Functional exhaustion of antiviral lymphocytes in COVID-19 patients was investigated. The study found that patients with SARS-CoV-2 infection had significantly reduced numbers of NK and CD8+ T cells, with increased expression of NKG2A, an inhibitory receptor linked to functional exhaustion. In patients recovering from infection, NK and CD8+ T cell counts were restored, along with reduced NKG2A expression, suggesting that functional exhaustion of cytotoxic lymphocytes is associated with SARS-CoV-2 infection. This may lead to early breakdown of antiviral immunity. The study analyzed 68 COVID-19 patients, including 55 with mild disease and 13 with severe disease. Patients showed varied clinical symptoms, with higher neutrophil counts and lower lymphocyte counts in severe cases. T cell and CD8+ T cell counts were significantly lower in both mild and severe cases compared to healthy controls. NK cell counts were also lower in severe cases. NKG2A expression was significantly increased on NK and CD8+ T cells in COVID-19 patients compared to healthy controls. This was associated with reduced function of these cells, as evidenced by lower expression of CD107a, IFN-γ, IL-2, granzyme B, and TNF-α. These findings suggest that NKG2A expression is linked to functional exhaustion of cytotoxic lymphocytes in COVID-19 patients. After antiviral therapy, the total number of T cells, CTLs, and NK cells recovered in most patients, with reduced NKG2A expression in recovered patients. This suggests that effective treatment may reduce NKG2A expression on cytotoxic lymphocytes, thereby improving antiviral immunity. The study highlights the importance of preventing functional exhaustion of NK and CTLs in early SARS-CoV-2 infection. Targeting NKG2A may help prevent this exhaustion and contribute to virus elimination. The findings suggest that immune checkpoint inhibitors, such as anti-PD-1 and anti-TIGIT, may be useful in restoring exhausted responses in SARS-CoV-2 infection.Functional exhaustion of antiviral lymphocytes in COVID-19 patients was investigated. The study found that patients with SARS-CoV-2 infection had significantly reduced numbers of NK and CD8+ T cells, with increased expression of NKG2A, an inhibitory receptor linked to functional exhaustion. In patients recovering from infection, NK and CD8+ T cell counts were restored, along with reduced NKG2A expression, suggesting that functional exhaustion of cytotoxic lymphocytes is associated with SARS-CoV-2 infection. This may lead to early breakdown of antiviral immunity. The study analyzed 68 COVID-19 patients, including 55 with mild disease and 13 with severe disease. Patients showed varied clinical symptoms, with higher neutrophil counts and lower lymphocyte counts in severe cases. T cell and CD8+ T cell counts were significantly lower in both mild and severe cases compared to healthy controls. NK cell counts were also lower in severe cases. NKG2A expression was significantly increased on NK and CD8+ T cells in COVID-19 patients compared to healthy controls. This was associated with reduced function of these cells, as evidenced by lower expression of CD107a, IFN-γ, IL-2, granzyme B, and TNF-α. These findings suggest that NKG2A expression is linked to functional exhaustion of cytotoxic lymphocytes in COVID-19 patients. After antiviral therapy, the total number of T cells, CTLs, and NK cells recovered in most patients, with reduced NKG2A expression in recovered patients. This suggests that effective treatment may reduce NKG2A expression on cytotoxic lymphocytes, thereby improving antiviral immunity. The study highlights the importance of preventing functional exhaustion of NK and CTLs in early SARS-CoV-2 infection. Targeting NKG2A may help prevent this exhaustion and contribute to virus elimination. The findings suggest that immune checkpoint inhibitors, such as anti-PD-1 and anti-TIGIT, may be useful in restoring exhausted responses in SARS-CoV-2 infection.