C-terminus of Heat-shock protein-70 interacting protein (CHIP) is an E3 ubiquitin ligase canonically known to mark misfolded Heat shock protein (Hsp) clients for degradation. A recent publication from the Craik lab demonstrated CHIP can directly interact with numerous proteins outside of Hsps. While the authors demonstrate the occurrence of Hsp-independent CHIP interactions in cells and that CHIP can ubiquitinate substrates without chaperones in biochemical assays, they were unable to show Hsp-independent substrate ubiquitination in cells. Successful demonstration of CHIP’s Hspindependent enzymatic activity in cellular contexts could elucidate molecular underpinnings of multiple disease states, including neurodegeneration, cancer, and viral infections, as well as provide insights into the feasibility using Hsp-independent CHIP interactions for targeted degradation of proteins. Towards this goal, we developed CHIP inhibitors and further characterized a predicted Hspindependent CHIP interaction with a human herpes virus 8 (HHV-8) protein. Previous approaches used peptides to competitively inhibit CHIP substrate binding, so we instead generated recombinant antibodies to inhibit CHIP’s functions. These were shown to have distinct epitopes and were able to inhibit both CHIP substrate binding and ubiquitination. When reformatted into scFvs for intracellular expression, these antibodies can bind to CHIP and maintain some level of inhibitory function. The recombinant antibodies can be used to examine molecular mechanisms of CHIP interactions in disease states and enable structural studies. Next, we examined the predicted, Hsp-independent, CHIP interaction with the HHV-8 protein ORF28. Data indicates this interaction occurs in cells, and preliminary results show this interaction may be a mechanism of host protein regulation. Further studies will allow for non-biased identification of interactors and determination of the impacts of these interactions on viral replication.