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. The profound viral suppression achievable with modern-day HAART regimens, coupled with the limitations and concerns of prolonged treatment, have revitalized serious consideration of the prospect for eradicating HIV from the body. We propose a novel approach to eradicate the HIV infected cells that persist despite highly suppressive HAART. The central hypothesis is that targeted toxin therapy, directed against the viral Env glycoprotein expressed on the surface of productively infected cells, will significantly reduce virus load persisting in the presence of HAART. The rationale is based on the fact that HAART drugs potently suppress virus replication, but do not directly eliminate cells that are already infected;the targeted toxin directly kills infected cells. We refer to this approach as HAART complementation, to be distinguished from the actively pursued strategy of HAART intensification whereby an additional replication inhibitor is added to an existing suppressive HAART regiment. Drs. E. Berger and I. Pastan at NIH have designed and characterized CD4-PE, a targeted toxin directed to gp120. CD4-PE potently kills cells expressing Env of HIV or SIV, and is highly synergistic with HAART drugs both in cell culture and a murine model. We propose to test the ability of CD4-PE to complement highly suppressive HAART, using the RT-SHIV/macaque treatment model developed by Drs. T. North and P. Luciw at UC Davis. Large quantities of clincal grade CD4-PE are available, and the necessary amounts will be provided for this study, which will be conducted at the California National Primate Research Center. Highly sensitive and quantitative assays developed by the North group will be used to measure plasma viremia, as well as viral RNA and DNA in lymph nodes and various relevant tissues following necropsy. A significantly delayed virus rebound will be evidence for efficacy of this combination approach. Targeted toxin killing is proposed as a critical complement to HAART for HIV eradication. The proposed studies are also expected to yield novel insights into the mechanism(s) of HIV persistence during HAART.
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