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128 Suppression of CCR5 Density as a Novel Way to Enhance the Anti-HIV Activity of Fusion Inhibitors and CCR5 Antagonists

Latinovic, Olga; Heredia, Alonso; Gallo, Robert C; Redfield, Robert R

JAIDS Journal of Acquired Immune Deficiency Syndromes: April 2011 - Volume 56 - Issue - p 52
doi: 10.1097/01.qai.0000397316.47707.8b

Institute of Human Virology University of Maryland School of Medicine, Baltimore, MD

The CCR5 chemokine receptor plays a crucial role in HIV-1 infection. We have established methods to quantify CCR5 density and to evaluate its impact on virus infectivity in spreading/single cycle infection and direct virus-cell fusion assays. In our preliminary studies, we use a stochiometry model (Kuhmann et al, 2006) to calculate a number of CCR5 molecules needed for HIV-1 pseudovirus infection. In addition, using low doses of the drug Rapamycin, a CCR5 suppressor, we demonstrate decreased R5 HIV-1 infectivity and enhanced potency of entry inhibitors. Our data show that Rapamycin reduction of CCR5 density restores sensitivity of drug-resistant R5 HIV-1 to fusion inhibitor Enfuvirtide (T-20) and to all of three new generation of CCR5 antagonists: Vicriviroc, Maraviroc and Aplaviroc. We found that Rapamycin induced reduction of CCR5 density in lymphocytes increased sensitivity to Vicriviroc (VCV) in VCV-resistant strains, inhibiting production by ∼ 90%. Novel Beta-lactamase (BlaM) entry assay revealed the differences in the activity between VCV sensitive and VCV resistant virus. In the case of VCV sensitive virus, we observed complete inhibition in cell lines with high and physiological CCR5 levels. In the case of the resistant virus, there is no inhibition in higher CCR5 expressive cells, but in cells with physiological expression of CCR5, we do observe susceptibility to VCV resistant virus.

As an alternative anti-HIV therapy approach, we successfully employ the CCR5 antibodies in order to determine the affinity of resistant virus Envelope in cases when it is free versus occupied CCR5 site by the CCR5 antagonist, Maraviroc. Identifying the most effective drug combinations of Rapamycin or CCR5 antibodies with the CCR5 antagonists (with the lowest possible side effects) has relevant clinical implications in anti-viral therapy.

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