Tissue-Specific DNA Methylation Changes in CD8⁺ T Cells During Chronic Simian Immunodeficiency Virus Infection of...

Robust CD8⁺ T cell responses are critical for the control of HIV infection in both adults and children. Our understanding of the mechanisms driving these responses is based largely on studies of cells circulating in peripheral blood in adults, but the regulation of CD8⁺ T cell responses in tissue sites is poorly understood, particularly in pediatric infections. DNA methylation is an epigenetic modification that regulates gene transcription. Hypermethylated gene promoters are associated with transcriptional silencing and, conversely, hypomethylated promoters indicate gene activation. In this study, we evaluated DNA methylation signatures of CD8⁺ T cells isolated from several different anatomic compartments during pediatric AIDS-virus infection by utilizing the SIV_mac239/251 infected infant rhesus macaque model. We performed a stepwise methylation analysis starting with total cellular DNA, to immunomodulatory cytokine promoters, to specific CpG sites within the cytokine promoters in CD8⁺ T cells isolated from peripheral blood, lymph nodes, and intestinal tissue during the chronic phase of infection. Tissue-specific methylation patterns were determined for transcriptionally active promoters of key immunomodulatory cytokines: interferon gamma (IFNγ), interleukin-2 (IL-2), and tumor necrosis factor alpha (TNFα). In this study, we observed tissue-specific differences in CD8⁺ T cell modulation by DNA methylation in SIV-infected infant macaques, highlighting the importance of evaluating cells from both blood and tissues to obtain a complete picture of CD8⁺ T cell regulation during pediatric HIV infection.