Background T-cell responses during chronic viral infections become exhausted, which is reflected by upregulation of inhibitory receptors (iRs) and increased interleukin 10 (IL-10). We assessed 2 iRs—PD-1 (programmed cell death protein 1) and Tim-3 (T-cell immunoglobulin and mucin domain–containing protein 3)—and IL-10 mRNAs in peripheral blood mononuclear cells (PBMCs) and their soluble analogs (sPD-1, sTim-3, and IL-10) in plasma in chronic HIV-1/hepatitis C virus (HCV) coinfection and explored the effect of HCV treatment on these markers. We also aimed to establish whether iR expression may be determined by the HCV CD8+ T-cell immunodominant epitope sequence. Methods Plasma and PBMCs from 31 persons with chronic HIV-1/HCV coinfection from the Swiss HIV Cohort Study were collected before and after HCV treatment. As controls, 45 persons who were HIV-1 negative with chronic HCV infection were recruited. Exhaustion markers were assessed by enzyme-linked immunosorbent assay in plasma and by quantitative reverse transcription polymerase chain reaction in PBMCs. Analysis of an HCV epitope sequence was conducted by next-generation sequencing: HLA-A*02–restricted NS31073–1081 and NS31406–1415 and HLA-A*01–restricted NS31436–1444. Results The study revealed higher plasma sPD-1 (P =.0235) and IL-10 (P =.002) levels and higher IL-10 mRNA in PBMCs (P =.0149) in HIV-1/HCV coinfection. A decrease in plasma sPD-1 (P =.0006), sTim-3 (P =.0136), and IL-10 (P =.0003) and Tim-3 mRNA in PBMCs (P =.0210) was observed following successful HCV treatment. Infection with the HLA-A*01–restricted NS31436–1444 ATDALMTGY prototype variant was related to higher sTim-3 levels than infection with the ATDALMTGF escape variant (P =.0326). Conclusions The results underscore the synergistic effect of coinfection on expression of exhaustion markers, their reduction following successful HCV treatment and imply that iR levels may operate on an epitope-specific manner. [ABSTRACT FROM AUTHOR]