increases with cell activation and is also associated with replication kinetics. We recently postulated and confirmed that cytostatic agents that induced prolongation of G1-S transition were associated with down regulation of CCR5 expression and that this resulted in enhanced potency of both CCR5 antagonist and fusion entry inhibitors. In addition, we demonstrated that this effect also enhanced the potency of antibodies which block viral entry. The potency of all tested entry inhibitors was directly related to CCR5 density. Prototype CCR5 resistant R5 viruses demonstrated wild type susceptibility when tested in cells with reduced but physiologic CCR5 density. Another established target for HIV therapy is HIV reverse transcriptase using nucleoside/nucleotide analogs. These agents compete with natural nucleosides however their efficacy is compromised by development of drug resistance. Resveratrol is an agent which inhibits ribonucleotide reductase and induces a prolongation of S phase. We postulated and confirmed that this reduction of cellular nucleotide pools results in enhanced potency of nucleoside/nucleotide analogs. We further show that this enhanced potency is such that highly resistant HIV isolates to analog alone demonstrate wild type susceptibility when evaluated in combination with Resveratrol.

These data suggest that targeting cell cycle and specific host cell pathways could have therapeutic implications and warrants further clinical evaluation especially in the setting of established drug resistance.

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