Human pegivirus co-infection in SARS-CoV-2: Prevalence and clinical associations

• Systematic screening of human pegivirus (HPgV), an unmonitored viral co-infection, in COVID-19 (N = 634). • HPgV prevalence in COVID-19 mirrored population estimates but was markedly enriched in HIV (positive control). • HPgV-positive COVID-19 cases showed trends toward milder clinical outcomes. • Findings highlight the potential relevance of immunomodulatory viral co-infections in SARS-CoV-2 infection. This study investigates the prevalence of human pegivirus (HPgV) in SARS-CoV-2-positive patients within the context of viral co-infections that may modulate COVID-19 outcomes and assesses whether HPgV co-infection is associated with COVID-19 severity. HPgV is a widely circulating but rarely monitored human virus with documented immunomodulatory effects in other viral infections, including HIV and Ebola. While HPgV prevalence is low in the general U.S. population (1–2%), it rises markedly in the setting of chronic viral co-infections, particularly HIV (15–40%). Given its immunologic effects and persistence, HPgV represents a biologically plausible but unexplored viral co-factor SARS-CoV-2 infection. Methods : We analyzed four cohorts: SARS-CoV-2–positive individuals, ICU patients with respiratory symptoms but SARS-CoV-2–negative, HIV-positive individuals as a positive control for HPgV detection, and uninfected controls. Results : HPgV prevalence in COVID-19 patients was low (2.1%) and comparable to population estimates. As expected, HPgV prevalence was substantially higher in the HIV cohort (34%), validating assay performance and cohort stratification. Among HPgV-positive COVID-19 cases, most experienced mild disease, with directional trends toward reduced severity despite high baseline risk factors. Healthcare workers in the control group showed unexpectedly elevated HPgV prevalence (9.6%). Conclusions : HPgV is an unmonitored but widely circulating viral co-infection in humans that may influence host responses to SARS-CoV-2. Although limited by small numbers, these findings are descriptive and hypothesis-generating, supporting further investigation of HPgV and other immunomodulatory viral co-infections in COVID-19. Larger studies will be required to determine whether the observed patterns are reproducible and clinically meaningful.