This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. ABSTRACT Chronic Fatigue Immune Dysfunction Syndrome (CFIDS) is a severely debilitating disorder for which there is presently no cure. Treatment options are limited, and to date, no drugs have been developed specifically for CFIDS. Our long range research goals are 1) to understand fully the mechanisms of CFIDS disease progression, and 2) the development of improved therapeutic intervention strategies for CFIDS. The etiology, pathogenesis, and mechanisms of immune dysfunction in CFIDS are all poorly understood;however there is growing evidence that Human Herpes Virus-6 (HHV-6) infection may play a role in CFIDS pathogenesis. Our hypotheses are: 1) HHV-6 establishes persistent infection in monocytes through alterations in host-cell proteins involved in immune response and 2) Targeted nanoparticulate-formulation delivery systems of Ribonucleotide Reductase Inhibitors are effective against HHV-6 DNA replication. The primary rationale is that viruses often evade host defense through proteolysis of immune response mediators, and thus raises the possibility that HHV's are responsible for degradation of STAT1 and native RNase-L in CFIDS. Moreover, available treatments for HHV-6 active infection are limited. We will test our hypothesis in this pilot project through the following 3 Specific Aims: (1) Obtain a Protein Signature of the primary structures and molecular weights of host cellular and viral proteins expressed in cell-line models (HL-60 and U937 leukemia cells) of productive versus latent HHV-6 infection of human monocytes of PBMCs. (2) Determine the susceptibility of HHV-6 infected and non-infected HL-60 and U937 leukemia cell models to Ribonucleotide Reductase inhibition. (3) Determine in-vitro the pharmacology and toxicity of nanocapsules of HHV-6 DNA replication inhibitors in Herpes-virus infected HL-60 and U937 leukemia cell models. Successful completion of the aims in this pilot study will enhance the long-term developmental objectives of the PI, while obtaining sufficient Preliminary Data for investigator-initiated grant applications. Supported by NIH/NCRR/RCMI G12RR03020.
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