The implementation of highly active antiretroviral therapy for HIV disease led to dramatic improvements in patient morbidity and mortality. That said in many HIV patients who had good CD4 T cell recovery and viral suppression there still existed persistent level of immune activation and inflammation. These changes in the immune system have been linked to persistent alterations in gastrointestinal tract permeability and microbial translocation .More recent studies have focused on the cause of these gut abnormalities and found they are linked to alterations in the gut microbiome. This presentation will provide novel data on the changes seen in the gut microbiome in HIV subjects highlighting the alterations in specific bacterial species and how the bacterial metabolic profile leads to persistent systemic inflammation especially with the loss of short chain fatty acid producing bacteria. Further data will focus on the critical changes in the tryptophan catabolic pathway and its pro inflammatory profile that contributes to non HIV co morbidities especially cardiovascular disease diabetes and neurocognitive outcomes. The additional metabolic profiles of the gut bacteria will be discussed including changes in TMAO and ceramides Data will be presented utilizing animal models to demonstrate the critical role of diet in modifying the host microbiome. The talk will conclude with a discussion of the current therapeutic paradigm for modifying the host microbiome with pre or probiotics and the prospective of fecal transplants in HIV The talk will conclude with a detailed description of the inflammatory pathways contributing to non HIV co morbidities and what novel interventional strategies are being utilized as interventional approaches. This will include studies evaluating immune based therapies targeting IL6 or IL1-beta and Jak stat inhibitors and methotrexate. In addition there will be a discussion of repurposing drugs from other therapeutic areas such as diabetes with new trials being pursued with metformin.