Utilizing the infant rhesus macaque SIVmac239/251 infection model, we describe the tissue-specific methylation signatures of CD8+ T cells during chronic SIV infection by performing a stepwise methylation analysis of total genomic DNA, immunomodulatory cytokine promoters, and CpG sites within those cytokine promoters across peripheral blood, lymph nodes, and intestinal tissue. Here, CD8A is linked to infection.