Understanding the mechanisms underlying antibody-mediated immunity and viral entry is critical for developing effective antiviral strategies and vaccines. The studies discussed in this dissertation integrates findings from recent investigations into canine parvovirus (CPV) and influenza A virus, focusing on the molecular and structural determinants of host immune responses and viral infectivity. To elucidate the antibody response to CPV, a canine-adapted B-cell cloning strategy was employed to isolate and characterize monoclonal antibodies from an immunized dog. Fluorescence-activated cell sorting (FACS) and in vitro culture enabled the identification of CPV-specific B cells, followed by amplification and cloning of immunoglobulin genes. Three monoclonal antibodies exhibited broad reactivity against CPV variants, with two sharing an identical heavy chain, and binding the B-site of the viral capsid, while the third targeted the A-site. Cryo-electron microscopy (cryoEM) analysis revealed significant epitope overlap with the viral receptor (transferrin receptor type-1, TfR) binding site. However, the antibodies displayed varying neutralization activities against CPV infection, consistent with their ability to compete for the receptor. The monoclonal antibodies here corresponded to some of the structures observed in the cryoEM analysis of polyclonal sera, including those present in a different dog than the monoclonal source. These results demonstrate that CPV infection elicits a focused antibody response, with a limited number of dominant antibodies contributing to viral neutralization and host protection. Beyond antibody-mediated immunity, viral entry mechanisms remain a key determinant of infection. Influenza A viruses (IAVs) engage surface sialic acid (Sia) moieties on host glycoproteins for cell entry, but the role of associated carrier proteins remains incompletely understood. To aid the exploration of IAV entry pathways in greater details, an artificial receptor was engineered by fusing an anti-hemagglutinin (HA) single-chain variable fragment (scFv) to an ‘ectodomain-less' TfR. When expressed in Sia-deficient cells, this receptor facilitated virus binding, endocytosis, and infection at levels comparable to Sia-expressing cells. Lower-affinity receptor variants enhanced viral uptake, and clathrin-mediated endocytosis was identified as the primary internalization pathway. These findings provide evidence that influenza A virus can utilize alternative receptor-mediated entry mechanisms independent of Sia, and could be beneficial in teasing apart IAV’s internalization mechanisms. Collectively, these studies deepen our understanding of antibody-virus interactions, viral neutralization mechanisms, and host receptor utilization. They elucidate the evolutionary dynamics between viruses and antibodies, the specificity and diversity of antibody responses to viral antigens, and the intricate interplay between viral antigens, antibody binding, and host receptor interactions.