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This generally requires entry through the endocytic pathway, where endosomal proteases have first access for processing. Thus, understanding virus escape during cross-presentation requires an understanding of resistance to endosomal proteases, such as cathepsin S (CatS). We have modified HIV-1<sub>MN</sub> gp120 by mutating a key CatS cleavage site (Thr<sup>322</sup>Thr<sup>323</sup>) in the V3 loop of the immunodominant epitope IGPGRAFY<u>TT</u> to IGPGRAFY<u>VV</u> to prevent digestion. We found this mutation to facilitate cross-presentation and provide evidence from MHC binding and X-ray crystallographic structural studies that this results from preservation of the epitope rather than an increased epitope affinity for the MHC class I molecule. In contrast, when the protein is expressed by a vaccinia virus in the cytosol, the wild-type protein is immunogenic without this mutation. 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