Viruses, including HIV, perform complex biophysical processes at the molecular level, ranging from chemical bond cleavage to changes in protein shape (i.e., conformation) to the self-assembly of large biomolecular complexes for replication. These microscopic processes are innately multiscale and are central to the molecular machinery that underlies and enables viral activity. Our research is focused on developing computational techniques to elucidate the mechanisms that govern replication in HIV, using theory, physics-based modeling, and computer simulations. We recently performed the first molecular simulations of the binding of a small-molecule compound called inositol hexakisphosphate (IP6) to the capsid of HIV, which revealed that IP6 promotes capsid self-assembly of the capsid by binding to and stabilizing distinct oligomeric states of capsid monomers. In addition, we developed coarse-grained approaches to model how TRIM5a, an innate immune protein, blocks HIV infection by self-assembling into a hexagonally patterned lattice that cages the capsid prior to nuclear import and thus infection. By combining computational techniques with cryo-EM microscopy, we also quantified the strain present on the capsid during uncoating events that occur deep within the nucleus of the host cell. The identification and characterization of these processes advance fundamental knowledge of HIV replication and contribute to the development of new therapeutic strategies.