Distinct from HIV-1 infection, Meth has also been shown to alter the expression of inflammatory cytokines in several murine tissues, in the serum of self-administering rats, and in the plasma of human subjects in early recovery from addiction (10–12). Specifically, Meth increased Interleukin-1β (IL-1β) mRNA and protein expression in dendritic cells, and in the rat hypothalamus (13, 14). Chronic increased expression of IL-1β can result in deleterious over-stimulation of the innate immune response, and tissue damage (15). Fine-tuning the innate immune response is crucial for effective immunity. Type I Interferons (IFNs) have been shown to participate in a counter-regulatory antagonistic relationship with IL-1β to maintain the balance necessary for innate immunity (15). Interestingly, Meth suppressed expression of IFNα, a type I IFN, in macrophages (4). Notably, increased IL-1β expression and down regulation of IFN stimulated genes, including TRAF6, are associated with enhanced HIV-1 infection and replication (4, 16, 17). MicroRNAs (miRNAs) participate in transcriptional and translational regulation, cellular homeostasis and feedback regulation, and can serve as indicators of disease states (18–21). For example, miRNA signatures have been established as markers for different cancers, and can act either as oncogenes or tumor suppressors (22). miRNAs contain a highly conserved sequence at their 5′ end, known as a seed region, which binds a target sequence to cause translational repression and mRNA decay (23). Targeted transcripts are highly sensitive to changes in miRNA expression (23–25). In particular, miR-146a has garnered attention recently for its roles in immune regulation (19, 26–28). miR-146a can target TNF Receptor-Associated Factor 6 (TRAF6) and Interleukin-1 Receptor-Associated Kinase 1 (IRAK1) to suppress innate immune responses via negative feedback regulation (19). TRAF6 and IRAK1 serve as fundamental molecules for effective signal transduction resulting from innate immune stimuli (29). Several studies indicate a role for IL-1β in the induction of miR-146a (30, 31). Furthermore, miR-146a plays an important role in T-cell homeostasis, and overexpression of miR-146a in mice results in an autoimmune-like T-cell profile in the periphery (32). These functions of miR-146a merit its exploration it as a target of Meth in HIV-1 pathobiology.