Progressive human immunodeficiency virus type 1 (HIV-1) infection is often associated with high plasma virus load (pVL) and impaired CD8⁺ T-cell function; in contrast, CD8⁺ T cells remain polyfunctional in long-term nonprogressors. However, it is still unclear whether CD8⁺ T-cell dysfunction is the cause or the consequence of high pVLs. Here, we conducted a longitudinal functional and phenotypic analysis of virus-specific CD8⁺ T cells in a cohort of patients with chronic HIV-1 infection. During the initiation and maintenance of successful antiretroviral therapy (ART), we assessed whether the level of pVL was associated with the degree of CD8⁺ T-cell dysfunction. Under viremic conditions, HIV-specific CD8⁺ T cells were dysfunctional with respect to cytokine secretion (gamma interferon, interleukin-2 [IL-2], and tumor necrosis factor alpha), and their phenotype suggested limited potential for proliferation. During ART, cytokine secretion by HIV-specific CD8⁺ T cells was gradually restored, IL-7Rα and CD28 expression increased dramatically, and PD-1 levels declined. Thus, prolonged ART-induced reduction of viral replication and, hence, presumably antigen exposure in vivo, allows a significant functional restoration of CD8⁺ T cells with the appearance of polyfunctional cells. These findings indicate that the level of pVL as a surrogate for antigen load has a dominant influence on the phenotypic and functional profile of virus-specific CD8⁺ T cells.