The clinical manifestations of coronavirus disease (COVID-19) are highly variable, ranging from asymptomatic cases to life-threatening complications and death. Severe disease progression is more common in older individuals and males, as well as in the presence of various comorbidities. Beyond these risk factors, the intrinsic characteristics of the virus and the host genetic factors also contribute to the heterogeneous clinical course of COVID-19. Genetic research is fundamental in understanding the biological mechanisms underlying congenital diseases, identifying the genes and proteins responsible for the susceptibility to various inherited conditions, recognizing therapeutically relevant targets, suggesting drug repurposing, and clarifying causal relationships for modifiable environmental risk factors. Although these studies typically take a long time to conduct, especially to translate their findings into clinical practice, the scientific community has swiftly uncovered genetic signals underlying the diverse COVID-19 phenotypes. In this review, in addition to a concise summary of SARS-CoV-2 recognition and the initial steps of the immune responses, we aim to provide an overview of the literature concerning the genetic factors associated with susceptibility to the disease and its severe progression. We also review the pioneering research in identifying the affected genes and the most significant genome-wide association studies, covering both common and rare genetic variants, which have greatly contributed to understand the etiology of the disease and have guided effective COVID-19 treatment during the most challenging times.

Advanced age, comorbidities, and immunocompromised states remain major risk factors for severe or persistent COVID-19 despite vaccination and antivirals, underscoring the need for innovative treatments such as adoptive T-cell therapy (ATT). In this prospective single-center study, we evaluated the safety, feasibility, and efficacy of two ATT approaches in immunocompromised patients with high-risk or persistent SARS-CoV-2 infection: interferon-γ cytokine capture system virus-specific T cells (IFN-γ CCS VST, n = 12; median age 59) and CD45RA + T-cell depleted donor lymphocyte infusion (CD45RA⁺ TCD DLI, n = 11; median age 46). Most patients (73.9%) had undergone prior hematopoietic stem cell transplantation (HSCT). Both treatments were safe, with no adverse events observed. One-year overall survival (OS) did not differ significantly between groups (p = 0.8907 overall; p = 0.5907 in HSCT recipients). However, CD45RA⁺ TCD DLI showed a trend toward improved 1-year COVID-19–free survival (p = 0.058) and significantly better survival among HSCT recipients (p = 0.0362). Viral clearance was achieved in most patients (90.9% vs. 83.3%). Immunomonitoring revealed distinct immune dynamics: between weeks 5–8, IFN-γ CCS VST promoted naïve T-cell expansion with broad cytokine elevation, while CD45RA⁺ TCD DLI expanded memory T cells with a more restricted cytokine profile. IFN-γ CCS VST also elicited stronger in vivo expansion of SARS-CoV-2–specific CD4 + and CD8 + T cells. In summary, both ATT approaches are safe and effective in immunocompromised patients with persistent COVID-19. CD45RA⁺ TCD DLI, which can be generated from convalescent donors as an off-the-shelf product, may provide a practical strategy for pandemic preparedness and treatment of vulnerable patients with immune senescence.