Accumulating evidence indicate that people living with HIV (PLWH) are at higher risk of developing cancer compared to the general population. In addition, the ability of HIV to imprint epigenetic changes in myeloid cells may paly acritical role in reshaping the overall immune performance of PLWH. This is important since it will address a gap of knowledge on the link between epigenetic modifications underlying a dysfunctional immune response and susceptibility to cancer development in HIV+ individuals with low or undetectable viral load. Our data indicate the presence of specific epigenetic modifications found in the genome of monocytes isolated from HIV+ patients. These epigenetic changes can be subsequently linked to monocyte abnormal function and abnormal differentiation. When challenged with environmental signals, such as β-glucan or LPS, normal monocytes are expected to execute a type of innate program called either “trained immunity” or “tolerance”, characterized by hyper-responsiveness or hypo-responsiveness to secondary stimuli, respectively. This delicate balance between trained immunity and tolerance, characterized by epigenetic and metabolic reprogramming, is defective in HIV+ monocytes, and represents the major focus of this proposal. Our model involves isolation of CD14+ monocytes from HIV+ individuals and healthy controls, which are analyzed in vitro following polarization toward a pro-inflammatory (M1-like) phenotype. Upon LPS stimulation, which activates toll-like receptor 4 (TLR4), the cells from HIV+ individuals demonstrated a significant increase in the pro-inflammatory expression of IL6, TNFα and IL1B. In parallel, we observed a significantly lower expression of miR-146a-5p, a miRNA involved in the negative regulation of LPS-induced inflammation, in HIV-derived cells. By contrast, a pro- inflammatory and oncogenic miRNA, miR-155-5p, was upregulated in HIV-derived cells compared to controls. In addition, our ChIP-seq data show a differential enrichment of chromatin activation marks at promoters (H3K4me3) and distal enhancers (H3k4me1) of freshly isolated HIV-derived cells compared to controls. We also found lower expression of transcriptional repressors and inhibitors of TLR4 signaling pathway, which suggests inability of HIV-derived cells to establish a negative feedback mechanism required to dampen inflammation following LPS. Therefore, our experimental plan proposed here is intended to test the overall hypothesis that epigenetic marks and specific metabolic features found in HIV-derived monocytes prime these immune cells to hyper-responsiveness following secondary insults, leading to increased cytokine production and immune dysfunction, contributing to cancer susceptibility in PLWH.