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Background. Studies aimed at defining the association between host immune responses and human immunodeficiency virus (HIV) persistence during therapy are necessary to develop new strategies for cure.Methods. We performed a comprehensive assessment of ultrasensitive plasma HIV RNA levels, cell-associated HIV RNA levels, proviral HIV DNA levels, and T cell immunophenotyping in a cohort of 190 subjects in whom HIV levels were suppressed by highly active antiretroviral therapy.Results. The median CD4+ T cell count was 523 cells/mm3, and the median duration of viral suppression was 31 months. Cell-associated RNA and proviral DNA levels (but not ultrasensitive plasma HIV RNA levels) were positively correlated with frequencies of CD4+ and CD8+ T cells expressing markers of T-cell activation/dysfunction (CD38, HLA-DR, CCR5, and/or programmed cell death protein 1 [PD-1]) (P < .05). Having a low CD4+ T-cell count despite receipt of virologically suppressive therapy was associated with high cell-associated RNA and proviral DNA levels (P < .01) and higher frequencies of CD4+ T cells expressing CD38, HLA-DR, CCR5, and/or PD-1 (P < .0001).Conclusions. Cell-based measurements of viral persistence were consistently associated with markers of immune activation and the frequency of PD-1–expressing CD4+ T cells. Treated patients with a low CD4+ T-cell count had higher frequencies of PD-1–expressing CD4+ T cells and cell-based measures of viral persistence, suggesting that HIV infection in these individuals may be more difficult to cure and may require unique interventions.