INTRODUCTION: We investigated whether prior SARS-CoV-2-specific IFN-gamma and antibody responses in Ugandan COVID-19 pre-pandemic specimens aligned to this population\'s low disease severity. METHODS: We used nucleoprotein (N), spike (S), NTD, RBD, envelope, membrane, SD1/2-directed IFN-gamma ELISpots, and an S- and N-IgG antibody ELISA to screen for SARS-CoV-2-specific cross-reactivity. RESULTS: HCoV-OC43-, HCoV-229E-, and SARS-CoV-2-specific IFN-gamma occurred in 23, 15, and 17 of 104 specimens, respectively. Cross-reactive IgG was more common against the nucleoprotein (7/110, 15.5%; p = 0.0016, Fishers\' Exact) than the spike (3/110, 2.72%). Specimens lacking anti-HuCoV antibodies had higher rates of pre-epidemic SARS-CoV-2-specific IFN-gamma cross-reactivity (p-value = 0.00001, Fishers\' exact test), suggesting that exposure to additional factors not examined here might play a role. SARS-CoV-2-specific cross-reactive antibodies were significantly less common in HIV-positive specimens (p=0.017; Fishers\' Exact test). Correlations between SARS-CoV-2- and HuCoV-specific IFN-gamma responses were consistently weak in both HIV negative and positive specimens. DISCUSSION: These findings support the existence of pre-epidemic SARS-CoV-2-specific cellular and humoral cross-reactivity in this population. The data do not establish that these virus-specific IFN-gamma and antibody responses are entirely specific to SARS-CoV-2. Inability of the antibodies to neutralise SARS-CoV-2 implies that prior exposure did not result in immunity. Correlations between SARS-CoV-2 and HuCoV-specific responses were consistently weak, suggesting that additional variables likely contributed to the pre-epidemic cross-reactivity patterns. The data suggests that surveillance efforts based on the nucleoprotein might overestimate the exposure to SARS-CoV-2 compared to inclusion of additional targets, like the spike protein. This study, while limited in scope, suggests that HIV-positive people are less likely than HIV-negative people to produce protective antibodies against SARS-CoV-2.