This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. To understand the pharmacokinetics of the highly active anti-retroviral therapy (HAART) regimen, combinations of protease inhibitors (HPIs) in humans with HIV-AIDS, preclinical studies had previously analyzed both P-gp (an ABC transporter) and Cyp3A4 (a CYP-450 isozyme) expression in small models, such as mice, rats and rabbits, where bioavailability and peak plasma levels were determined as a measure of anti-HIV efficacy of HPIs. However, recent studies demonstrated significant species-specific variations in the expression of both ABC-transporters and CYP-450 isozymes, which may profoundly alter the correct determination of therapeutic dosing of HPIs, especially GI-submucosa of HIV-positive patients. We plan to develop an ex vivo model of SIV persistence in intestinal reservoirs despite antiretroviral therapy, and identify novel strategies towards inhibition of the host factors which cause this inefficacy. We hypothesize that both P-gp and Cyp-3A4 suppress HPI transport across intestinal barriers and strategies towards their inhibition will abrogate the persistence of submucosal viral reservoirs in SIVinfected monkey models. The project is currently in process. All animals have been assigned and animals are actively infected with SIV. Samples are currently being collected and processed for viral load and expression levels of P-gp and Cyp-450 mRNA and protein levels. The animals will soon be treated with ketoconozole for the analysis of the effects on intestinal reservoirs.
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