S1-S9 Figs can be found in the pdf file.

<div><p>Antiretroviral treatment of HIV infected individuals cannot eliminate the HIV reservoir and immune control of HIV is rarely seen upon treatment interruption. In long-term non-progressors (LTNP), an effective CD8 T cell response is thought to contribute to be immune control of HIV. Here we studied the transcriptional profile of virus specific CD8 T cells during the asymptomatic phase of disease, to gain molecular insights in CD8 T cell functionality in HIV progressors and different groups of LTNP: HLA-B*57 LTNP, non-HLA-B*57 LTNP and individuals carrying the MAVS minor genotype (rs7262903/rs7269320). Principal component analysis revealed distinct overall transcriptional profiles between the groups. The transcription profile of HIV-specific CD8 T cells of LTNP groups was associated with increased cytokine/IL-12 signaling and protein/RNA metabolism pathways, indicating an increased CD8 T cell functionality. Although the transcription profile of CMV-specific CD8 T cells differed from that of HIV-specific CD8 T cells, with mainly an upregulation of gene expression in progressors, similar affected pathways were identified. Moreover, CMV-specific CD8 T cells from progressors showed increased expression of genes related to effector functions and suggests recent antigen exposure. Our data shows that changes in cytokine signaling and the energy demanding RNA and protein metabolism are related to CD8 T cell dysfunction, which may indicate that mitochondrial dysfunction is an important driver of T cell dysfunctionality during chronic HIV infection. Indeed, improvement of mitochondrial function by IL-12 and mitoTempo treatment, enhanced in vitro IFNγ release by PBMC from PWH upon HIV gag and CMV pp65 peptide stimulation. Our study provides new insights into the molecular pathways associated with CD8 T cell mediated immune control of chronic HIV infection which is important for the design of novel treatment strategies to restore or improve the HIV-specific immune response.</p></div>